AU2003215370B2 - Human analogs of murine deubiquitinating protease genes - Google Patents

Description

WO 03/072724 PCT/US03/05338 -1- Human Analogs of Murine Deubiquitinating Protease Genes Background of the Invention The role of ubiquitin in protein degradation was discovered and the main enzymatic reactions of this system elucidated in biochemical studies in a cell-free system from reticulocytes. In this system, proteins are targeted for degradation by covalent ligation to ubiquitin, a 76-amino-acid-residue protein. Briefly, ubiquitin-protein ligation requires the sequential action of three enzymes. The C-terminal Gly residue of ubiquitin is activated in an ATP-requiring step by a specific activating enzyme, El (Step This step consists of an intermediate formation of ubiquitin adenylate, with the release of PPi, followed by the binding of ubiquitin to a Cys residue of El in a thiolester linkage, with the release of AMP. Activated ubiquitin is next transferred to an active site Cys residue of a ubiquitin-carrier protein, E2 (Step In the third step catalyzed by a ubiquitin-protein ligase or E3 enzyme, ubiquitin is linked by its C-terminus in an amide isopeptide linkage to an -amino group of the substrate protein's Lys residues (Step 3).

Proteins ligated to polyubiquitin chains are usually degraded by the 26S proteasome complex that requires ATP hydrolysis for its action. The 26S proteasome is formed by an ATP-dependent assembly of a 20S proteasome, a complex that contains the protease catalytic sites, with 19S "cap" or regulatory complexes. The 19S complexes contain several ATPase subunits and other subunits that are presumably involved in the specific action of the 26S proteasome on ubiquitinylated proteins. The roles of ATP in the assembly of the 26S proteasome complex and in its proteolytic action are not understood. The action of the 26S proteasome presumably generates several types of products: free peptides, short peptides still linked to ubiquitin via their Lys residues, and polyubiquitin chains (Step The latter two products are converted to free and reusable ubiquitin by the action of ubiquitin-C-terminal hydrolases or isopeptidases (Steps 5 and Some isopeptidases may also disassemble certain ubiquitin-protein conjugates (Step 7) and thus prevent their proteolysis by the 26S proteasome.

The latter type of isopeptidase action may have a correction function to salvage incorrectly ubiquitinylated proteins or may have a regulatory role. Short peptides formed by the above processes can be further degraded to free amino acids by cytosolic peptidases (Step 8).

WO 03/072724 PCT/US03/05338 -2- Ubiquitin-mediated degradation of protein is involved in various biological processes.

The selective and programmed degradation of cell-cycle regulatory proteins, such as cyclins, inhibitors of cyclin-dependent kinases, and anaphase inhibitors are essential events in cellcycle progression. Cell growth and proliferation are further controlled by ubiquitin-mediated degradation of tumor suppressors, protooncogenes, and components of signal transduction systems. The rapid degradation of numerous transcriptional regulators is involved in a variety of signal transduction processes and responses to environmental cues. The ubiquitin system is clearly involved in endocytosis and down-regulation of receptors and transporters, as well as in the degradation of resident or abnormal proteins in the endoplasmic reticulum. There are strong indications for roles of the ubiquitin system in development and apoptosis, although the target proteins involved in these cases have not been identified. Dysfunction in several ubiquitin-mediated processes causes pathological conditions, including malignant transformation.

Our knowledge of different signals in proteins that mark them for ubiquitinylation is also limited. Recent reports indicate that many proteins are targeted for degradation by phosphorylation. It was observed previously that many rapidly degraded proteins contain PEST elements, regions enriched in Pro, Glu, Ser, and Thr residues. More recently, it was pointed out that PEST elements are rich in S/TP sequences, which are minimum consensus phosphorylation sites for Cdks and some other protein kinases. Indeed, it now appears that in several (though certainly not all) instances, PEST elements contain phosphorylation sites necessary for degradation. Thus multiple phosphorylations within PEST elements are required for the ubiquitinylation and degradation of the yeast Gl cyclins Cln3 and Cln2, as well as the Gcn4 transcriptional activator. Other proteins, such as the mammalian G1 regulators cyclin E and cyclin D1, are targeted for ubiquitinylation by phosphorylation at specific, single sites. In the case of the IkBa inhibitor of the NF-kB transcriptional regulator, phosphorylation at two specific sites, Ser-32 and Ser-36, is required for ubiquitin ligation. p-cateinin, which is targeted for ubiquitin-mediated degradation by phosphorylation, has a sequence motif similar to that of IkBa around these phosphorylation sites. However, the homology in phosphorylation patterns of these two proteins is not complete, because phosphorylation of other sites of B-catenin is also required for its degradation. Other proteins targeted for degradation by phosphorylation include the Cdk inhibitor Siclp and the STAT 1 transcription factor. Though different patterns of phosphorylation target different proteins for degradation, a WO 03/072724 PCT/US03/05338 -3common feature appears to be that the initial regulatory event is carried out by a protein kinase, while the role of a ubiquitin ligase would be to recognize the phosphorylated form of the protein substrate. It further appears that different ubiquitin ligases recognize different phosphorylation patterns as well as additional motifs in the various protein substrates.

However, the identity of such E3s is unknown, except for some PULC-type ubiquitin ligases that act on some phosphorylated cell-cycle regulators in the budding yeast. The multiplicity of signals that target proteins for ubiquitin-mediated degradation (and of ligases that have to recognize such signals) is underscored by observations that the phosphorylation of some proteins actually prevents their degradation. Thus the phosphorylation of the c-Mos protooncogene on Ser3 and the multiple phosphorylations of c-Fos and c-Jun protooncogenes at multiple sites by MAP kinases suppress their ubiquitinylation and degradation.

In addition to the families of enzymes involved in conjugation of ubiquitin, a very large family of deubiquitinating enzymes has recently been identified from various organisms.

These enzymes have several possible functions. First, they may have peptidase activity and cleave the products of ubiquitin genes. Ubiquitin is encoded by two distinct classes of genes.

One is a polyubiquitin gene, which encodes a linear polymer of ubiquitins linked through peptide bonds between the C-terminal Gly and N-terminal Met of contiguous ubiquitin molecules. Each copy of ubiquitin must be released by precise cleavage of the peptide bond between Gly-76-Met-1 of successive ubiquitin moieties. The other class of ubiquitin genes encodes ubiquitin C-terminal extension proteins, which are peptide bond fusions between the C-terminal Gly of ubiquitin and N-terminal Met of the extension protein. To date, the extensions described are ribosomal proteins consisting of 52 or 76-80 amino acids. These ubiquitin fusion proteins are processed to yield ubiquitin and the corresponding C-terminal extension proteins. Second, deubiquitinating enzymes may have isopeptidase activities. When a target protein is degraded, deubiquitinating enzymes can cleave the polyubiquitin chain from the target protein or its remnants. The polyubiquitin chain must also be disassembled by deubiquitinating enzymes during or after proteolysis by the 26 S proteasome, regenerating free monomeric ubiquitin. In this way, deubiquitinating enzymes can facilitate the ability of the 26 S proteasome to degrade ubiquitinated proteins. Third, deubiquitinating enzymes may hydrolyze ester, thiolester, and amide linkages to the carboxyl group of Gly-76 of ubiquitin.

Such nonfunctional linkages may arise from reactions between small intracellular compounds such as glutathione and the El-, E2-, or E3-ubiquitin thiolester intermediates. Fourth, WO 03/072724 PCT/US03/05338 -4deubiquitinating enzymes may compete with the conjugating system by removing ubiquitin from protein substrates, thereby rescuing them from degradation or any other function mediated by ubiquitination. Thus generation of ubiquitin by deubiquitinating enzymes from the linear polyubiquitin and ubiquitin fusion proteins and from the branched polyubiquitin ligated to proteins should be essential for maintaining a sufficient pool of free ubiquitin. Many deubiquitinating enzymes exist, suggesting that these deubiquitinating enzymes recognize distinct substrates and are therefore involved in specific cellular processes. Although there is recent evidence to support such specificity of these deubiquitinating enzymes, the structurefunction relationships of these enzymes remain poorly studied.

Deubiquitinating enzymes can be divided broadly on the basis of sequence homology into two classes, the ubiquitin-specific processing protease (UBP or USP, also known as type 2 ubiquitin C-terminal hydrolase (type 2 UCH)) and the UCH, also known as type 1 UCH).

UCH (type 1 UCH) enzymes hydrolyze primarily C-terminal esters and amides of ubiquitin but may also cleave ubiquitin gene products and disassemble polyubiquitin chains. They have in common a 210-amino acid catalytic domain, with four highly conserved blocks of sequences that identify these enzymes. They contain two very conserved motifs, the CYS and HIS boxes. Mutagenesis studies revealed that the two boxes play important roles in catalysis.

Some UCH enzymes have significant C-terminal extensions. The functions of the C-terminal extensions are still unknown but appear to be involved in proper localization of the enzyme.

The active site of these UCH enzymes contains a catalytic triad consisting of cysteine, histidine, and aspartate and utilizes a chemical mechanism similar to that of papain. The crystal structure of one of these, UCH-L3, has been solved at 1.8 A resolution. The enzyme comprises a central antiparallel B-sheet flanked on both sides by helices. The 1-sheet and one of the helices are similar to those observed in the thiol protease cathepsin B. The similarity includes the three amino acid residues that comprise the active site, Cys 9 5 His 169 and Asp 84 The active site appears to fit the binding of ubiquitin that may anchor also at an additional site.

The catalytic site in the free enzyme is masked by two different segments of the molecule that limit nonspecific hydrolysis and must undergo conformational rearrangement after substrate binding.

UBP (type 2 UCH) enzymes are capable of cleaving the ubiquitin gene products and disassembling polyubiquitin chains after hydrolysis. It appears that there is a core region of WO 03/072724 PCT/US03/05338 about 450 amino acids delimited by CYS and HIS boxes. Many of these isoforms have Nterminal extensions and a few have C-terminal extensions. In addition, there are variable sequences in the core region of many of the isoforms. The functions of these divergent sequences remain poorly characterized. Another interesting function of specific UBPs is the regulation of cell proliferation. It was observed that cytokines induced in T-cells specific deubiquitinating enzymes (DUBs), termed DUB-1 and DUB-2. DUB-1 is induced by stimulation of the cytokine receptors for IL-3, IL-5, and GM-CSF, suggesting a role in its induction for the B-common (betac) subunit of the interleukin receptors. Overexpression of a dominant negative mutant of JAK2 inhibits cytokine induction of DUB-1, suggesting that the regulation of the enzyme is part of the cell response to the JAK/STAT signal transduction pathway. Continued expression of DUB-1 arrests cells at Gj; therefore, the enzyme appears to regulate cellular growth via control of the Go-GI transition. The catalytic conserved Cys residue of the enzyme is required for its activity. DUB-2 is induced by IL-2 as an immediate early (IE) gene that is down-regulated shortly after the initiation of stimulation. The function of this enzyme is also obscure. It may stimulate or inhibit the degradation of a critical cell-cycle regulator.

Cytokines, such as interleukin-2 activate intracellular signaling pathways via rapid tyrosine phosphorylation of their receptors, resulting in the activation of many genes involved in cell growth and survival. The deubiquitinating enzyme DUB-2 is induced in response to IL-2 and is expressed in human T-cell lymphotropic virus-I (HTLV-1)transformed T cells that exhibit constitutive activation of the IL-2 JAK/STAT (signal transducers and activators of transcription) pathway, and when expressed in Ba/F3 cells DUB- 2 markedly prolonged IL-2-induced STAT5 phosphorylation. Although DUB-2 does not enhance IL-2-mediated proliferation, when withdrawn from growth factor, cells expressing DUB-2 had sustained STATS phosphorylation and enhanced expression of IL-2-induced genes cis and c-myc. DUB-2 expression markedly inhibited apoptosis induced by cytokine withdrawal allowing cells to survive. Therefore, DUB-2 has a role in enhancing signaling through the JAK/STAT pathway, prolonging lymphocyte survival, and, when constitutively expressed, may contribute to the activation of the JAK/STAT pathway observed in some transformed cells. (Migone, et al., Blood. 2001;98:1935-1941).

Protein ubiquitination is an important regulator of cytokine-activated signal transduction pathways and hematopoietic cell growth. Protein ubiquitination is controlled by WO 03/072724 PCT/US03/05338 -6the coordinate action of ubiquitin-conjugating enzymes and deubiquitinating enzymes.

Recently a novel family of genes encoding growth-regulatory deubiquitinating enzymes (DUB-1 and DUB-2) has been identified. DUBs are immediate-early genes and are induced rapidly and transiently in response to cytokine stimuli. By means of polymerase chain reaction amplification with degenerate primers for the DUB-2 complementary DNA, 3 murine bacterial artificial chromosome (BAC) clones that contain DUB gene sequences were isolated. One BAC contained a novel DUB gene (DUB-2A) with extensive homology to DUB-2. Like DUB- 1 and DUB-2, the DUB-2A gene consists of 2 exons. The predicted DUB-2A protein is highly related to other DUBs throughout the primary amino acid sequence, with a hypervariable region at its C-terminus. In vitro, DUB-2A had functional deubiquitinating activity; mutation of its conserved amino acid residues abolished this activity. The 5' flanking sequence of the DUB-2A gene has a hematopoietic-specific functional enhancer sequence. It is proposed that there are at least 3 members of the DUB subfamily (DUB-1, DUB-2, and DUB-2A) and that different hematopoietic cytokines induce specific DUB genes, thereby initiating a cytokinespecific growth response. (Baek, et al, Blood. 2001;98:636-642).

Protein ubiquitination also serves regulatory functions in the cell that do not involve proteasome-mediated degradation. For example, Hicke and Riezman have recently demonstrated ligand-inducible ubiquitination of the Ste2 receptor in yeast. Ubiquitination of the Ste2 receptor triggers receptor endocytosis and receptor targeting to vacuoles, not proteasomes. Also, Chen et al. have demonstrated that activation of the IB kinase requires a rapid, inducible ubiquitination event. This ubiquitination event is a prerequisite for the specific phosphorylation of IB and does not result in subsequent proteolysis of the kinase complex. The ubiquitination of Ste2 and IB kinase appears reversible, perhaps resulting from the action of a specific deubiquitinating enzyme.

A large superfamily of genes encoding deubiquitinating enzymes, or UBPs, has recently been identified. UBPs are ubiquitin-specific thiol-proteases that cleave either linear ubiquitin precursor proteins or post-translationally modified proteins containing isopeptide ubiquitin conjugates. The large number of UBPs suggests that protein ubiquitination, like protein phosphorylation, is a highly reversible process that is regulated in the cell.

WO 03/072724 PCT/US03/05338 -7- Interestingly, UBPs vary greatly in length and structural complexity, suggesting functional diversity. While there is little amino acid sequence similarity throughout their coding region, sequence comparison reveals two conserved domains. The Cys domain contains a cysteine residue that serves as the active enzymatic nucleophile. The His domain contains a histidine residue that contributes to the enzyme's active site. More recent evidence demonstrates six homology domains contained by all members of the ubp superfamily.

Mutagenesis of conserved residues in the Cys and His domains has identified several residues that are essential for UBP activity.

Recently, a growth regulatory deubiquitinating enzyme, DUB-i, that is rapidly induced in response to cytokine receptor stimulation was identified. DUB-1 is specifically induced by the receptors for IL-3, granulocyte macrophage-colony-stimulating factor, and suggesting a specific role for the c subunit shared by these receptors. In the process of cloning the DUB-1 gene, a family of related, cross-hybridizing DUB genes was identified. From this, other DUB genes might be induced by different growth factors. Using this approach, an IL-2inducible DUB enzyme, DUB-2 and closely related DUB-2a were identified. DUB-1 and DUB-2 are more related to each other than to other members of the ubp superfamily and thereby define a novel subfamily of deubiquitinating enzymes.

Hematopoietic-specific, cytokine induced DUBs in murine system have shown to prolong cytokine receptor, see Migone, T. et al. (2001). The deubiquitinating enzyme DUB-2 prolongs cytokine-induced signal transducers and activators of transcription activation and suppresses apoptosis following cytokine withdrawal, Blood 98, 1935-41; Zhu, et al., (1997). DUB-2 is a member of a novel family of cytokine-inducible deubiquitinating enzymes, J Biol Chem 272, 51-7 and Zhu, et al., (1996). The murine DUB-1 gene is specifically induced by the betac subunit of interleukin-3 receptor, Mol Cell Biol 16, 4808- These effects are likely due to the deubiquitination of receptors or other signaling intermediates by DUB-1 or DUB-2, murine analogs ofhDUBs. Inhibition ofhDUBs may achieve downregulation of specific cytokine receptor signaling, thus modulating specific immune responses.

Cytokines regulate cell growth by inducing the expression of specific target genes. A recently identified a cytokine-inducible, immediate-early gene, DUB-1, encodes a WO 03/072724 PCT/US03/05338 -8deubiquitinating enzyme with growth regulatory activity. In addition, a highly related gene, DUB-2, that is induced by interleukin-2 was identified. The DUB-2 mRNA was induced in T cells as an immediate-early gene and was rapidly down-regulated. Like DUB-i, the DUB-2 protein had deubiquitinating activity in vitro. When a conserved cysteine residue of DUB-2, required for ubiquitin-specific thiol protease activity, was mutated to serine deubiquitinating activity was abolished. DUB-1 and DUB-2 proteins are highly related throughout their primary amino acid sequence except for a hypervariable region at their COOH terminus. Moreover, the DUB genes co-localize to a region of mouse chromosome 7, suggesting that they arose by a tandem duplication of an ancestral DUB gene. Additional DUB genes co-localize to this region, suggesting a larger family ofcytokine-inducible DUB enzymes. We propose that different cytokines induce specific DUB genes. Each induced DUB enzyme thereby regulates the degradation or the ubiquitination state of an unknown growth regulatory factor, resulting in a cytokine-specific growth response.

On the basis of these structural criteria, additional members of the DUB subfamily can be identified in the GenBank

T

The highest degree of homology is in the Cys and His domains.

Additionally, this putative human DUB protein contains a Lys domain (amino acids 400-410) and ahypervariable region (amino acids 413-442).

Murine DUB (mDUB) subfamily members differ from other UBPs by functional criteria as well. mDUB subfamily members are cytokine-inducible, immediate-early genes and may therefore play regulatory roles in cellular growth or differentiation. Also, DUB proteins are unstable and are rapidly degraded by ubiquitin-mediated proteolysis shortly after their induction.

mDUB reports demonstrate that specific cytokines, such as IL-2 and IL-3, induce specific deubiquitinating enzymes (DUBs). TheDUB proteins may modify the ubiquitinproteolytic pathway and thereby mediate specific cell growth or differentiation signals. These modifications are temporally regulated. The DUB-2 protein, for instance, is rapidly but transiently induced by IL-2. Interference of DUB enzymes with specific isopeptidase inhibitors may block specific cytokine signaling events.

Defensins constitute a major family of antimicrobial peptides in mammals. Depending on the distribution of the cysteines and the linkages of the disulfide bonds, human defensins WO 03/072724 PCT/US03/05338 -9can be divided into two categories: a-defensins, which can be found in granulocytes and in epithelial cells of the small intestine, and P-defensins, which are expressed by epithelial cells and leukocytes including macrophages. Some defensins are expressed constitutive manner in granulocytes and epithelial cells where as others are induces by either exposure to microbial pathogens or pro-inflammatory cytokines such as IL- 1 TNF-a and interferon-y. The genes coding for human defensins are clustered within 1 Mb segment on chromosome 8P23, and it has been suggested that p-defensins may predate the a-defensin family during recent gene amplification since a-defensin cannot be detected even in many mammalians including cow.

Cow has at least 13 p-defensins but no a-defensin. P-defensins contribute to early host defense against several bacterial and fungal pathogens, as an important mechanism of innate immune response. Beside this antimicrobial activity, a chemoattractant activity on both immature dentritic cells and memory T cells, as well as monocytes, has been recently described, demonstrating that P-defensins may promote both innate and adaptive immune response.

Summary of the Invention The present invention is directed to analogs of murine DUBs, hematopoietic-specific, cytokine-inducible deubiquitinating proteases found as a cluster of genes on chromosomes 4 and 8 and respective regulatory regions. Eleven novel human DUBs and four potential genes that express truncated form of DUBs not previously reported in public databases were identified by searching human genome database using murine DUB-1 and DUB-2 sequences.

These genes share open reading frames (ORFs) that are 88 to 99% amino acid identity to each other, when gaps caused by deletion and N-terminal and/or C-terminal extension was not counted as mismatch, and exhibit approximately 50% identity to murine DUBs. Eight of eleven ORFs generate a protein of 530 amino acids. Two ORFs (hDUB8.3 and hDUB8.11) have internal in-frame deletions such that the genes are capable of generating 497 and 417 amino acid long polypeptides, respectively. One ORF (hDUB4.5) exhibits extension at both and 3' end of the ORF so that the gene is capable of expressing 574 amino acid long polypeptide. Surprisingly, this 5' extension results in specific pro-polypeptide sequence that can direct polypeptide targeting to the mitochondria. Furthermore, the respective regulatory regions, putative promoters, of these genes also share close to 90% identity each other suggesting that their expression is coordinated. In addition, we found that two of these genes WO 03/072724 PCT/US03/05338 can be expressed under the control of separate promoters that can be controlled independently and expressing potentially distinctive protein products.

Manipulation of these gene products by small molecular compounds can reduce inflammation by regulating proinflammatory cytokine signaling, modulate autoimmune diseases by regulating cytokine receptor signaling that are critical for lymphocytes proliferation, and immune over-reaction during infection using above mechanisms.

Two of cluster genes (hDUB4.1 and hDUB4.2) possesses two distinctive promoter domains in front of their ORFs such that they can be regulated independently in their transcription potential. The longer transcripts of these ORFs (called hDUB4.1 a and hDUB4.2a) has 12 and 4 exons respectively and capable of generating 1016 and 1021 amino acid long polypeptides, respectively. These polypeptides share C-terminal 530 amino acids with their shorter form that can be expressed separately from independent promoters (called hDUB4.lb and hDUB4.2b, respectively). In addition, two other ORFs are capable of generating longer than 530 amino acid polypeptides (hDUB4.10 and hDUB4.11).

Remarkably, these two deduced polypeptides shares significant homology within portion of N-terminal portions (I added alignment file of these at the end of sequence file). Three of the ORFs (hDUB4.5, 4.8, and 8.2) has N-terminal insertion that is typical for mitochondria targeting sequence. An alignment of these sequences is provide in the Tables. The promoter sequences defined as upstream of initiation ATG of the ORF exhibit remarkable level of homology each other except that of hDUB4.la. The sequence identity among all promoter sequences except that of hDUB4.la is approximately 90% in 2000 base pair span upstream of initiation ATG. Two of the promoter sequences (hDUB8.3 and 8.11) have 334 nucleotides insertion at approximately 1000 base pair upstream of initiation ATG. Interestingly, hDUB8.3 and hDUB8.11 are the only ones with shorter ORFs due to the internal deletions. In addition to these ORFs, there are 5 ORFs that are capable of expressing polypeptides (hDUB4.4, hDUB4.9, hDUB8.2, hDUB8.9, and hDUB8.10) that share initiation codon with other 530 amino acid long polypeptides but terminate prematurely due to the in frame termination sequences. These also shares significant homology upstream of ATG initiation codon suggesting they may expressed as truncated proteins, potential regulatory functions. All 11 hDUB8 genes are clustered with the defensin clusters within 2 Mb region in 8P23, implying that both acquisition and amplification are relatively recent event, perhaps during mammalian WO 03/072724 PCT/US03/05338 -11evolution. It is of interest that hDUB4 gene cluster is also in highly amplified cluster region of chromosome 4P16 that is yet to be assigned in chromosome location. These data suggest that hDUB4s and hDUB8s are within very dynamic region of the human chromosomes (both 4pl6 and 8p23) that are undergoing volatile amplifications. The data also suggest that expression of hDUB8 may also be coordinated in conjunction with defensins that are critical components of innate immune response and inflammation.

Search methods for identifying human analogs of mDUBs: In order to identify human analogs ofmDUBl, -2A, mDUB1 (U41636), mDUB2 (NM_010089), and mDUB2A (AF393637) DNA sequences were used to search against Ensembl entire "golden path" (as contigs) using Ensembi blast search engine (http://www.ensembl.org/perl/blastview). All three mDUBs have significant alignments with contig AC083981, AF252831, AF228730, AF252830, AC068974 on chromosome 8 with the high score above 2000 and the probability less than e-87. In order to find all the homolog genes in the genome, exhaust search was performed using genomic aligned sequence to search against the "golden path" contigs. Two more contigs were found to have significant alignment that has probability less than e-100: one is AC074340 on chromosome 8 and the other is AC022770 on chromosome 4.

DNA sequences for contig AC083981, AF252831, AF228730, AF252830, AC068974, AC074340 and AC022770 were downloaded from Ensembl and gene annotation for each contig was performed using GenScan gene annotation program. Genes having homolog with mDUBs were named in sequence based on their locations on chromosomes.

For example, hDUB8.1 was derived from AF228730, 8.2, 8.3 were derived from AF252830, were derived from AC074340, 8.6 were derived from AF252831, 8.7, 8.8 and 8.9 were derived from AC083981, and 8.10 and 8.11 were derived from AC068974. hDUB4.1, 4.2, 4.3, 4.4, 4.5 were derived from AC022770 on chromosome 4.

Using these hDUB4s and hDUB8s, both Ensemble and NCBI blast search was performed.

Further contig NT_028165 that covers chromosome 4 was identified. From this and already assembled chromosome 4pl6.1 region, further annotation was performed using GenScan gene annotation program. From this we identified hDUB4.6, 4.7, 4.8, 4.9, 4.10, and 4.11.

WO 03/072724 PCT/US03/05338 -12- Analysis of the hDUB gene clusters in chromosome 4 reveals that at least five ORFs in an unmapped cOntig (AC022770) were identified by nucleotide homology search with murine DUB1 and 2. At least four out of five ORFs share core 530 amino acid sequences. Two ORFs (hDUB4.1 and hDUB4.2) are multi-exon ORFs that extend N-terminal part of polypeptides that shares minimal sequence identity. However, there is a conserved putative promoter sequences that encompass over 2,000 bases in the intron region proximal to the last exon that is conserved among all 5 genes. Three of the ORFs (hDUB4.5, 4.8, and 8.2) has Nterminal insertion that is typical for mitochondria targeting sequence. The hDUB genes cluster in 4P16 of the human chromosome, which is an unmapped part of the human chromosome.

Analysis of the hDUB gene clusters in chromosome 8 reveals that at least eleven ORFs in six different contigs (AC068974, AC074340, AC083981, AF228730, AF252830, and AF252831) were identified by nucleotide homology search with murine DUB1 and 2. At least seven out of eleven ORFs share significant identities with similar length. There are conserved putative promoter sequences that encompass over 2,000 bases in all 11 genes. The hDUB genes cluster in 8P23.1 of the human chromosome and clustered with defensin molecules (at lease 9 defensins are clustered with hDUB8s) and the whole domain belongs the olfactory GPCR cluster.

Analysis of the deduced amino acid sequences of the hDUBs reveals polypeptides consistent with mDUBs, which contain highly conserved Cys and His domains that are likely to form the enzyme's active site. The putative active site nucleophile ofmDUB-2 is a cysteine residue (Cys- 60 in the Cys domain. Both mDUB-1 and mDUB-2 have a lysine rich region (Lys domain; amino acids 374-384 of mDUB-2) and a short hypervariable region (amino acids 385- 451 of mDUB-2), in which the mDUB-1 and mDUB-2 sequences diverge considerably. The hypervariable (HV) region of mDUB-2 contains a duplication of the eight-amino acid sequence: PQEQNHQK.

TaqMan real time PCR analysis of expression of hDUB4s and hDUB8s in human immunocytes upon various stimulation WO 03/072724 PCT/US03/05338 -13- Protocol of reverse transcription (RT) from total cellular RNA using random hexamer as primer (using TaqMan Reverse Transcription Reagents Cat# N808-0234) 1 ug of total RNA preparation in 100 ul of lxTaqMan RT Buffer Mix, 5.5mM MgCl 2 mM dNTPs, 2.5 uM Random Hexamers, 40 U RNAse inhibitor, 125U Multiscribe Reverse Transcriptase. Mix by pipeting up and down. Incubate 25 0 C for 10 minutes (annealing step), 48 0 C for 30 minutes (reverse transcription), and 95°C for 5 minutes (heat killing of the enzyme). The samples can be left at the machine at 4 0 C, or alternatively, can be stored at 0 C. Yield of cDNA synthesis can be measured by incorporation of small portion of radioactive dATP (or dCTP). Average efficiency for this protocol is between 60-80% of conversion of RNA to cDNA.

Protocol of TaqMan real-time quantitative PCR 1 ul of TaqMan RT product in 12.5 ul of lx master Mix (Applied Biosystems Cat# 4304437)containing all necessary reaction components except primers and probes, 0.9 uM forward primer 0.9 uM reverse primer, 0.2 uM probe. Mix by pipetting up and down.

Samples containing GADPH primer pair and probe were also prepared as control. Thermal cycling and detection of the real-time amplification were performed using the ABI PRISM 7900HT Sequuence Detection System. The quantity of target gene is given relative to the GADPH control based on Ct values determined during the exponential phase of PCR.

Primer-probe sets used and their specificities: Primer 4.1 is unique for hDUB 4.1 Primer 4.2 covers hDUB 4.2, 4.3, 4.5 and 8.1 Primer 8.3 covers hDUB 8.3 and 8.11 Primer 8.5 is unique for hDUB Primer 8.6 covers hDUB 8.6, 8.7 and 8.8 WO 03/072724 PCT/US03/05338 Table 1. Expression of hDUBs in PBMC stimulated with LPS (100 ng/ml) and PHA (5 ug/ml) for 7 hours.

Donor 1 Donor 2 Primer Fold-Upregulation Relative Fold-Upregulation Relative upon stimulation expression upon stimulation expression 4.1 2.2 1 3.8 1 4.2 2.0 21000 2.0 16400 8.3 1.8 5560 1.8 5500 2.1 80 3.1 310 8.6 2.6 19200 3.0 23000 Table 2. Expression ofhDUBs in PBMC stimulated with LPS (100 ng/ml) for 1.5, 7and 24 hours (Donor 3) hours 7 hours 24 hours Fold- Relative Fold- Relative Fold- Relative Upregulation expression Upregulation expression Upregulation expression upon upon upon stimulation stimulation stimulation 4.2 2.4 64 336 35.2 1.8 12.5 8.3 0.4 1 13.1 1 1.7 1 1.6 11 65.9 4.8 1.5 1.8 Table 3. Expression of DUBs in PBMC stimulated with LPS (100 ng/ml) and/or PHA ug/ml) for 1.5, 7, 24 hours (donor 4) Primer 4.2 LPS 8.3

S-Q

hours 7 hours Fold- Relative Fold- Relative Upregulation expression Upregulation expression upon upon stimulation stimulation 24 hours Fold- Upregulation uprglon Relative expression upon stimulation 0.4 39 0.5 5 2.5 54 1.6 48 1.6 6 1.1 7 0n 1 1 1.5 1.7 1.4 2 I I 4.2 3.5 367 4.4 94 0.9 26 PHA 8.3 1.5 13 1.7 6 0.7 1.9 2 0.9 1 0.7 1 8.6 2.3 103 2.5 23 0.8 17 LPS 4.2 1.2 129 3.4 73 0.8 23 8.3 1.0 9 2.2 8 0.7 PHA 8.5 1.0 1 0.9 1.3 0.9 1.2 8.6 1.3 56 2.5 33 0.8 18 There is no increase of expression in T lymphocytes (donor 5) and B lymphocytes (donor 6) when stimulated with anti-CD4/CD28 and anti-CD40/IL-4, respectively.

WO 03/072724 PCT/US03/05338 Table 4. Expression of hDUB 4.2, 4.3, 4.5 and 8.1 examined by primer 4.2 in different human organ panel by TaqMan analysis.

Tissue Type Adrenal Gland Bone marrow Brain Colon Fetal Brain Fetal Liver Heart Kidney Lung Mammary Gland Pancreas Placenta Prostate Salivary Gland Skeletal Muscle Small Intestine Spinal Cord Spleen Stomach Testis Thymus Thyroid Trachea Uterus PBMC/Control

PBMC/PMA

PBMC/PHA

PBMC/HDM

A549 Cells THP- 1 Ovary Positive Control Mean 29.72 34.02 26.92 32.03 27.59 33.22 33.09 29.93 32.10 30.00 34.83 36.60 29.14 32.11 28.27 34.33 27.04 32.45 32.15 28.57 31.01 28.84 31.39 30.37 33.98 33.62 34.20 34.23 31.98 35.48 31.84 29.61 S2 Mean 20.00 20.49 22.73 19.97 24.23 22.58 21.60 21.97 19.31 21.74 24.07 23.77 20.93 21.39 20.44 21.00 21.91 19.02 21.66 23.07 20.68 20.80 19.63 21.09 18.82 18.81 18.77 17.81 21.57 20.75 21.55 21.86 99 Ct Expression 10.08 13.89 4.54 12.42 3.71 10.99 11.85 8.32 13.15 8.61 11.11 13.19 8.55 11.07 8.18 13.69 5.47 13.78 10.84 5.87 10.69 8.39 12.11 9.64 15.52 15.17 15.78 16.77 10.77 15.09 10.65 8.11 0.92 0.07 42.84 0.18 76.15 0.49 0.27 3.13 0.11 2.56 0.45 0.00 2.66 0.46 3.45 0.08 22.48 0.07 0.55 17.16 0.61 2.97 0.23 1.25 0.02 0.03 0.02 0.01 0.57 0.00 0.62 3.62 Table 5. Expression of hDUB 4.2, 4.3, 4.5 and 8.1 examined by primer 4.2 in human immunocytes panel: Cell Type and stimulation condition Granulocyte resting Granulocyte TNF-P 4/24 hr CD19 (tonsillar CD40L) Mean B 2 Oa Ct Expression Mean 34.18 17.22 32.39 17.16 28.7 19.92 17.50 15.76 9.32 0.005 0.018 1.565 WO 03/072724 PCT/US03/05338 CD19 (tonsillar LPS)

FLS-REST

FLS-IL1 4/24 hr FLS-TNF-P 4/24 hr Monocyte resting (pool 1.5, 7, 24 hr) Monocyte LPS (pool 1.5, 7, 24 hr) Monocyte INF-g (pool 1.5, 7, 24 hr) Monocyte LPS IFN-q (pool 7, 24 hr) DCs progenitors (CD14+) DCs immature DCs mature THO resting THO activated Thl resting Thl CD28/CD3 Th2 resting Th2 CD28/CD3

BSMC

BSMC IL-4 TNF-P 24 hr BSMC IL-13 TNF-f 24 hr BSMC IL-4 IL-13 NHBE dO NHBE IL-4 +TNF-P dO NHBE IL-13 +TNF-tdO NHBE resting d7 d14 NHBE IL-4 TNF-t d7 d14 NHBE IL-13 TNF-P d7 d14 CD8 T cell 0 hour CD8 T cell a-CD3/CD28 4 hour CD8 T cell a-CD3/CD28 24 hour HMVEC resting HMVEC TNF-P IL-4 24hr HMVEC TNF-P 24hr HMVEC TNF-1 IL-13 24hr Normal synovium pool RA synovium pool Normal colon Colitis Colon Crohns colon pooled Normal Lung COPD Lung Positive control Cloning of h DUB4,8s by PCR 31.14 34.67 34.26 34.91 33.63 20.67 20.43 20.41 20.15 18.29 11.00 14.78 14.38 15.31 15.89 0.488 0.036 0.047 0.025 0.017 34.55 18.03 17.06 0.007 34.62 17.27 17.88 0.004 34.87 17.38 18.03 0.004 35.87 35.48 37.46 31.11 31.29 33.88 32.15 33.94 33.27 35.33 36.44 35.94 36.28 36.63 35.72 36.35 34.89 38.59 37.62 30.15 32.08 30.94 35.09 35.91 35.57 36.38 34.92 33.65 32.5 33.17 32.91 31.01 35.09 28.4 19.73 18.18 17.92 17.63 18.23 18.27 19.31 18.07 18.78 21.64 21.52 21.41 22.09 22.24 21.42 21.37 22.41 22.02 21.93 19.52 19.6 18.64 20.25 20.86 21.06 20.61 21.16 20.88 21.68 21.32 22.06 20.5 22.14 22.29 16.67 17.84 20.07 14.02 13.60 16.15 13.38 16.40 15.02 14.22 15.45 15.07 14.73 14.92 14.83 15.52 13.01 17.11 16.23 11.16 13.01 12.84 15.38 15.59 15.05 16.31 14.3 13.3 11.36 12.39 11.39 11.05 13.49 6.64 0.000 0.000 0.000 0.060 0.081 0.014 0.094 0.012 0.030 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.121 0.000 0.000 0.437 0.121 0.137 0.000 0.000 0.000 0.000 0.050 0.099 0.381 0.187 0.374 0.472 0.000 9.992 WO 03/072724 PCT/US03/05338 -17- Following promer set was used to clone 530 amino acid open reading frame portion of single exon hDUB4s and 8s from human genomic DNA: N-terminal primer: 5'-atggaggacgactcactct-3' (19 mer) C-terminal primer: 5'-ctggcacacaagcaga-3' (19 mer) Underlined triplet nucleotides in each primer represent translational initiation and termination codon. This primer set can amplify most of hDUB4s and hDUB8s as well as potentially yet to be identified hDUBs that are similar enough to hDUB4s and hDUB8s due to the high homology in nucleotide sequences in this part of the ORF. 1593 base pair fragment was successfully amplified from genomic DNA from two healthy human subjects and cloned into pCR2.1 vector and transformed into TOP 10 strain of E coli. Over 300 independent clones with appropriate size insert were obtained and sequences are obtained by ABI automated DNA sequencers.

Deubiquitination Assay Confirmation that the DUB is a deubiquitinating enzyme may be shown using previously identified deubiquitination assay of ubiquitin--galactosidase fusion proteins, as described previously in the literature. Briefly, a fragment of the DUB, of approximately 1,500 nucleotides, based on the wild-type DUB cDNA (corresponding to amino acids 1 to about 500) and a cDNA containing a missense mutation are generated by PCR and inserted, in frame, into pGEX (Pharmacia), downstream of the glutathione S-transferase (GST) coding element. Ub-Met--gal is expressed from a pACYC1 84-based plasmid. Plasmids are cotransformed as indicated into MC1061 Escherichia coli. Plasmid-bearing E. coli MC1061 cells are lysed and analyzed by immunoblotting with a rabbit anti--gal antiserum (Cappel), a rabbit anti-GST antiserum (Santa Cruz), and the ECL system (Amersham Corp.). in vitro deubiquitinating enzyme activity may be shown from purified hDUB fusion protein using commercial polyubiquitinated protein as substrate.

HDUB4s and hDUB8s are potential inflamatory cytokins specific Immediate-early Genes mDUB-1 was originally cloned as an IL-3-inducible immediate-early gene. Similarly, mDUB-2 was cloned as an IL-2-inducible immediate-early gene. We examined inducibility as WO 03/072724 PCT/US03/05338 -18well as cell-type specific expression of these genes using multiple TaqMan analysis from human organ RNA samples and human immunocytes RNA samples. Our data suggest that expression of hDUBs are not apparent in lymphocytes and granulocytes but high in fresh human PBMC from several donor. This strongly suggest that expression may be limited to the monocytes/macrophages and potentially NK cells. hDUB4s and hDUBSs are upregulated in PBMC stimulated with stimuli (LPS and/or PHA) that is known to upregulate various inflammatory cytokines such as TNF-alpha, IL-1 beta etc. This increase of expression is almost completely disappeared 20 to 24 hours after stimulation suggesting this is an early gene. The fact that there is only weak expression upregulation at 1.5 hours after stimulation suggests that stimuli by themselves may not upregulate hDUB4s and hDUB8s, but cytokines that are upregulated within couple of hours after stimulation may be responsible for upregulation of the hDUB4s and hDUB8s.

The DUB Subfamily of the ubp Superfamily From these data we propose that hDUB4s and hDUB8s are members of a discrete subfamily of deubiquitinating enzymes that shows the strongest similarity to mDUB subfamily including mDUB 1, mDUB2, and mDUB2A, called the DUB subfamily. DUB subfamily members contain distinct structural features that distinguish them from other ubps.

First, DUB subfamily members are comparatively small enzymes of approximately 500-550 amino acids. Second, DUB subfamily members share amino acid similarity not only in the Cys and His domains but also throughout their primary amino acid sequence. For instance, DUB proteins contain a lysine-rich region (Lys domain) and a HV domain near their carboxyl terminus.

The regulatory regions, or promoter regions, of each of the DUBs was analyzed for putative transcription factor binding motifs using TRANSFACFind, a dynamic programming method, see Heinemeyer, et al., "Expanding the TRANSFAC database towards an expert system of regulatory molecular mechanisms" Nucleic Acids Res. 27, 318-322, (1999). The Transfac database provides eukaryotic cis- and trans-acting regulatory elements.

Table 6, putative transcription factor binding motifs within the DUB regulatory or promoter, region of hDUB 4. la. The position is indicated by nucleotides.

WO 03/072724 WO 03/72724PCT/US03/05338 Transfac Position(Score) Name Description M00271 729..724(100) AML-lIa runt-factor AML-1I MOO0148 296..302(100) SRY sex-determining region Y gene product 1016.. 1010(96) 958..964(94)___ 474..480(94) 1982..1988(92) 129.. 123(90) 857. .863(90) 776. .782(90) 1919.. 1913(90) 1227.. 1233(90) 276..282(90) 1741.. 1735(90) 193.. 199(90) M00240 1600..1606(100) Nkx -2 .5 homeo domain factor homolog 700..694(100) M00083 892..899(100) MZF1 MZFI M0OI0l 162..156(100) CdxA CdxA 1008..,1002(100) 423. .429(100) 153.. 147(99) 359. .353(98) 1388..1394(98) 1644.. 1650(97) 1702..1696(97) 250. .256(97) 231..237(97) 617..611(94) 509..503(93) 432..426(92) 307..313(92) 153..159(92) 1832..1838(92) 1366..1372(92) 494.. 500(92) 1450..1456(91) 1456..1450(91) 722..716(90) 991.,985(90) 986..992(90) M0025 3 1142..1149(97) 1344. .135 1(96) 639..632(95) cap signal for transcription initiation WO 03/072724 WO 03/72724PCT/US03/05338 13 13..1320(94) 1872..1879(93) 269..262(92) 257..250(91) 1103..1110(91) 745. .752(9 1) 1596(90) M00099 978..993(96) S8 S8 1637.. 1652(94) MOOIOO 162.. 156(96) CdxA CdxA 1008.. 1002(96) 423. .429(96) 1774..1768(96) 415. .42 1(92) 860..854(91) 1026.. 1020(91) 494..500 91) M00285 725..713(95) TCFlI 1 TCF1 1/KCR-F1/Nrfl homodimers M00347 531..522(95) GATA-1 GATA-binding factor 1 M00135 1642.. 1660(95) Oct- I octamer factor 1 M00075 217..226(94) GATA-1 GATA-binding factor 1 M00278 530..522(94) Lmo2 complex of Lmio2 bound to Ta1-1, F2A and GATA-1, half-site 2 MOO0157 990..978(94) RORalpha2 RAR-related orphan rcceptor alpha2 M00127 533..520(93) GATA-1 GATA-binding factor 1 M00109 1933.. 1920(93) C/EBPbeta CCAAT/enhancer binding protein beta M00190 1656.. 1643(93) C/EBP CCAAT/enhancer binding factor M00137 1193..1205(93) Oct-i1 octamer factor 1 248..260(90) 1652.. 1640(90) M00302 1501.. 1512(92) NF-AT Nuclear factor of activated T-cells M00077 900. .908(91) GATA-3 GATA-binding factor 3 530. .522(90) M00126 533..520(91) GATA-1 GATA-binding factorlI M00159 123 1..1219(91) C/EBP CCAAT/enhancer binding protein M00074 1280.. 1292(91) c-Ets-1(p54) c-Ets-1I(p54) M00042 192..201(91) Sox-5 M00241 1650.. 1643(91) Nkx-2.5 homeo domain factor tiniman homolog -MOOl 16 138..125(91) C/EBPalpha CCAAT/enhancer binding Protein alpha M00138 1640.. 1662(91) Oct-I octamer factor I M00128 532..520(90) GATA-1 GATA-binding factor 1 -M00248 1645.. 1656(90) Oct- I octarner factor I M00289 1009.. 102 1(90) HFH-3 HNF-3/Fkh Homolog 3 Freac-6) WO 03/072724 PCT/US03/05338 -21- Table 7, putative transcription factor binding motifs within the DUB regulatory or promoter, region of hDUB 4.1b. The position is indicated by nucleotides.

Transfac Position(Score) Name Description M00254 1831.. 1 820(99) CCAAT cellular and viral CCAAT box M00101 832..826(98) C dx A CdxA 727..721(92) .64(92) 570..564(92) 523. .529(92) 425..431(92) 1682..1688(91) 1409.. 1415(91) 1682(91) M00054 470_.461(97) _NF-kappaB NIF-kappafl ____643..634(95) MOO0148 946. .940(96) SRY sex-determining region Y gene product 1564.. 1570(92) 1528.. 1534(92) 1092.. 1098(92) 1048..1054(90) 708..714(90) 655. .661(90) 1360..1t354(90 1824..1818(90) 396..390(90) 749..743(90) 1016..1010(90) 302..308(90) M00053 470..461(95) c-ReI c-Rel 643 634(94) M00285 1734..1746(95) TCF11 TCF11I/KCR-F1/Nrfl homodimers 17..5(90) M00052 470..461(95) NF-kappaB NIF-kappaB (p6 5 643. .634(94) M0071933.. 1941(95) GATA-3 GATA-binding factor 3 M00253 485..492(95) 1893.. 1886(95) 749..756(94) 834..841(93) 1484.. 1477(92) 511..504(92) 1194..1201(91) 163..170(91) cap signal for transcription initiation WO 03/072724 WO 03/72724PCT/US03/05338 321. .328(9 1) 340.. 347(9 1) 18 15.. 1808(90) M00096 652..660(95) Pbx-1 Pbx-1 M00194 472..459(95) NF-kappaB NF-kappaB M00209 1818..1831(94) NF-Y NF-Y binding site MOO 116 1238..1225(94) C/EBPalpha CCAAT/enhancer binding protein alpha M00203 1699.. 1689(94) GATA-X GATA binding site ____1227..1217(90) M00241 535..542(94) Nkx-2.5 homeo domain factor Nkx-2.5ICsx, tinman M00033 759..746(94) p 300 p 300 M00127 1703..1690(93) GATA-1 GAlA-binding factor I M00158 323,.310(93) COUP-TF COIJP/HNF-4 heterodimer M00075 1889..1898(93) GATA-1 GAlA-binding factor 1 142..133(90) 1745(90) M00286 963..976(93) GKLF gut-enriched Krueppel-like factor M00278 1933.. 1941(93) Lmo2 complex of Lmo2 bound to Tal-1, E2A proteins, GATA- 1, half-site 2 M00076 1932.. 1941(93) GATA-2 GATA-binding factor 2 ____983..992(92) M00208 471..460(93) N-F-kappaB NF-kappaB binding site M00185 1829.. 18 19(92) NF-Y nuclear factor Y (Y-box binding factor) M00302 232..243(92) NF-AT Nuclear factor of activated T-cells M00348 98.. 107(92) GATA-2 GATA-binding factor 2 M00134 308..326(92) H-F-4 hepatic nuclear factor 4 M00223 548..540(92) STATx signal transducers and activators of transcription M00039 1046.. 1039(92) CREB cAMP-responsive element binding protein M00271 1955.. 1960(92) AML-la runt-factor AI\L-1 M00074 231..243(91) c-Ets-1(p54) c-Ets-1(p54) _252..264(91) M00289 385..397(91) HFH-3 HNF-3/Fkh Homolog 3 Freac-6) M00199 1722.. 1714(91) AP-1 AP-1I binding site M00032 254..263(91) c-Ets-1(p54)lc-Ets-1(p54) M00147 782..773(91) HSF2 Iheat shock factor 2 MOO100 1101..1095(91) CdxA CdxA M00042 650. .659(90)_ Sox-5 MWO018 3 1026.. 103 5(90) c-Myb c-Myb M00240 963..957(90) Nkx-2.5 homeo domain factor Nkx-2.5/Csx, tinman _______homolog 1272.. M00190 1238.. 1225(90) C/EBP CCAAT/enhancer binding factor M00349..42(90) MZF1 MZF1 M014275..284(90) 1MyoD myoblast determining factor WO 03/072724 WO 03/72724PCT/US03/05338 M00087 980..991(90) Ik-2 Ikaros 2 M00221 1860..1850(90) SREBP-1 sterol regulatory element-binding protein I M00137 1388.. 1376(90) Oct- I octamer factor 1 Table 8, putative transcription factor binding motifs within the DUB regulatory or promoter, region of liDUB 4.2a. The position is indicated by nucleotides.

Transfac Position(Score Name Description M00148 992..986(100) SRY sex-determining region Y gene product 942..948(100) 919..913(96) 1544..1550(92) 1505..1511(92) 815..809(90) 1068..1074(90) 1196..1190(90) 133 133 1(90) 680..686(90) 1697..1691(90) 1802..1796(90) 368. .362(90) 721. .715(90) 274..280(90) M00100 1077..1071(10 CdxA CdxA 0) M00271 1933..1938(l0 AML-la runt-factor AML-1 0) M00101 1077..1071(99) CdxA CdxA 805..799(98) 699..693(92) 1384..1390(92) 936..942(92) 495..501(92) 1660.. 1666(91) 1666..1660(91) M00076 716..707(98) GATA-2 GATA-binding factor 2 1910..19 19 959..968(92) 1679..1670(91) M00285 1712..1724(96) TCF11 ITCF11/KCR-FI/Nrfl homodimers 1____1087..1099(91) M00272 1242..1251(96) p53 Itumor suppressor p53 M00253 135..142(96) 457..464(95) 187 1..1864(95) cap signal for transcription initiation WO 03/072724 WO 03172724PCT/US03/05338 721..728(94) 1461..1454(92) 312..319(92) 1989..1996(92) 1855..1848(9 1) 770. .777(90) 1793 1786(90) 295.. 302(90)_ _______1274..1281(90) M00106 627..636(95) CDP cut-like homeodomain protein MOO 116 1215..1202(95) C/EBPalpha CCAAT/enhancer binding protein alpha M00254 1809..1798(95) CCAAT cellular and viral CCAAT box M00249 1 117..1 105(95) CHOP- heterodimers of CHOP and C/EBPalpha M00054 442..433(95) NE-kappaB NF-kappaB M00147 2182..21 73(94) HSF2 heat shock factor 2 2173..2182(92) 754..745(91) MOO0104 634..625(94) CDP cut-like homeodomain protein M00134 280..298(94) HNF-4 hepatic nuclear factor 4 M00052 442..433(94) NF-kappaB NE-kappaB M00053 442..433(94) c-Rel c-Rel M00033 731..718(94) p 30 0 p 300 M00158 295..282(93) COUP-TF COUP/HNF-4 heterodimer M00032 225..216(93) c-Ets-1(p54) c-Ets-1(p54) M00172 1851..1861(92) ALP-i activator protein 1 M00223 520.. 512(92) STATx signal transducers and activators of transcription M00075 1679..1670(92) GATA-1 GATA-binding factor 1 M00184 1463..1472(91) MyoD) myoblast determining factor M00289 357..369(91) HFH-3 HNF-3/Fkh Homnolog 3 Freac-6) M00109 1202..1215(91) C/EBPbeta CCAAT/enhancer binding protein beta 203 6. .2023(90) M00268 937..950(91) XFD-2 Xcnopus fork head domain factor 2 M00208 443..432(90) NF-kappaB NF-kappaB binding site M00173 1851..1861(90) NP- activator protein 1 M00183 1002-1011(90) c-Myb c-Myb WO 03/072724 WO 03/72724PCT/US03/05338 M00240 217..21 1(90) Nkx-2.5 homeo domain factor Nkx-2.5/Csx, tinman homolog M00188 1851..1861(90) NAAP-i activator protein 1 M00099 1086..1101(90) S8 S8 M00302 813..802(90) NF-AT Nuclear factor of activated T-cells M00083 21..14(90) MZF1I MZF1 M00190 1215..1202(90) C/EBP CCAAT/enhancer binding factor M00221 1838,.1828(90)' SREI3P-1 sterol regulatory element-binding protein 1 M00294 1949..937(90) HFH-8 1{NF-3/Fkh Homolog-8 M00 137 1365.1353(90) Oct- I octamer factor 1 M00077 1911.. 19 19(90)1 GATA-3 GATA-binding factor 3 M00194 444..431(90) 1NF-kappaB NF-kappaB Table 9, putative transcription factor binding motifs within the DUB regulatory or promoter, region of IIDUB 4.2b. The position is indicated by nucleotides.

Transfac Position(Score) Name Description MOOIOG 1102-.1096(100) CdxA CdxA M00148 1017..1011(100) SRY sex-determining region Y gene product 967..973(100) 944..938(96) 1566.. 1572(92) 1530.. 1536(92) 840. .834(90) 1093.. 1099(90) 705 7 1](90) 1362.. 1356(90) 1719.. 1713(90) 1824..1818(90) 393..387(90) 746..740(90) 299. .305(90) M00253 1120.. 1127(99) cap cap signal for transcription initiation 160..167(96) 482. .489(95) 1893..1886(95) 746..753(94) 1486..1479(92) 337..344(92) 1877.. 1870(91) 795..802(90) 1815 1808(90) 320. .327(90) _______11299..1305(90) M00l0I 1102..1096(99) 830. .824(9 8) 1231..1225(98) 1409.. 1415(92) CdxA CdxA WO 03/072724 WO 03/72724PCT/US03/05338 724..718(92) 520..526(92) 1682..1688(91) 1682(91) M00076 741..732(98) GATA-2 GATA-binding factor 2 1932..1941(95) 984..993(92) 1692(9 1) M00285 1734..1746(96) TCF11 ITCF11/KCR-F/Nrfl homodimers M00272 1267.. 1276(96) p 53 tumor suppressor p53 MOO0106 652..661(95) CDP cut-like homeodomain protein M001 16 1240.. 1227(95) C/EBPalph CCAAT/enhancer binding protein alpha a M00254 183 1..1820(95) CCAAT cellular and viral CCAAT box M00249 1142.. 1130(95) CHOP- heterodimers of CHOP and C/EBPalpha C/EBPalp~h a M00054 467..458(95) NF-kappaB NF-kappaB M00104 659..650(94) CDP cut-like homeodomain protein 27..36(92) M00134 305..323(94) HNF-4 hepatic nuclear factor 4 M00052 467..458(94) NE-kappaB NF-kappaB M00053 467.,458(94) c-Ret c-Rel M00033 756..743(94) 2300 p300 MOO] 58 320. .307(93) COUP-TF CO{YP/HNF-4 heterodimer M00075 1889..1898(93) GATA-1 GATA-binding factor 1 1701..1692(92) 741..732(91) 341..332(90) MOO0160 965..976(93) SRY sex-detennining region Y gene product M00032 250..241(93) c-Ets- c-Ets-1(p54) l(p54) 1.,260(93) M00172 1873..1883(92) AP-1 activator protein 1 M00223 545..537(92) STATx signal transducers and activators of transcription M00271 1955..1960(92) AML-l1a runt-factor AML-1I M00184 1488..1497(91) MyoD myoblast determining factor 1497.. 1488(91) 272..281(90) M00289 382..394(91) HFH-3 HNF-3/Fkh Homolog 3 Freac-6) M00109 1227..1240(91) C/EBPbeta CCAAT/enhancer binding protein beta MOO0147 779..770(91) HSF2 heat shock factor 2 166.. 157(90) 1M00208 1468. .457(90) NF-kappaB NF-kappaB binding site IM00183 1027..1036(90) 1 -y c-1 WO 03/072724 WO 03/72724PCT/US03/05338 M00173 1873..1883(90) ALP-I activator protein 1 M00240 242..236(90) Nkx-2.5 homneo domain factor Nkx-2.5/Csx, tinmran homolog M00188 1873..1883(90) AMP- activator protein 1 M00302 1838..827(90) NF-AT Nuclear factor of activated T-cells M00083 46. .39(90) MZF1 MZF1 M00190 1240.. 1227(90) C/EBP CCAAT/enhancer binding factor M00096 1115..1123(90) Pbx-1 Pbx-1 M00221 1860.. 1850(90) SRIEBP-1 sterol regulatory clement-binding protein 1 1M00194 1469..456(90) INF-kappaB NF-kappaB IM00077 1933.. 1941(90) 1GATA-3 GATA-bin ding factor 3 Table 10, putative transcription factor binding motifs within the DUB regulatory or promoter, region of liDUB 4.3. The position is indicated by nucleotides.

Transfac Position(Score) Name Description M00148 1015..1009(100) SRY sex-determining region Y gene product 965..971(100) 942..936(96L_ 1566.. 1572(92) 1528.. 1534(92) 838 832(90) 1091..1097(90) 1219.. 1213(90) 703..709(90) 1360.1354(90)_ 1719.. 1713(90) 1824.. 1818(90) 391..385(90) 744..738(90) MOOlGO 1100..1094(100) CdxA CdxA M00101 1100..1094(99) CdxA CdxA 828..822(98) 1407.. 1413(92) 722..716(92) 959. .965(92) 518..524(92) 1682.. 1688(91) 1682(91) M00076 739. .730(98) GATA-2 GATA-binding factor 2 M00285 1734.. 1746(96) TCF1 I TCF1 1/KCR-FL/Nrfl homodimers M00O-272 1265.. 1274(96) p 53 -Itumor suppressor p53 WO 03/072724 WO 03/72724PCT/US03/05338 M00253 158.. 165(96) cap cap signal for transcription initiation 480..487(95) 1893..1886(95)_ 744.. 751(94) 1484.. 1477(92) 335..342(92) 1877..1870(91) 793..800(90) 318..325(90) 1297..1304(90) MOO0106 650..659(95) CDP cut-like homeodomain protein 657..648(93) M001 16 1238..1225(95) C/EBPalph CCAAT/enhancer binding protein alpha a M00254 1831.. 1820(95) CCAAT cellular and viral CCAAT box M00249 1 140..1 128(95) CHOP- heterodimers of CHOP and C/EBPalpha C/EBPalph a M00054 465..456(95) KF-kappaB NF-kappaB MOO0104 657. .648(94) CDP cut-like homeodomain protein M00134 303..321(94) HNF-4 hepatic nuclear factor 4 M00052 465..456(94) NE-kappaB NE-kappaB M00053 465..456(94) c-Rel c-Rel M00033 754..741(94) p300 p300 M001 58 319..305(93) COUIP-TF COUIP/HINF-4 heterodimcr M00075 1889..1898(93) GATA-1 GATA-binding factor 1 1701..1692(92) 739..730(91) 339..330(90) M00160 963..974(93) SRY sex-determining region Y gene product M00032 248..239(93) c-Ets- c-Ets-1(p54) 4 249. .258(93) M00172 1873..1883(92) AP-1I activator protein 1 M00223 543..535(92) STA~x signal transducers and activators of transcription M00271 1955..1960(92) AML-la runt-factor AML-1I M00173 1873..1883(91) AP-1I activator protein 1 MOO0184 1486..1495(91) MyoD myoblast determining factor 1495..1486(91) .279(90) M00289 380..392(91) HFH-3 HNF-3/Fkh Homolog 3 Freac-6) M00109 1225..123 8(9 1) C/EBPbeta CCAAT/enhancer binding protein beta MOO0147 777..768(91) HSF2 heat shock factor 2 164.. 15 5(90) M00208 466..455(90) NF-kappaB NF-kappaB binding site M00183 1025..1034(90) c-Myb c-Myb M0040240..234(90) Nlx-2.5 homeo domain factor Nkx-2.5/Csx, tinman.

WO 03/072724 WO 03/72724PCT/US03/05338 homolog M00099 1109..1124(90) S8 S8 M00302 836..825(90) N.F-AT Nuclear factor of activated T-cells M00083 44..37(90) MZFl MZF1 MOO0190 1238.. 1225(90) CIEBP CCAAT/enhancer binding factor M00221 1860.. 1850(90) SREBP-1 sterol regulatory element-binding protein 1 M00174 1873..1883(90) AP-1I activator protein 1 M00077 1933.. 1941(90) GATA-3 GATA-binding factor 3 M00194 467..454(90) INE-kappaBINE-kappaB Table 11, putative transcription factor binding motifs within the DUB regulatory or promoter, region of hDUB 4.4. The position is indicated by nucleotidcs.

Transfac Position(Score) Name Description M00100 1101..1095(100) CdxA CdxA M00148 1016.. 1010(100) SRY sex-determnining region Y gene product 966..972(100) 944. .938(96) 1566.. 1572(92) 1529.. 1535(92) 840..834(90) 1092.. 1098(90) 705. .7 11(90) 1361..1355(90) 1719.. 1713(90) 1824.. 1818(90) 393..387(90) 746..740(90) 299. .305(90) M00101 1101..1095(99) CdxA CdxA 830..824(98) 1230.. 1224(8_ 1408.. 1414(92) 724..718(92) 520..526(92) 1682..1688(91) 1688..1682(91) M00076 741. .732(98) GATA-2 GATA-binding factor 2 1932..1941(95) 983..992(92) M00O350 876. .867(96) GATA-3 GATA-binding factor 3 M00285 1734..1746(96) TCF11I TCF1I IIKCR-F I/Nrfl homodimers 1111..1123(91) M0-0272 1266..1275(96) p53 tumor suppressor p53 M00253 160.. 167(96) 482..489(95) cap signal for transcription initiation WO 03/072724 WO 03/72724PCT/US03/05338 1893..1886(95) 746..753(94) 1485..1478(92) 337..344(92) 1877..1870(91) 795..802(90) 1815..1808(90) 320..327(90) 1298,.1305(90) M00106 652..661(95) CDP cut-like homeodomain protein 659..650(93) MOO 116 1239.. 1226(95) C/EBPalpha CCAAT/enhancer binding protein alpha M00254 1831..1820(95) CCAAT cellular and viral CCAAT box M00249 1141..1 129(95) CHOP- heterodimers of CHOP and C/EBPalpha _______C/EBPalpha.

M00349 876.. 867(95) GATA-2 GATA-binding factor 2 M00054 467..458(95) NE-kappaB NF-kappaB M00104 659..650(94) CDP cut-like homeodomain protein .36(92) M00134 305..323(94) HNF-4 hepatic nuclear factor 4 M00052 467..458(94) NIF-kappaB NF-kappaB M00053 467..458(94) c-Rel c-R.d M00033 756..743(94) p 30 0 p300 M00348 876.. 867(93) GATA-2 GATA-binding factor 2 M00158 320..307(93) COIJP-TF COUIP/HNF-4 heterodimer M00075 1889_.1898(93) GATA-1 GATA-binding factor 1 1701..1692(92) 741..732(91) M00160 964..975(93) SRY sex-determining region Y gene product M00347 876..867(93) GATA-1 GATA-binding factor 1 M00032 250..241(93)__ c-Ets-1(p54) c-Ets-1(p54) 251..260(93) M00172 1873..1883(92) AP-1I activator protein 1 M00223 545..537(92) STATx signal transducers and activators of transcription M00271 1955..1960(92) AML-la runt-factor AML-1I MOO0184 1487..1496(91) MyoD) myoblast determining factor t496.. 1487(91) ___272..281(90) M00289 382..394(91) HFH-3 HNF-3/Fkh Homolog 3 Freac-6) M00109 1226..1239(91) C/EBPbeta CCAAT/enhancer binding protein beta M00208 468..457(90) NIF-kappaB NE-kappaB binding site M00183 1026..1035(90) c-Myb c-Myb M00173 1873..1883(90) AP-1I activator protein 1 M00240 242..236(90) Nkx-2.5 homeo domain factor Nkx-2.5/Csx, tinman ________homolog M00188 1873..1883(90) 1 AP-1 Iactivator protein 1 M00099 1110..1125(90) 1 S8 IS8 WO 03/072724 WO 03/72724PCT/US03/05338 M00302 838..827(90) NF-AT Nuclear factor of activated T-cells M00083 46..39(90) MZFlI MZF1I MOO0190 1239.. 1226(90) G/EBP CCAAT/enhancer binding factor M00147 166..157(90) HSF2 heat shock factor 2 M00080 874..864(90) Evi-1 ectopic viral integration site 1 encoded factor M00082 874..864(90) Evi-1 ectopic viral integration site 1 encoded factor M00221 1860..1850(90) SREBP-l sterol regulatory element-binding protein 1 M00194 469..456(90) NF-kappaB _NF-kappaB M00077 1933.-1941(90) GATA-3 CATA-binding factor 3 Table 12, putative transcription factor binding motifs within the DUB regulatory or promoter, region of hDUIB 4.5. The position is indicated by nucleotides.

Transfac Position(Score) Name Description M00148 963..969(100) SRY sex-determining region Y gene product 1013 1007(100) 940..934(96) 1526..1532(92) 1089.. 1095(90) 836..830(90) 701 707(90) 135 1352(90) 1720.. 17 14(90) 1825..1819(90)- 389..383(90) 742..736(90) 295..301(90) MOOI100 1098..1092(100) CdxA CdxA M00101 1098.. 1092(99) CdxA CdxA 826..820(98) 1405.. 1411(92) 720,.714(92) 957..963 (92)- 16. .522(92) 1683..1689(91) 1689..1683(91) M00076 737..728(98) GATA-2 GATA-binding factor 2 980..989(92) 1702..1693(91) 1299..1308(90) [M00285 1735..1747(96) TCF1 I TCF II/KCR-F I/Nrfl homnodimers 1108..1120(91) M0221263..1272(96) p 5 3 tumor suppressor p53 M00253 156.. 163(96) 478..485(95) 742..749(94) 1482.. 1475(92) cap signal for transcription initiation WO 03/072724 WO (3107724PCT/US03/05338 333..340(92) 791..798(90) 1816..1809(90) 316,.323(90) M00106 648..657(95) CDP cut-like homneodomain protein 655..646(93) MOO 116 1236.. 1223(95) C/EBPalpha CCAAT/enhancer binding protein alpha M00254 1832.,1821(95) CCAAT cellular and viral CCAAT box M00249 1138.. 1126(95) CHOP- heterodimers of CHOP and C/EBPalpha ___C/FBPalpha M00054 463. .454(95) NF-kappaB NE-kappaB M001 83 1493..1484(94) c-Myb c-Myb 1023.. 1032(90) MOO0104 655..646(94) CDP cut-like homeodomain protein 23..32(92) M00134 301..319(94) HNF-4 hepatic nuclear factor 4 M00052 463..454(94) NE-kappaB NF-kappaB (p6 5 M00053 463..454(94) c-Rel c-Rdl 806..815(90) M00033 752. .739(94) p300 p300 M00158 316..303(93) COUP-TF COUP/HNF-4 heterodimer M00032 246. .237(93) c-Ets- c-Ets-1(p54) (p54) 247. .256(93) M00278 1300.. 1308(92) Lmo2 complex of Lmno2 bound to Tal-1, E2A proteins, and 1, half-site 2 M00223 541..533(92) STATx signal transducers and activators of transcription M00075 1702.. 1693(92) GATA-1 GATA-binding factor 1 737..728(91) M00077 1300.. 1308(91) GATA-3 GATA-binding factor 3 M00289 379..390(91) HFHI-3 HNF-3/Fkh Homnolog 3 Freac-6) M00109 1223.. 1236(91) C/EBPbeta CCAAT/enhancer binding protein beta M00268 958..971(91) XFD-2 Xenopus fork head domain factor 2 MOO0147 775..766(91) HSF2 heat shock factor 2 M00208 464. .453(90) NE-kappaB NE-kappaB binding site M00240 238..232(90) Nkx-2.5 homneo domain factor Nkx-2.5/Csx, tinman homnolog M00099 1107..1122(90) S8 S8 M00302 834..823(90) NE-AT Nuclear factor of activated T-cells M00083 42..3(90) MZF1 MZF1 M0 f0184 268..277(90) MyoD myoblast determining factor M00190 1236.. 1223(90) C/EBP CCAAT/enhancer binding factor M00221 1861..1851(90) SREBP-1 sterol regulatory element-binding protein I M00294 970. .958(90) HFH-8 HNF-3/Fkh Homnolog-8 M00137 1386..1374(90) Oct-i joctamer factor 1 MOO0194 465..452(90) 1NF-kappaB INF-kappaB WO 03/072724 PCT/US03/05338 -33- Table 13, putative transcription factor binding motifs within the DUB regulatory or promoter, region of IiDUB 8. 1. The position is indicated by nucleotides.

Transfac Position(Score) Name Description M00148 1015.. 1009(100) SRY sex-determining region Y gene product 965..971(100) 942..936(96) 1544.. 1550(92)_ 838..832(90) 702. .708(90) 1719.. 1713(90) 1824..1818 390..384(90) 1384.. 1390(90) 1356..1350(90) 296..302(90) 63. .69(90) M00100 1100..1094(100) CdxA CdxA 724.. 73 0(96) 1547.. 1541(91) M00349 93.. 102(100) GATA-2 GATA-binding factor 2 M00350 93..102(100) GATA-3 GATA-binding factor 3 M00241 1800.. 1807(100) Nkx-2.5 homeo domain factor Nkx-2.5/Csx, tinman homolog M00348 93..102(100) GATA-2 GATA-binding factor 2 MOQOI 1100..1094(99) CdxA CdxA 828..822(98) 1229.. 1223(98) 1203.. 1209(94) 721. .7 15(92) 959. .965(92) 1386.. 1380(92) .59(92) 517..523(92) 419..425(92) 1682.. 1688(91) 1682(91) M00203 95..105(98) GATA-X GATA binding site M00347 93..102(97) GATA-i1 GATA-binding factor 1 M00075 1838..1847(97) GATA-1I GATA-binding factor 1 1701.. 1692(95) 137.. 128(92) 1483..1492(92) 1889..1898(91) 1736.. 1745(90) M0fQ0158 317..304(96) COUP- COUP/I{NF-4 heterodimner TF WO 03/072724 WO 03/72724PCT/US03/05338 M00253 158 165(96) 1794..1801(95) 479..486(95) 1297..1304(93) 337..344(93) 48..55(93) 1484..1477(92) 1324.. 13 17(91) 557..564(91) 1893..1886(91) 1877..1870(91) 793. .800(90) 1356.. 1363(90) 1815..1808(90) 317..324(90) cap Icap signal for transcription initiation M00285 1734..1746(95) TCF11I TCF11/KCR-F1/Nrfl homodimers 1110..1122(91) 1(90) MO00134 302..320(95) HNF-4 hepatic nuclear factor 4 M00077 1933..1941(95) GATA-3 GATA-binding factor 3 M00096 1827..1819(95) Pbx-1 Pbx-1 M00141 451..459(94) Lyf-1I LyF-1 M00199 1797..1789(94) AP-1 AP-1I binding site MOO 174 1788..1798(94) AP-1 activator protein 1 M00076 1483.. 1492(93) GATA-2 GATA-binding factor 2 1932..1941(93) 1701.. 1692(92) 982..991(92) M00278 1933..1941(93) Lmo2 complex of Lmo2 bound to Tal-1, E2A proteins, and half-site 2 M00099 1813..1798(92) S8 S8 1109..1124(90) M00294 1551.. 15 39(92) HFH-8 HNF-3/Fkh Homolog-8 M00223 542..534(92) STATx signal transducers and activators of transcription M00073 36..46(92) deltaEFlI deltaEFl M00O271 1955..1960(92) AML-la runt-factor AML-1 132.. 127(92) M00137 335..323(91) Oct-i1 octamer factor 1 M00042 644..653(91) Sox-5 1829..1820(90) 1 M00289 379..391(91) HFH-3 HNF-3/Fkh Homolog 3 Freac-6) M00183 1025..1034(90) c-Myb c-Myb M00240 239..233(90) Nlx-2.5 homeo domain factor Nkx-2.5/Csx, tinman homolog -&018 8 1788..1798(90) AP- 1 activator protein 1 M00302 836..825(90) NT-AT Nuclear factor of activated T-cells MOO0128 92..104(90) GATA-1 GATA-binding factor 1 M00184 269..278(90) MyoD myoblast determining factor WO 03/072724 WO 03/72724PCT/US03/05338 M00147 164.. 155(90) HSF2 heat shock factor 2 M00087 979..990(90) Ik-2 Ikaros 2 M00172 1788..1798(90) A-P-1I activator protein 1 M0O0221 1860..1850(90) SREBP- sterol regulatory element-binding protein 1 Table 14, putative transcription factor binding motifs within the DUB regulatory or promoter, region of hDUB 8.2. The position is indicated by nucleotides.

Transfac Position(Score) Name Description M00241 1804..1811(100) Nkx-2.5 homco domain factor Nkx-2.5/Csx, tinman homolog M00240 556..562(100) Nkx-2.5 homeo domain factor Nkx-2.5ICsx, tinman homnolog 1354,.1360(90) 1____301..307(90) M00096 1342.. 1350(100) Pbx-1 Pbx-1I 1823(96) M00271 702..707(100) AML-la runt-factor AML- 1 1955..1960( 92) 175(92) M00050 104..111(100) E2F E2F M00148 1271..1277(100) SRY sex-determining region Y gene product 1572.. 1578(92) 1345 135 1(90) 1719A.713(90)_ 1828.. 1822(90) 1634.. 1628(90) M00272 472..463 (97) p53 tumor suppressor p53 463..472(97) 295..286(91) M00075. 1842..1851(97) GATA-1 GATA-binding factor 1 1893..1902(93) 1380.. 1371(92) 1740.. 1749(90) M00253 1072.. 1065(96) cap cap signal for transcription initiation 1798..1805(95) 1897.. 1890(95) 769. .776(92) 1701.. 1708(92) 188 1..1874(91) 497..504(90) 1819..1812(90) M00285 1738..1750(95) TCF11 TCFI1/KCR-F/Nrfl homodimers- 366..378(93) M-0-0077 1933..194](95) GATA-3 GATA-binding factor 3 MOO0147 148..139(94) HSF2 heat shock factor 2 ___139..148(92) 1_ WO 03/072724 WO 03/72724PCT/US03/05338 M00199 1801..1793(94) A-P-1 AP-1 binding site 1037..1029(94) 1793..1801(91) M00174 1792..1802(94) AP-1 activator protein 1 1028(92) M00074 1247..1259(93) c-Ets- c-Ets-1 (p54) I 1 (p 5 4 M0021 1 702..710(93) Poly Retroviral Poly A downstream element 153 15 39(9 1) M00124 1339..1353(93) Pbxlb homeo domain factor Pbx-1 M002'78 1933..1941(93) Lmo2 complex of Lmo2 bound to Tal-l1, E2A proteins, and GATA-1, half-site 2 M00052 1261..1252(93) NF- NIF-kappaB kappaB M00076 1932..1941(93) GATA-2 GATA-binding factor 2 837..828(90) M00099 1817..1802(92) S8 S8 M00101 987..981(92) CdxA CdxA M00042 1635..1626(92) Sox-5 M00254 1835..1824(91) CCAAT cellular and viral CCAAT box M00008 252. .243(91) SpI stimulating protein 1 1323..1314(91) M00227 933..941(90) v-Myb Iv-Myb M00141 1328..1320(90) Lyf- I LyF-1 MOO] 83 1033..1042(90) c-Myb Ic-Myb M00001 654. .665(90) MyoD myoblast determination gene product M00188 1792..1802(90) A-P-1 activator protein 1 M00184 23..14(90) MyoD myoblast determining factor M00172 1792..1802(90) A-P-1 activator protein 1 M00221 1864..1854(90) SRIEBP-1 sterol regulatory element-binding protein I M00037 871..861(90) NF-E2 NF-E2 M00053 1261..1252(90) c-Rel c-Rel M00249 823. .835(90) CHOP- heterodimers of CHOP and C/EBPalpha C/EBPalph a M00302 1248..1259(90) 1NF-AT Nuclear factor of activated T-cells WO 03/072724 PCT/US03/05338 -37- Table 15, putative transcription factor binding motifs within the DUB regulatory or promoter, region of hDIJB 8.3. The position is indicated by nucleotides.

Trausfac Position(Score) Name Description M00348 71..80(100) GATA-2 GATA-binding factor 2 M00349 71..80(100) GATA-2 GATA-binding factor 2 MOO0148 990..984(100) SRY sex-determining region Y gene product 1654..1648(100) 813..807(96) 917..911(96) 1848..1854(92) 1840..1846(92) 1826..1832(92) 1504..1498(92) 139 1..1397(90) 680..686(90) 2094..2088(90) 368..362(90) 721..715(90) 1002. .996(90) 1900..1894(90) M00350 71..80(100) GATA-3 GATA-binding factor 3 M00100 595..589(100) CdxA CdxA M00101 595..589(99) CdxA CdxA 1400..1394(99) 803..797(98) 1527.. 1521(98) 1705.. 1711(92) 699 693 (92) 934..940(92) 43. .37(92) 495 501(92) 1397..403(92) M00141 1274.. 1266(98) Lyf-1 LyF-1 M00347 71..80(97) GATA-1I GATA-binding factor 1 M00272 1563..1572(96) p53 tumor suppressor p53 M00253 1128..1135(96) 136.. 143(96) 2064..2071(95) 457 464(95) 2 163. .2156(95) 721..728(94) 660..653(94) 1782..1775(92) 312..319(92) cap signal for transcription initiation WO 03/072724 WO 03172724PCT/US03/05338 1622..1615(91) 535..542(91) 2085..2078(9 1) 2 147. .2 140(9 1) 1350..1357(91) 768..775(90) 295..302(90) M00285 2004..2016(95) TCF11 TCF 11 /KCR-F I Nrfl homodimers 1410..1422(91) M00254 2101..2090(95) CCAAT cellular and viral CCAAT box M00130 1647..1658(95) HFH-2 KNF-3/Fkh Homolog 2 M00054 442..433(95) NF-kappaB NE-kappaB M00077 2203..221 1(95) GATA-3 GATA-binding factor 3 M00052 442..433(94) NF-kappaB NF-kappaB M00203 73. .83(94) GATA-X GATA binding site MOO 199 2067..2059(94) AP-i AP- I binding site 2059..2067(91) 1984..1992(90) M00174 2058..2068(94) NP-i activator protein 1 M00075 895..886(94) GATA-1 GATA-binding factor 1 2159..2168(93) 1082..1073(93) 1971..1962(92) 2006..2015(90) M00053 442..433(94) c-Rel c-Rel M00241 2070. .2077(94) Nkx-2.5 homeo domain factor Nkx-2.5/Csx, tinman ________homolog M00076 716..707(94) GATA-2 GATA-binding factor 2 1599.. 1608(92) 7..966(92) 895..886(91) 1971..1962(91) MOO 106 627..636(94) CDP cut-like homeodomain protein M00033 731..718(94) p300 p 30 0 M00227 2139..2131(94) v-Myb v-Myb MOO0158 295..282(93) COUP-IF COIJP/HNF-4 heterodimer MOO0162 2070. .2083(93) Oct-i octamer-binding factor 1 MOO0134 280..298(93) HNF-4 hepatic nuclear factor 4 M00032 226..235(93) c-Ets-1(p54) c-Ets-l(p54) MOO 117 1080..1067(92) C/EBPbeta CCAAT/enhancer binding protein beta M00223 520.. 512(92) STATx signal transducers and activators of transcription M00042 1901..1892(92) Sox-5 622..631(91) M00073 13..23(92) deltaEFi deltaEFlI M00099 2083..2068(91) S8 S8 2066..2081(90) 1424(90) WO 03/072724 WO 03/72724PCT/US03/05338 M00299 1647.1659(911 HFH-3 HNF-3/Fkh Homolog 3 Freac-6) 1647..1659(91) 357..369(91) MOO0147 752..743(91) HSF2 heat shock factor 2 142.. 133(90) M00208 443..432(90) NF-ka-ppaB NF-kappaB binding site M00217 115.. 108(90) USF USF binding site M00183 1325..1334(90) c-Myb c-Myb M00240 217..21 1(90) Nkx-2.5 homeo domain factor Nkx-2.5/Csx, tinman M00188 2058..2068(90) AP-1 activator protein 1 M00184 1955..1964(90) MyoD) myoblast determining factor 247..256(90) M00087 954..965(90) Tk-2 Ikaros 2 M00128 70..82(90) GATA-1 GATA-binding factor I M00172 2058..2068(90) AP-1 activator protein 1 M00145 1339..1354(90) Bmn-2 POU factor Bmn-2 M00062 1217..1205(90) IRF-1 in terferon regulatory factor I M001 94 1444..431(90) 1NF-kappaB INF-kappaB Table 16, putative transcription factor binding motifs within the DUB regulatory or promoter, region of hDIJB 8.4. The position is indicated by nucleotides.

Transfac Position(Score) Name Description MOO100 1105..1099(100) CdxA CdxA M00241 1800..1807(100) Nkx-2.5 homeo domain factor Nkx-2.5ICsx, tinman M00148 1020..1014(100) SRY sex-determining region Y gene product 970..976(100) 947..941(96) 1550..1556(92) 843 837(90) 707..713(90) 1362..1356(90) 1719..1713(90) 1824..1818(90) 395..389(90) 748..742(90) 3 00. .306(90) M-RO 0l10 1105..1099(99) CdxA CdxA 833. .827(98) 1385..1379(98) 1409.. 1415(92) 964. .970(92) 726. .720(92) .430(92) M 0075 183 1847(97) 1889.1898(93) GATA-1 GATA-binding factor 1 WO 03/072724 WO (3107724PCTIUS03/05338 925..916(93) 1745(90) M00272 1267.. 1276(96) p53 tumor suppressor p53 M00253 161.. 168(96) cap cap signal for transcription initiation 1794..1801(95) 484..491(95) 1893 1886(95) 1452..1459(94)- 798..805(94) 748..755(94) 957..964(94) 1486..1479(92) 338..345(92) 1697..1704(92) 562..569(91)_ 1877..1870(91) 1815..1808(90) 321. .328(90) 1326.. 13 19(90) M00096 1827..1819(96) Pbx-1I Pbx-1 M00285 1734..1746(95) TCFI1 TCFI I/KCR-F1/Nrfl homodimers M00077 1933.. 1941(95) GATA-3 GATA-binding factor 3 M00054 469..460(95) NF-kappaB KF-kappaB M00141 456..464(94) Lyf-1 LyE-I MOO0134 306..324(94) HNF-4 hepatic nuclear factor 4 M00052 469. .460(94) NF-kappaB NE-kappaB M00199 1797..1789(94) AP-1 AP-1 binding site M00174 1788..1798(94) AP-1 activator protein 1 M00053 469..460(94) c-Rel c-Rel M00033 758..745(94) p1300 p1300 808..795(92) MOO0158 321..308(93) COIJP-TF COUP/HNF-4 heterodimer M00278 1933..1941(93) Lmo2 complex of Lmo2 bound to Tal-l1, E2A and GATA- 1, half-site 2 M00076 1932..1941(93) GATA-2 GATA-binding factor 2 1303..1312(92) 743.,734(92) 987. .996(92) 925. .9 16(90) M00099 1813..1798(92) S8 S8 MOO0104 28..37(92) CDP cut-like homeodornain protein M00223 547.. 539(92) STATx signal transducers and activators of it tanscription M00271 1955..1960(92) AML-la Irunt-factor AML-1 WO 03/072724 WO (3107724PCT/US03/05338 M00254 1831..1820(91) CCAAT cellular and viral CCAAT box M00042 649..658(91) Sox-5 M00289 384..396(91) HFH-3 HNF-3/Fkh Homolog 3 Freac-6) M00302 1384..1395(91) NE-AT Nuclear factor of activated T-cells M00155 367..382(91) AIRP-l apolipoprotein Al regulatory protein 1 M00208 470. .459(90) NF-kappaB NE-kappaB binding site M00183 1030.. 1039(90) c-Myb c-Myb M00240 243. .237(90) Nkx-2.5 homeo domain factor Nkx-2.5/Csx, tinman homolog 11454.. 1448(90) M00188 1788.. 1798(90) AP- I activator protein 1 M00083 47..40(90) MZF1 MZF1 MOO0184 273..282(90) MyoD) myoblast determining factor MOO0147 167.. 15 8(90) HSF2 heat shock factor 2 M00087 984..995(90) Ik-2 Ikaros 2 M00172 1788..1798(90) AP- 1 activator protein 1 M00221 1860..1850(90) _SREBP-1 sterol regulatory element-binding protein 1 M00194 471..458(90) NF-kappaB NE-kappaB Table 17, putative transcription factor binding motifs within the DUB regulatory or promoter, region of hDUB 8.5. The position is indicated by nucleotides.

Transfac Position(Score) Name Description M00100 1105..1099(100) CdxA CdxA M00241 1800..1807(100) Nkx-2.5 homeo domain factor Nkx-2.5/Csx, tinman ______homolog M00271 27..32(100) AML-la runt-factor AML- 1 1955.. 1960(92) M00148 1020.. 10 14(100) SRY sex-determining region Y gene product 970..976(100) 947..941(96) 1553 155992 100..106(92) 141..135(90) 843..837(90) 1365..1359(90) 1719.. 1713(90) 1824.. 1818(90) M00l0I 1105.. 1099(99) 833 827(98) 1234.. 1228(98) 1388.. 13 82(98) 1300.. 1294(93) 1412.. 1418(92) 964..970(92) 1682.. 1688(91) CdxA lCdxA WO 03/072724 WO 03/72724PCT/US03/05338 1682(9 1) M00278 618..610(98) Lmo2 complex of Lmo2 bound to TaT-i, E2A proteins, GATA- 1, half-site 2 M00075 1838..1847(97) GATA- 1 GATA-binding factor 1 619..610(97) 1701..1692(95) 1889..1898(93) 903..894(91) 1736..1745(90) M00054 442..45t(96) NE- NF-kappaB kappaB M00253 175.. 168(96) cap cap signal for transcription initiation 1794..1801(95) 1893..1886(95) 1455..1462(94) 798..805(94) 629..636(94) 1489.. 1482(92) 433..426(92) 1329.. 1322(91) 1877.. 1870(91) 921..928(91) 957. .964(90) 1815..1808(90) 1302.. 1309(90) M00272 1270..1279(96) p53 tumor suppressor p53 M00096 1827..1819(96) Pbx-1 Pbx-1 M00285 1734..1746(95) TCFI I TCF11/KCR-F1/Nrf1 homodimers 1115..1127(91) 1490..1478(91) M00076 619..610(95) GATA-2 GATA-binding factor 2 1932..1941(93) 1701..1692(92) 1306..,13 15(92) 987. .996(92) M00077 1933.. 1941(95) GATA-3 GATA-binding factor 3 .6 10(92) M00199 1797.. 1789(94) AP-1 AP-1I binding site 1797(91) M00174 1788..1798(94) AP-1I activator protein I M00083 566..559(93) MZF1 MZFI M00099 1813..1798(92) S8 S8 1114..1129(90) M00208 441. .452(92) NE- NE-kappaB binding site kappaB M00033 808. .795(92) p300 p 30 0 WO 03/072724 WO 03/72724PCT/US03/05338 M00227 1677,.1669(91) v-Myb v-Myb M00254 1831..1820(91) CCAAT cellular and viral CCAAT box M00183 166..157(91) c-Myb c-Myb 1030..1039(90) 1400267 102..89(91) XFD-l Xenopus fork head domain factor 1 M400240 1457..1451(90) Nkx-2.5 borneo domain factor Nkx-2.5/Csx, tinman homolog 296..302(90) M400188 1788..1798(90) A-P-1 activator protein 1 1400302 841..830(90) NE-AT Nuclear factor of activated T-cells M00087 984..995(90) Jk-2 Ikaros 2 M400172 1788..1798(90) A-P-I jactivator protein 1 M400003 965..956(90) v-Myb v-Myb M400221 1860..1850(90) SR-EBP-1 sterol regulatory elemnent-binding protein 1 1400053 441 450(90) c-Re1 c-Rel Table 18 putative transcription factor binding motifs within the DUB regulatory or promoter, region of hDUB 8.6. The position is indicated by nucleotides.

Transfac Position(Score) Name Description 1400100 1105..1099(100) CdxA CdxA 1400241 1800..1807(100) Nkx-2.5 homeo domain factor Nkx-2.5/Csx, tinman 1400148 1020..1014(100) SRY sex-determnining region Y gene product 970..976(100) 947..941(96) 1550.. 1556(92) 843 837(90) 707..713(90) 1362..1356 9 1719..1713(90) 1824..1818(90) 395..389(90) 748..742(90) M0OIOI 1105..1099(99) CdxA CdxA 833..827(98) 1385 1379(98) 1409.. 1415(92) 964..970(92) 726..720(92) M00075 1838..1847(97) GATA-1I GATA-binding factor 1 1889..1898(93) 925..916(93) 140072 167.16() p 53 Itumor suppressor p53 WO 03/072724 WO 03/72724PCT/US03/05338 M00253 161..168(96) 1794..1801(95) 484-491(95) 1893..1886(95) 1452.. 1459(94) 798..805(94) 748..755(94) 957..964(94) 1486.. 1479(92) 338..345(92) 1697..1704(92) 562..569(91) 1877..1870(91) 1815..1808(90) 321..328(90) 1326..1319(90) 1299..1306(90) cap cap signal for transcription initiation M00096 1827..1819(96) Pbx- 1 Pbx-1 M00285 1734..1746(95) TCF1 1 TCF 11/KCR-F 1/Nrfl homodimers 1115..1127(91) M00077 1933.. 1941(95) GATA-3 GATA-binding factor 3 M00054 469..460(95) N-F-kappaB N-F-kappaB M00141 456.-464(94) Lyf-1 LyF-1 _M00134 306..324(94) HNF-4 -hepatic nuclear factor 4 M00052 469. .460(94) N-F-kappaB NF-kappaB M00199 1797.. 1789(94) AP-1 AP-1 binding site MOO0174 1788..1798(94) AP- 1 activator protein 1 M00053 469..460(94) c-Rel c-Rel M00033 758..745(94) p1300 p300 795(92) M00158 321..308(93) COUP-TF COUP/HN F-4 heterodimer M00278 1933..1941(93) Lmo2 complex of Lmo2 bound to Tal-1, E2A proteins, and GATA- 1, half-site 2 M00076 1932..1941(93) GZATA-2 GATA-binding factor 2 1303..1312(92) 743. .734(92) 987. .996(92) 925..916(90) M00099 1813..1798(92) S8 S8 1114..1129(90) MOO0104 28..37(92) CDP cut-like homeodomain protein M00223 547. .539(92) STATx signal transducers and activators of __________transcription M00271 1955..1960(92) AML-lIa runt-factor AM/L-1I M00254 183 1..1820(91) CCAAT cellular and viral CCAAT box M00042 649. .658(91) Sox-5 M029 384. .396(91) HFH-3 HNF-3/Fkh Homolog 3 Freac-6) WO 03/072724 WO 03/72724PCT/US03/05338 M00302 1384.. 1395(9 1) NF-AT Nuclear factor of activated T-cells 841..830(90) M00155 367..382(91) ARMP- apolipoprotein Al regulatory protein 1_ M00208 470..459(90) i±-ap~pa NV-kappaB binding site M00183 1030..1039(90) c-Myb c-Myb M00240 243..237(90) Nkx-2.5 homeo domain factor Nkx-2.5/Csx, tinman homolog 1454.. 1448(90) M00188 1788..1798(90) AP-1 activator protein 1 M00083 47..40(90) MZF1 MZF1 M00184 273..282(90) MyoD) myoblast determining factor M00147 167-158(90) HSF2 heat shock factor 2 M00087 984. .995(90) Jk-2 Ikaros 2 M00172 1788..1798(90) AP-lI activator protein 1 M00221 1860.. 1850(90) SREBP-1 1sterol regulatory element-binding protein 1 M0094471 458(90) 1NF-kappaB INF-kappaB Table 19, putative transcription factor binding motifs within the DUB regulatory or promoter, region of hDUIB 8.7. The position is indicated by nucleotides.

Transfac Position(Score) Name Description M00349 94..103(100) GATA-2 GATA-binding factor 2 M00348 94..103(100) GATA-2 GATA-binding factor 2 M00241 1800..1807(100) Nkx-2.5 homeo domain factor Nkx-2.5ICsx, tinman homolog MOOI100 1102..1096(100) CdxA CdxA M00148 1017.. 1011(100) SRY sex-determining region Y gene product 967. .973( 100) 704..710(1 00) 944. .938(96) 1550..1556(92) 840. .834(90) 1362.. 1356(90) 17 19.. 1713(90 1824.. 1818(90) 392- 386(90) 745..739(90) 298..304(90) M00350 194.. 103(100) GATA-3 IGATA-binding factor 3 M00I0I 1102..1096(99) 830. .824(98) 1231.. 1225(98) 1385.. 1379(98) 1297..1291(93) 1409.. 141 5(92) 723..717(92) 961..967(92) CdxA CdxA WO 03/072724 WO 03/72724PCT/US03/05338 66. .60(92) 421..427(92) 1682..1688(91) M00203 96.. 106(98) GATA-X GATA binding site M00347 94.. 103(97) GATA-1 GATA-binding factor I M00075 1838.. 1847(97) GATA-1 GATA-binding factor 1 1701.. 1692(95) 1889..1898(93) 900..891(91) 138 129(90) M00158 319..306(96) COUP-TF COUP/IINF-4 heterodimer M00272 1267.. 1276(96) p 53 tumor suppressor p53 MOO0134 304..322(96) HNF-4 hepatic nuclear factor 4 M00096 1827..1819(96) Pbx-1 Pbx-1I M00285 1734.. 1746(95) TCF1 1 TCF IIfKCR-F I/Nrfl homodimners M00077 1933.. 1941(95) GATA-3 GATA-binding factor 3 M00253 1794.. 180 1(95) cap cap signal for transcniption initiation M 0 48466.458(95) NFapBN-apa M00146 1653.16(9) HF etsokfco M00141 453..41(94) Ly- LE- 795546.4572(94) NFkpa N-kpB(p) 6569 19..799) A- 1bnigst 159..19(91) M00 ~74518..72(9) A- ciao rti M00054 466..457(94) cF-Relp Nc-elp M0017 196..156949) Lmo2 coe okfaco Lm2bontoT ,E2preis and6ATA.,6hlf-ste) WO 03/072724 WO 03/72724PCT11JS03/05338 M00076 1932..1941(93) GATA-2 GATA-binding factor 2 1701..1692(92) 1303..1312(92) 984..993(92) M00099 1813..1798(92) S8 S8 1111..1126(90) M00184 271..280(92) MyoD myoblast determining factor M00223 544..536(92) STA~x signal transducers and activators of transcription M00073 36..46(92) deltaEFl1 deltaEFlI M00033 805..792(92) p300 p300 M00271 1955..1960(92) AML-la runt-factor AML-1 M00254 183 1..1820(91) CCAAT cellular and viral CCAAT box M00277 281..270(91) Lmo2 complex of Lmo2 bound to Tal-1, E2A proteins, GATA- 1, half-site 1 M00289 391 393(91) HFH-3 HNF-3/Fkh Homolog 3 Freac-6) M00208 467..456(90) NF-kappaB NF-kappaB binding site M00183 1027..1036(90) c-Myb c-Myb M00240 241 235(90) Nkx-2.5 homeo domain factor Nkx-2.5/Csx, tinman 1448(90) M00188 1788..1798(90) AP-1 -activator protein 1 M00302 838..827(90) NF-AT Nuclear factor of activated T-cells M00128 93.. 105(90) GATA-1 GATA-binding factor 1 M0008'7 981..992(90) Jk-2 Ikaros 2 M00172 1788..1798(90) AP-1 activator protein 1 M00042 69..78(90) o- M000 96..953(90) v-Myb v-Myb M00221 1860..1850(90) SREBP-1 sterol regulatory element-binding protein 1 M00194 468..455(90) NF-kappaB NF-kappaB Table 20, putative transcription factor binding motifs within the DUIB regulatory or promoter, region of hDUB 8.8. The position is indicated by nucleotides.

Transfac Position(Score) Name Description M00148 1020..1014(100) SRY sex-determining region Y~gene product 970..976(100) 947..941(96) 1550..1556(92) 843..837(90) 707..713(90) 1362.. 1356(90) 1719..1713(90) 1824..1818(90) 395..389(90) 748. .742(90) M02 13100..0(00) Nkx-2.5 homeo domain factor Nkx-2.5/Csx, tinman WO 03/072724 WO 03/72724PCT/tTS03/05338 M00100 1105..1099(100) CdxA CdxA M00101 1105..1099(99) CdxA CdxA 833..827(98) 1385..1379(98) 1409.. 1415(92) 964.. 970(92) 726..720(92) M00075 1838.. 1847(97) GATA-1 GATA-binding factor 1 1889.. 1898(93) 925 916(93) 1745(90) M00272 1267.. 1276(96) p53 tumor suppressor p53 M00253 161..168(96) cap cap signal for transcription initiation 1794..1801(95) 484..491(95) 1893..1886(95) 1452.. 1459(94) 798 805(94) 748..755(94) 957..964(94) 1486.. 1479(92) 338.,345(92) 1697..1704(92) 562..569(91) 1877..1870(91) 1815..1808(90) 321..328(90) 1326..1319(90) M00096 1827..1819(96) Pbx-1 Pbx-lI M00285 1734..1746(95) TCFI TCFI1/KGR-F1/Nrfl homodimers M00077 1933..1941(95) GATA-3 GATA-binding factor 3 M00054 469..460(95) NIF-kappaB NF-kappaB M00141 456..464(94) Lyf-1I LyF-1 MOO0134 306..324(94) HNF-4 hepatic nuclear factor 4 M00052 469. .460(94) NF-kappaB NF-kappaB (p 6 M00199 1797..1789(94) AP-1 AP-1 binding site 1789..1797(91) M0174 1788..1798(94) AP-1 activator protein 1 M00053 469..460(94) c-Rcl c-Rel 1\00033 758..745(94) p300 p130 0 M00158 321..308(93) COUP-TF COUPIHNF-4 heterodimer M00278 1933..1941(93) Lmo2 complex of Lmo2 bound to Tal-1, E2A proteins, 1,_half-site_2 WO 03/072724 WO 03172724PCTIUS03/05338 M00076 1932.. 1941(93) GATA-2 GATA-binding factor 2 1303..13 12(92) 743..734(92) M00099 1813..1798(92) SS S8 M0004 28..37(92) CDP cut-like homeodomain protein M00223 547..539(92) STATx signal transducers and activators of transcription M00271 1955.. 1960(92) AML-la runt-factor AML-1I M00254 183 1..1820(91) CCAAT cellular and viral CCAAT box M00042 649..658(91) Sox-5 M00289 384.,396(91) HFH-3 HNF-3/Fkh Homolog 3 Freac-6) M00302 1384..1395(91) NE-AT Nuclear factor of activated T-cells 841..830(90) M00155 367..382(91) ARP-1 apolipoprotein Al regulatory protein 1 M00208 470..459(90) NE-kappaB NF-kappaB binding site M00183 1030..1039(90) c-Myb c-Myb M00240 243.,237(90) Nkx-2.5 homeo domain factor Nkx-2.5/Csx, tinman homolog 1454.. 1448(90) M00188 1788..1798(90) AP-1 activator protein I M00083 47..40(90) MZF1 MZF1 M00184 273..282(90) MyoD myoblast determining factor MOO0147 167.. 158(90) HSF2 heat shock factor 2 MOO0172 1788..1798(90) AP-1 activator protein 1 M00221 1860..1850(90) SREBP-1 sterol regulatory element-binding protein 1 M00194 1471..458(90) NIF-kappaB NE-kappaB Table 21, putative transcription factor binding motifs within the DUB regulatory or promoter, region of hDUB 8.9. The position is indicated by nucleotides.

Transfac Position(Score) Name Description MOO0148 991..997(100) SKY sex-determining region Y gene product 1040.. 1034(100) 967..961(96) 1576.. 15 82(92) 1550..1556(92) 13 85 1379(90) 1824.. 18 18(90) 13 19(90) 415..409(90) 727. .733(90) MO0l0l 1125..1119(100) 1254.. 1248(98) 1167..1161(97) 542. .548(97) 884. .878(94) CdxA CdxA WO 03/072724 WO 03172724PCT/US03/05338 1432.. 1438(93) 743. .737(92) 89..83(92) 592..586(92) 1280..1286(92) 444. .450(92) 1682..1688(91) 1682(91) M00083 779..772(100) MZF1 MZFI 68..61(90) M00241 1800.. 1807(100) Nkx-2.5 homeo domain factor Nkx-2.5/Csx, tinman homolog M00272 1290.. 1299(96) p 53 tumor suppressor p53 M00253 182.. 189(96) cap cap signal for transcription initiation 1794.. 1801(95) 1893.. 1886(95) 1475.. 1482(94) 768. .775(94) 1506.. 1499(93) 1349.. 1342(91) 582. .5 89(9 1) 351. .358(90) 1815.. 1808(90) 342. .349(90) 1877.. 1870(90) 504. .5 11(90) 1329(90) MOOLOO 1125..1119(96) CdxA CdxA M00042 742..751(96) Sox-5 669. .678(92) .735(92) M00096 1827..1819(96) Pbx-1 Pbx-1I M00077 1933.. 1941(95) GATA-3 GATA-binding factor 3 M00045 1877.. 1888(95) E4BP4 E4BP4 M00054 489. .480(95) NF-kappaB N F -la p paaB M00141 476. .484(94) Lyf-1 LyF-1 M00052 489. .480(94) NF-kappaB NF-kappaB M00199 1797.. 1789(94) AP-I AP-1 binding site 1789.. 1797(91) M00174 1788.. 1798(94) AP-1t activator protein 1 M00053 489. .480(94) -c-Rel c-Rel M00278 1933..1941(93) Lmo2 complex of Lmo2 bound to Tal-1, E2A proteins, GATA-1, half-site 2 M00076 1932.. 1941(93) GATA-2 GATA-binding factor 2 1007.. 1016(92) 1701 1692(91) M0R02 85 1734..1746(92) TCF1 I TCF11/KCR-Ft/Nrfl homodimers 11 35..1147(91)t WO 03/072724 WO 03/72724PCT11TS03/05338 M00099 1813,.1798(92) S8 S8 1134..1149(90 M00104 49..58(92) CDP cut-like homeodomain protein M00223 567..559(92) STATx signal transducers and activators of transcription M00075 1701.. 1692(92) GATA-1 GATA-binding factor 1 161.. 152(90) 1736.. 1745(90) M00348 316.. 32 5(92) GATA-2 GATA-binding factor 2 M00109 873..886(91) C/EBPbeta CCAAT/enhancer binding protein beta M00254 1831.. 1820(9 1) CCAAT cellular and viral CCAAT box M00203 318..328(91) GATA-X GATA binding site M00350 1316..325(91) GATA-3 GATA-binding factor 3 M00289 404..416(91) HFH-3 -NF-3/Fkh Homolog 3 Freac-6) MOOl 113 833..822(90) CREB cAMP-responsive element binding protein M00249 1 t65.. 1153(90) CHOP- heterodimers of CHOP and C/EBPalpha C/EBPalpha.

M00208 490. .479(90) NF-kappaB NF-kappaB binding site M00190 1263.. 1250(90) C/EBP CCAAT/enhancer binding factor M00349 316.. 325(90) GATA-2 GATA-binding factor 2 M001 16 1263.. 1250(90) C/EBPalpha CCAAT/enhancer binding protein alpha M00183 1050.. 1059(90) c-Myb c-Myb M00240 263..257(90) Nkx-2.5 homeo domain factor Nkx-2.5/Csx, tinman ________homolog 1471(90) M001 88 1788..1798(90) AP-1 activator protein 1 M00302 1407..1418(90) NF-AT Nuclear factor of activated T-cells M001 84 293 302(90) MyoD) myoblast determining factor MOO0147 188.. 179(90) HSF2 heat shock factor 2 M00087 1004.. 1015(90) Ik-2 Ikaros 2 MOO0172 1788..1798(90) AP-1 activator protein 1 M00221 1860..1 850(90) SREBP-1 sterol regulatory element-binding protein I M00033 778..765(90) p300 p 3 00 M014491..478(90) 1NF-kappaB INF-kappaB Table 22, putative transcription factor binding motifs within the DUB regulatory or promoter, region of hDUB 8. 10. The position is indicated by nucleotides.

Trans fac I Position(Score) f Name IDescription M00148 103 8. .1032(100) 965. .959(96) 1550..1556(92) 725..731(90) 1382..1376(90) 3 10. .3 16(90) 1715..1709(90) 1824..1818(90) 12..18(90) SRY sex-determining region Y gene product WO 03/072724 WO 03/72724PCT/US03/05338 413..407(90) 1630..1624(90) 319..325(90) M00241 1800..1807(100) Nkx-2.5 homeo domain factor N-kx-2.5/Csx, tinman homolog MOO100 1123..1117(100) CdxA CdxA M00240 1240..1234(100) Nkx-2.5 homeo domain factor Nkx-2.5/Csx, tinnian homolog 262..256(90) M00141 474..482(100) Lyf-I LyF-1 M00101 1123..1117(99) CdxA CdxA 540. .546(97)_ 1429.. 1435(94) 982..988(92) 88..82(92) 741..735(92) 442. .448(92) M00075 1838..1847(97) GATA- I GATA-binding factor 1 1889..1898(93) 1736..1745(90) M00253 766..773(96) cap cap signal for traniscription initiation 181..188(96) 1794..1801(95) 1893..1886(95) 1210.. 1217(94) 816..823(94) 1506.. 1499(92) 357..364(92) 1697..1704(92) 1090..1097(91) 1346.. 1339(91) 1877..1870(91) 71..78(90) 580. .587(90) 1815..1808(90) 340. .347(90) 502. .509(90) _______1319..1326(90) M00096 1827..1819(96) Pbx-1 Pbx-1I M00285 1734..1746(95) TCFI I TCFI1IKCR-F1/Nrfl homodimers 1133 1145(91) 35..23(91) _______1089..1101(90) -M00134 325..343(94) HNF-4 hepatic nuclear factor 4 M00199 1797..1789(94) API1 AP-1 binding site M00174 1788..1798(94) AP-1 activator protein 1 M00042 740..749(94) Sox-5 WO 03/072724 WO 03172724PCTIUS03/05338 1631..1622(92) 667. .676(91) MOO 106 672..681(94) CDP cut-like homeodomain protein M00158 340..327(93) COIJP-TF COUP/HINE-4 heterodimer M00076 761..752(93) GATA-2 GATA-binding factor 2 1323..1332(92) 1005.. 10 14(92) M00099 1813..1798(92) S8 S8 1132..1147(90) MOO 104 48..57(92) CDP cut-like homeodomain protein M00223 565..557(92) STATx signal transducers and activators of transcription M00033 826..813(92) p300 p300 M00271 1955..1960(92) AJYL-la runt-factor AML-1I M00254 183 1..1820(91) CCAAT cellular and viral CCAAT box M00289 402..414(91) HFH-3 HNF-3/Fkh Homolog 3 Freac-6) M00217 160..153(90) USF USF binding site M00183 1048..1057(90) c-Myb c-Myb M00188 1788..1798(90) AP-1 activator protein 1 M00083 67..60(90) MZF1 MZF1 MOO 184 292..301(90) MyoD myoblast determining factor M00147 187.. 178(90) HSF2 heat shock factor 2 M00087 1002..1013(90) Ik-2 Ikaros 2 MOO0172 1788..1798(90) AP- t activator protein 1 M00O221 1 860..1850(90) SREBP-1 sterol regulatory -element-binding protein 1 Table 23, putative transcription factor binding motifs within the DUB regulatory or promoter, region of hDUJB 8. 11. The position is indicated by nucleotides.

Transfac Position(Score) Name Description M00348 71..80(100) GATA-2 GATA-binding factor 2 M00350 71..80(100) GATA-3 GATA-binding factor 3 M00349 71..80(100) GATA-2 GATA-binding factor 2 MOO0148 990..984(100) 1664..1658(100) 813..807(96) 917..911(96) 1858..1864(92) 1850..1856(92) 1836..1842(92) 1399.. 1405(90) 1514..1508(90) 680..686(90) 2104..2098(90) 368..362(90) 721.,715(90) 1002..996(90) SRY sex-determining region Y gene product WO 03/072724 WO 03/72724PCTUS03/05338 1910..1904(90) .280(90) MOO100 595..589(100) CdxA CdxA 1408..1402(100) M00101 595..589(99) CdxA CdxA 1408..1402(99) 803..797(98) 1537..1531(98) 1715..1721(92) 699..693(92) 934.. 940(92) 43..37(92) M00141 1282..1274(98) Lyf-1 LyF-1I M00347 71..80(97) GATA-1 GATA-binding factor I M00272 1573..1582(96) p53 tumor suppressor p53 M00253 1137..1144(96) cap cap signal for transcription initiation 136.. 143(96) 2074. .208 1(95) 457..464(95) 2173..2166(95) 721-.728(94) 1444..1437(94) 660..653(94) 1792..1785(92) 312..319(92) 1632..1625(91) 535..542(91) 2095..2088(91) 1358..1365(91) 768 775(90) 295..302(90) .2150(90) M00096 2107..2099(96) Pbx-1 Pbx-1I M00285 2014..2026(95) TCF11 TCF11IKCR-FI/Nrfl homodimers 1418.. 1430(9 1) M00130 1657..1668(95) HFH-2 HMF-3/Fkh Homolog 2 M00077 221 3..2221 (95) GATA-3 GATA-binding factor 3 M00O054 442..433(95) NE-kappaB NF-kappaB M00052 442..433(94) NE-kappaB NIF-kappaB M00203 73. .83(94) GATA-X GATA binding site M00199 2077. .2069(94) AP-1 AP-1 binding site 2069..2077(91) 1994. M 00174 2068..2078(94) AP-1I activator protein 1 1436.. 1446(90) M00075 1895..886(94) GATA- I GATA-binding factor 1 WO 03/072724 WO 03172724PCT/US03/05338 2169..2178(93) 109 1..1082(93) 1981..1972(92) M00053 442..433(94) c-ReT c-Rel M00241 2080. .2087(94) Nkx-2.5 homeo domain factor Nkx-2.5/Csx, tinman M00076 716..707(94) GATA-2 GATA-binding factor 2 2212..2221(93) 1609..1618(92) 957..966(92) 895..886(91) 1981..1972(91) MOO0106 627..636(94) CDP cut-like homeodomain protein M00033 731..718(94) p30 0 p 30 0 M00227 2149..2141(94) v-Myb v-Myb MO00158 295..282(93) COUP-TF COUIPfHNF-4 heterodimer MOO162 2080..2093(93) Oct- I octamer-binding factor 1 M00278 2213..222] (93) Lmo2 complex of Lmo2 bound to Tal-1, E2A proteins, and GATA-1, half-site 2 MOO 134 280..298(93) HNF-4 hepatic nuclear factor 4 M00032 226..235(93) c-Ets-1(p54) c-Ets-1 p54) MOO 172 1436..1446(92) API1 activator protein 1 MO0l117 1089..1076(92) C/EBPbeta CCAAT/enhancer binding protein beta M00223 520..512(92) STATx signal transducers and activators of transcription M00042 1911..1902(92)- Sox-5 622..63 1(9 1) M00073 13..23(92) deltaEFlI deltaEFl MOO188 1436..1446(91) AP- I activator protein 1 M00254 211 1..2100(91) CCAAT cellular and viral CCAAT box M00099 2093..2078(91) S8 S8 2076..2091(90) 1417.. 1432(90) M00289 1657..1669(91) HFH-3 HNF-3/Fkh Homolog 3 (Freac-6) 357..369(91) MOO0147 752..743(91) HSF2 heat shock factor 2 142.. 133(90) M00208 443..432(9O) NF-kappaB NF-kappaB binding site M00217 115..108(90) USF USE binding site M00183 1333..1342(90) c-Myb c-Myb M00173 1436..1446(90) AP-1I activator protein 1 M00O240 217..211(90) Nkx-2.5 homeo domain factor Nkx-2.5/Csx, tinman homolog M00184 1965..1974(90) MyoD myoblast determining factor 1_____247..256(90) M00087 1954..965(90) Ik-2 Tkaros 2 WO 03/072724 PCT/US03/05338 -56- M00128 70..82(90) GATA-1 GATA-binding factor 1 M00145 1347..1362(90) Bm-2 POU factor Brn-2 M00194 444..431(90) NF-kappaB NF-kappaB References: 1. Baek, K. Mondoux, M. Jaster, Fire-Levin, and D'Andrea, A. D. (2001).

DUB-2A, a new member of the DUB subfamily of hematopoietic deubiquitinating enzymes, Blood 98, 636-42.

2. Jaster, Baek, K. and D'Andrea, A. D. (1999). Analysis of cis-acting sequences and trans-acting factors regulating the interleukin-3 response element of the DUB-1 gene, Biochim Biophys Acta 1446, 308-16.

3. Jaster, Zhu, Pless, Bhattacharya, Mathey-Prevot, and D'Andrea, A. D.

(1997). JAK2 is required for induction of the murine DUB-1 gene, Mol Cell Biol 17, 3364-72.

4. Migone, T. Humbert, Rascle, Sanden, D'Andrea, Johnston, J. Baek, K. Mondoux, M. Jaster, Fire-Levin, et al. (2001). The deubiquitinating enzyme DUB-2 prolongs cytokine-induced signal transducers and activators of transcription activation and suppresses apoptosis following cytokine withdrawal, Blood 98, 1935-41.

Zhu, Carroll, Papa, F. Hochstrasser, and D'Andrea, A. D. (1996a). DUB-1, a deubiquitinating enzyme with growth-suppressing activity, Proc Natl Acad Sci U S A 93, 3275-9.

6. Zhu, Lambert, Corless, Copeland, N. Gilbert, D. Jenkins, N. and D'Andrea, A. D. (1997). DUB-2 is a member of a novel family of cytokine-inducible deubiquitinating enzymes, J Biol Chem 272, 51-7.

7. Zhu, Pless, Inhom, Mathey-Prevot, and D'Andrea, A. D. (1996b). The murine DUB-1 gene is specifically induced by the betac subunit ofinterleukin-3 receptor, Mol Cell Biol 16, 4808-17.

WO 03/072724 PCT/US03/05338 -57- Nucleotide sequence for hDUB4.l atgaccctgcaacagagcatgccctt ctgcat tgagcatgcaatcatgaatcacaggcggaggaactgcgagagt gcctacgttagcccaaggcctgacccgacgatcccaggga~cctcgactaactggccccgcctcccgggcccca aacccggactcggcccccccgaagctccggatcctggggcccgCCCCtggccccgcgtcggaagaCCatgggctc gctcctgggccttcctcaaaccctccgcagtccaggcccggcttcctccaggtctccaggcaacgctgCggctCC gcccacgtcatggcgcccgaggagaacgcggggacagaactctggctgcagggtttcgagcgccgcttcctggCq gcgcgctcactgcgctccttcccctggcaagcttagaggcaaagttaagagactcatcagattctgagctgctg cgggatattttgcagaagactgtgaagcatcccgtgtgtgtgaagcacccgccatcagtcaagtatgcccggtc tttctctcagaactcatcaaaaagggtgcatctgtggtaccagcagcacgagggctgtCCacacggagcctttg gacgagctgtacgaggtgctgcggagactctgatggccaaggagtccacccagggccaccggagctatttgctg cectcgggaggctcgttcacactttccgagatcacagccatcatctcccatggtactacaggcctggtcacatgg gacgccaccctctaccttgcagaatgggccatcgagaacccagcagccttcactaacagggtgtcctagagctt ggcagtggcgctggcctcacaggcctggccatctgcaagattgtcgcccccaggcatacatcttcagcgactgt cacagccgggtcctcgagcagctccgagggaatgtccttctcaatggcctctcattagaggcagacatcactgcc aacttagacgccccaggagaccacaggagaaaaacaaccacttctggacgaggacaggg~ccctgagaaaaggt ggtgtttggctgggccaccgaaaacccctcacccctgccagcacactcagtcccctctctggtggaacagagctc tgcctgtggccctgggtcccagccctgaaacccaaggtcagcggtggcagggacacaggcccacccctgcaa gccagcagaccaaacggcagacacctgaaacaagaagt tcacgacgtgctgtattgcccagaagccatcgtgtca ctggtcggggtcctgcggaggctggctgcctgccggagcacaagcaggctcctgaggtctacctggcctttacc gtccgcaacccagagacgtgccagctgttcaccaccgagctagagatagcgtctttctgcaacctgcgtcccag cagaaaaaccttgtgatccttgttccagtcgacatgaggacgactcactctacttgggaggtgagtggcagttc aaccttaacccttccgcgtcgttgtaacactctttcta aagtcaccactctcatgtgagacccgtgtcgacctctgtgatgatttggctcttggcaagacagcttgct~ccc agggagaagcctcctctgagtagcaggagacctgctgcggtgggggctgggctccagaatatgggaaatacctgc tacgtgaacgcttccctgcagtgcctgacatacaaaccgccacttgccaactacatgctgttccgggagcactct caaacgtgtcatcgtacaagggctgcatgctctgtactatgcaagctcacatcacaagggccctccacattcct ggccatgtcatccagccctcacaggcattggctgctggcttccatagaggcaagCaggaagatgcccatgaattt ctcatgttcacttgagccatgagaaaggcatgccttcccgggcacaagcaggtagatcgtcactctaaggac accaccctcatccaccaaatatttggaggctactggagatctcaaatcaagtgtctccactgccacggcatttca gacacttttgacccttacctggacatcgccctgatatccaggcagctcagagtgtccagcaagctttggaacag ttggtgaagcccgaagaactcaatggagayaatgcctatcattgtggtgtttgtctccagagggcgccggcctcc aagacgttaactttacacaactctgccaaggtcctcatccttgtattgaagagattccccgatgtcacaggcaac aaaattgccaagaatgtgcaatatcctgagtgccttgacatgcagccatacatgtctcagcagaacacagacct ctcgtctatgtcctctatgctgtgctggtccacgctgggtggagttgtcacaacggacattactcctcttatgtc aaagctcaagaaggccagtggtataaaatggatgatgccgaggtcaccgcctctagcatcacttctgtcctgagt caacaggcctacgtcctcttttacatccagaagagtgaatgggaaagacacagtgagagtgtgtcaagaggcagg gaaccaagagcccttgcgtagaagacacagacaggcgagcaacgcaaggaagctcaaaaaccacccc tgc ctccaggcccccgagttggacagcacttggtggaaagagccactcaggaaagcaccttagaccactggaaattc cttcaagagcaaaacaaaacgaagcctgagt tcaacgtcagaagagtcgaaggtacggtgcctcccgacgtactt gtgattcatcaatcaaaatacaagtgtcggatgaagaaccatcatcctgaacagcaaagctccctgctaaacctc tcttcgacgaccccgacagatcaggagtccatgaacactggcacactcgCttccctacgagggaggaccaggaga tccaaagggaagaacaaacacagcaagagggctctgcttgtgtgccagtga hDUB4.la deduced polypeptide seqluence MTLQQSMPFC IEHAIMNHRRRNCESAYVSPRPDPTIPGTLDLTGPASRAPNPDSAPPKLRILGPAPGPASEDHGL APGPS9NPPQSRPGFLQVSRQRCGSAflVMAPEENAGTELWLQGFERRFLAARSLRS

FPWQSLEAKLPDSSESELL

RDILQKTVKHPVCVKHPPSVKYARCFLSELT

KKGASVXTSSTRAVHTEPLDELYEVLAETLMAKESTQGHRSYLL

PSGGSFTLSEITAI ISHGTTGLVTVWDATLYLAEWAIENPAAFTNRGVLELGSGAGLTGLAICKMCRPQAYIFSDC HSRVLEQLRGNVLLNGLSLEADITANLDAPGDI{RRKTTTSGTRTGPLRKGGVWLGHRKPLTPASTLS

PLSGGTEL

CLPVAKTP-ADGPQSPGHKEVDLCEISVVRLARHQPVLF

VRNPETCQLFTTELE lAS FCNLRSQQKNLVI LVPVDMEDDSLYLGGEWQFNHFSKLTS SRPDAAFAE IQRTSLPE KSPLSCETRVDLCDDLAPVARQLAPREKPPLS SRRPAAVGAGLQNMGNTCYVNASLQCLTYKPPLANYMLFREHS QTCHRHKGCMLCTMQAHITRALHI PGHVIQPSQALAAGFHRGKQEDAHEFLMFTVDAMRKACLPGHKQVDRHSKD TTLIHQT FGGYWRSQIKCLHCHGISDTFDPYLDTALD)IQAAQSVQQALEQLVKPEELNGENAYHCGVCLQRAPAS KTLTLHNSAKVLILVLKRFPDVTGNKIAKNVQYPECLDMQPYMS QQNTGPLVYVLYAVLVHAGWSCHNGHYS SYV KAQEGQWYKMDDAEVTASS ITSVLSQQAYVLFYIQKSEWERHSESVSRGREPRALGVEDTDRRATQGELKRDHPC

LQAPELDEHLVEPATQESTLDHWKFLQEQNKTKPEFNVRRVEGTVPPDVLVIHQSKYKCRMKNHHPEQQSSLLNL

SSTTPTDQESMNTGTLASLRGRTRRSKGKNKHSKRALLVCQ

WO 03/072724 PCT/US03/05338 -58- Nucleotidc sequcnce for hDTJB4. lb atggaggacgactcactctacttgggaggtgagtggcagttcaaccacttLtcaaaactcacatCttctcggcca gatgcagcttttgctgaaatccagcgtacttctCtccctgagaagtcaccactctcatgtgagacccgtgtcgac ctctgtgatgatttggctcctgtggcaagacagcttgctcccagggagaagcctcctctgagtagcaggagacct gctgcggtgggggctgggctccagaatatgggaaatacctgctacgtgaacgcttccctgcagtgcctgacatac aaaccgccacttgccaactacatgctgttccyggagcactctcaaacgtgtcatcgtcacaagggctgcatgctc tgtactatgcaagctcacatcacaagggccctccacattcctggccatgtcatccagccctcacaggcattggct gctggcttccatagaggcaagcaggaagatgcccatgaatt tctcatgttcactgtggatgccatgagaaaqgca tgccttcccgggcacaagcaggtagatcgtcactctaaggacaccaccctcatccaccaaatatttggaggctac tggagatctcaaatcaagtgtctccactgccacggcatttcagacacttttgacccttacctggacatcgccctg gatatccaggcagctcagagtgtccagcaagctttggaacagttggtgaagcccgaagaactcaatggagagaat gcctatcattgtggtgtttgtctccagagggcgccggcctccaagacgttaactttacacaactctgccaaggtc ctcatccttgtattgaagagattccccgatgtcacaggcaacaaaattgccaagaatgtgcaatatcctgagtgc cttgacatigcagccatacatgtctcagcagaacacagga~cctctcgtctatgtcctctatgctgtgctggtccac gctgggtggagttgtcacaacggacattactcctcttatgtcaaagctcaagaaggccagtggtataaaatggat gatgccgaggtcaccgcctctagcatcacttctgtcctgagtcaacaggcctacgtcctcttttacatcCagaag agtgaatgggaaagacacagtgagagtgtgtcaagaggcagggaaccaagagcccttggcgtagaagacacagac aggcgagcaacgcaaggagagctcaagagagaccacccctgcctccaggcccccgagttggacagcacttggtg gaaagagccactcaggaaagcaccttagaccactggaaattccttcaagagcaaaacaaaacgaagcctgagttc aacgtcayaagagtcgaaggtacggtgcctcccgacgtact tgtgattcatcaatcaaaatacaagtgtcggatg aagaaccatcatcctgaacagcaaagctccctgctaaacctctcttcgacgacccgacagatcaggagtccatg aacactggcacac tcgcttccctacgagggaggaccaygagatccaaagggaagaacaaacacagcaagagggct ctgcttgtgtgccagtga hDT3B4.lb deduced polypeptide sequence MEDDSLYLGGEWQFNHFSKLTSSRPDAAFAEI QRTSLPEKS PLSCETRVDLCDDLAPVARQLAPREKPPLS SRRP

AVGAGLQNMGNTCYVNASLQCLTYKPPLANYMLFREHSQTCHRHKGCMLCTMQAHITRALHIPGHVIQPSQALA

AC.FHRGKQEDA1HEFLMFTVDAMRKACLPGHKQVDRHSKlTTLIHQI FGGYWRSQIKCLHCHGI SDTFDPYLD IAL DIQAAQSVQQALEQLVKPEELNGENAYHCGVCLQRAPASKTLTLHNSAKVL

ILVLKRFPDVTNKIAGNVQYPEC

LDMQPYMSQQNTGPLVYVLYAVLVHAGWSCHNGHYSSYVKAQEGQWYKMDDAEVTASS

ITSVLSQQAYVLFYIQK

SEWERHSESVSRGREPRALGVEDTDRRATQGELKRDHPCLQAPELDEHLVERATQESTLDHWKFLQEQNKTKPEF

NRRVEGTVPPDVLVIHQSKYKCRMKNHHPEQQSSLLNLSSTTTDQESMNTGTLASLRGRTRRSKGKNKESKRA

LLVCQ

Nucleotide sequence for hDUB4. 2a atgggaaatacctgctacgtgaacgcttccttgcagtgcctgacatacacaccgccccttgccaactacatgctg tcccgggagcactctcaaacgtgtcatcgtcacaagggctgcatgctctgtactatgcaagctcacatcacacyy gccctccacaatcctggccacgtcatccagcctcacaggcattggctgctggcttccatagaggcaagcaggaa gatgcccatgaatttctcatgttcactgtggatgccatgaaaaaggcatgccttcccaggcacaagcaggtagat catcactctaaggacaccaccctcatccaccaaatatttggaggctactggagatctcaaatcaagtgtctccac tgccacggcatttcagacacttttgacccttacctggacatcgccctgatat~caggcagCtcagagtgtCCag caagct ttggaacagttggtgaagcccgaagaactcaatggagagaatgcctatcattgtggtgtttgtctccag agggcgccggcctccaagacgttaactttacacacctctgccaaggtcctcatccttgtattgaagagattctCC gatgtcacaggcaacaagattgccaagaatgtgcaatatCctgagtgccttgacatgcagccatacatgtctcag cagaacacaggacctcttgtctatgtcctctatgctgtgctggccacgctgagtggagttgtcacaacggacat tact tc tcttatgtcaaagctcaagaaggccaqggtataaaatggatgatgccgaggtcaccgccgctagcatc acttctgtcctgagtcaacaggcctacgtcctcttttacatccagaagagtgaatgggaaagacatagtgagagt gtgtcaagaggcagggaaccaaga9c ccttggcgcagaagacacagacaggcgagcaacgcaaggagagctcaag agagaccacccctgcctccaggcccccgagttggacgagcacttggtggaaaagCCactcaggaaagcacctta gaccactggaaattccttcaagagcaaaacaaaacgaagcctgagttcaacgtcagaaaagtcaaaggtacagtg atcaaagttgaccagccccagaggaaagctgcccagggcacaactcagggctccgtagaaccacagaatcttggg cgcaaccctgctcaagcacccaaatgtgcatacgaaagggtctccgtgtgacggaacatgtccactttcggcag cattacaattttggcaccaaatgtgctaactgcaattccaccatacaatgcgtaactggaaatggaggcaacatc gc cgat cctgaacgatcgatgcgagaat~ccaggatatgcacggct tatt ttggcc ttt tcc cac tgaaacaaggg ccagtattaaaaatgcagaaaaaccttgtgatcctcgttccagtcgacatggaggacgactcactctacttga WO 03/072724 PCT/US03/05338 -59ggtgagtgqcagttcaaccacttttcaaaactcacatcttctcggcccgatgcagcttttgctgaaatccagcgg acttctctccctgaqaagtcaccactctcatgtgagacccgtgtcgacctctgtgatgatttggctcctgtggca agacagcttyctcccagggagaagcttcctcbgagtagcaggagacctqctgcggtgggggctgggctccagaat atgggaaatacctgctacgtgaacgcttcctbgcagtgcctgacatacacaacgccccttgccaactacatgctg tcccgggagcactctcaaacgtgtcatcgtcacaagggctgcatgctctgtactatycaagctcacatcacacgg qccctccacaatcctggccacgtcatccagccctcacaggcattggctgctggcttccatagaggcaagcaggaa gatgcccatgaatttctcatgttcactgtggatgccatqaaaaaggcatgccttcccgggcacaagcaggtagat cacccagaacccctccaaatgagtcgaaccataggcca tgccacggcatttcayacacttttgacccttacctgyacatcgccctagatatccayycayctcagagtgtccag caayctttgyaacagttggtgaagcccgaagaactcaatggaqagaatgcctatcattctggtgtttgtctccag agggcgccggcctccaagacgttaactttacacacctctgccaaggtcctcatccttgtattgaagagattctcc gatgtcacaggcaacaagattgccaagaatgtgcaatatcctgagtgccttgacatycagccatacatgtctcag cagaacacayyacctcttgtctatgtcctctatyctgtgctggtccacgctgggtggagttgtccacgacat tacttctcttatgtcaaagctcaagaaggccagtggtataaaatggatgatgccgaggtcaccgccgctagcatc acttctgccctgagtcaacaggcctacgtcctcttttacatccagaagagtgaatgggaaaqacacagtgagagt gtgtcaagaggcagggaaccaagaycccttggcacagaagacacagacaggcgagcaacgcaaggagagctcaag agayaccacccctgcctc caggcccccgagttggacgagcacttggtggaaagagccactcaggaaagcacctta gaccactggaaattccttcaagagcaaaaCaaaacgaagcctgagtt caacgt cagaaaagtcgaaggtaccctg cctcccgacgtacttgtgattcatcaatcaaaatacaagtgtgggatgaagaaccatcatcctgaacagcaaagc tccctgctaaacctctcttcgtcgaccccgacacatcaggagtccatgaaCactggCacactcgcttccatgcga gggagggccagqagatc caaagggaagaacaaacacagcaagagggctctgcttgtgtgccagtga bflUE4.2a deduced polypeptide sequence

MGNTCYVNASLQCLTYTPPLANYMLSREHSQTCHRHKGCMLCTMQAHITRALENPGHVTQPSQALAAGPARGKQE

DAHEFLMFTVDANKKACLPRHKQVJHHSKDTTLIHQI FGGYWRSQIKCLHCHGISDTFDPYLDIALDIQAAQSVQ QALEOLVKPEELNGENAYHCGVC-QRAPAS KTLTLHTSAKVL ILVLKRFSDVTGNKIAKNVQYPECLDNQFYMSQ

QNTGPLVYVLYAVLVHAEWSCHNGHYFSYVKAQEGQWYKMDDAEVTAASITSVLSQQAYVIFYIQKSEWERHSES

VSRGREPRALGAEDTDRR-ATQGELKRDHPCLQAPELDEELVERATQESTLDHWKFLQEQNKTKFEFNRKVKGTV

IKVDQPQRKAAQGTTQGSVEPQNLGRNFAQAPKCAYEQGLRVTEHVHFRQHYNFGTKCANCNSTIQCVTGNGGNI

ADPERSNRESRI CTAYFGLFPLKQGPVLKMQKNLVILVPVDMEDDS LYLGGEWQFNEFSKLTSSRPDAAFAE IQR TSLPECS PLSCETRVDLCDDLAPVARQLAPREKLPLSSRRPAAVGACLQNNGNTCYVNASLQCLTYTTPLANYNL

SREHSQTCHRHKGCMLCTMQAIITRALHNPGHVIQPSQALAAGFHRGKQEDAXEFLMFTVDAMKKACLPGHKQVD

HHSKDTTLIHQ IFGGYWRSQ IKCLHCHGI SDTFDPYLDIALD IQAAQSVQQALEQLVKPEELNGENAYHSGVCLQ

RAPASKTLTLHTSAKVLILVLKRFSDVTGNKIAKNVQYPECLDMQPYMSQQNTGPLVYVLYAVLVAGWSCHNGH

YFSYVKAQEGQWYKMDDAEVTAAS ITSALSQQAYVLFYTQKSEWERHSESVSRGREFRALGTEDTDRRATQGELK RDHPCLQAPELDEHLVERATQESTLDHWKFLQEQ11KTKPEFNVRKVECTLPPDVLVIHQSKYKCGMKNPEQQS SLLNLS SSTPTHQESMNTGTLASLRG-ARRSKGKNXHSKRALLVCQ Nucleotide sequence for hDUB4. 2b atggaggacgactcactctacttgggagqtgagtggcagttcaaccacttttcaaaactcacatcttctcggccc gatgcagcttttgctgaaatccagcggacttctctccctgagaagtcaccactctcatgtgagacccgtgtcgac ctctgtgatgatttggctccttggcaaacagcttgctcccagggagaagcttcctctgagtagcaggagacct gctgcggtgggggc tgggctccagaatatgggaaatacctgctacgtgaacgcttccttgcagtgcctgacabac acaacgccccttgccaactacatgctgtcccgggagcactctcaaacgtgtCatcgtcacaagggctycatgctc tgtactatgcaagctcacatacacagggccctccacaatcctgccacgtcatccaQccctcacaggCattggct gctggct tccatagaggcaagcaggaagatgcccatgaatttctcatgttcactgtggatgccatgaaaaaggca tgccttcccgggcacaagcaggtagatcatcactctaaggacaccaccctcatccaccaaatatttgagctac tggagatctcaaatcaagtgtctccactgccacggcatttcayacacttttyacccttacctgyacatcgcccta gatatccaggcagctcagagtgtccagcaagctttggaacagttggtgaagcccgaagaactcaatggagagaat 9 c 0 tatcattctggtgtttgtctccagagggcgccggcctccaagacgttaactttacacacctctgccaaggtc ctcatccttgtattgaagagattctccgatgtcacaggcaacaagattgccaagaatgtgcaatatcctgagtgc cttgacatgcagccatacatgttctcaycagaacacaggacctcttgtctatgtcctctatgctgtgctggtccac gctgggtggagttgbcacaacggacattaC ttctcttatgtcaaagct caagaaggccagtggtataaaatggat gatgccgaggtcaccgccgctagcatcacttctgccctgagtcaacaggcctacgtcctcttttacatccagaay agtgaatgggaaagacacagtgagagtgtgtcaagaggcagggaaccaayagccc ttggcacagaagacacagac aggcgagcaacgcaaggagagctcaagagayaccacccctycctccagcccccaqttSgacgagcacttggtg gaaqgagccactcaggaaagcacctta93ccactggaaattccttcaagagcaaaacaaaacgaagcctgattc aacgtcagaaaagtcgaaggtaccctgcctcccgacgtacttgtgattcatcaatcaaaatacaagtgtgggatg WO 03/072724 PCT/US03/05338 aagaaccatcatcctgaacagcaaagctccctgctaaacctctcttcgtcgaccccgacacatcaggagtccatg aacactggcacact cgcttccctgcgagggagggccaggagatccaaagggaagaacaaacacagcaagagggct ctgcttgtgtgccagtga hDUE4.2b deduced polypeptide sequence MEDDSLYLGGEWQFNHFSKLTSSRPDA-AFAEIQRTSLPEKS

PLSCETRVDLCDDLAPVARQLAPREKLPLSSRRP

AAVGAGLQNMGNTCYVNASLQCLTYTTPLANYMLSRESQTCRKGCMLCTMQAITALHNPGRVIQPSQALA

AGFHRGKQEDAHEFLMFTVDAMVKKACLPGHKQVDHHSKDTTLIHQ IFGGYWRSQI KCLHCHGISDTFDPYLD TAL

DIQAAQSVQQALEQLVKPEELNGENAYHSGVCLQRAPASKTLTLHTSAKVLILVLKRFSDVTGNKIAKNVQYPEC

LDMQPYMSQQNTGPLVYVLYAVLVHAGWSCHNGHYFSYVKAQEGQWYKMDDAEVTAAS

ITSALSQQAYVLFYIQK

SEWERHSESVSRGREPRALGTEDTDRRATQGELKRDHPCLQAPELDEHLVERATQESTLDHWKFLQEQNKTKPEF

NVRKVEGTLPPDVLVIHQSKYKCGMKNHHPEQQSSLLNLSS STPTHQESMNTGTLASLRGR-ARRS KGKNKHS KRA

LLVCQ

Nucleotide scquence for hDUB4 .3 atggaggacgactcactctacttgggaggtgagtggcagttcaaccacttttcaaaactcacatcttctcggCCC gatgcagcttttgctgaaatccagcggacttctctccctgagaagtcaccactctcatgtgagacccgtgtcgac ctctgtgatgatttggctcctgtggcaagacagcttgctcccagggagaagcttcctctgagtagcaggagacct gctgcggtgggggctgggctccagaatatgggaaatacctgctacgtgaacgcttccttgcagtgcctgacatac acaccgccccttgccaactacatgctgtcccgggagcactctcaaacgtgtcatcgtcacaagggctgcatgctc tgtacgatgcaagctcacatcacacgggccctccacaatcctggccacgtcatccagcctcacaggcattggct gctggcttccatagaggcaagcaggaagatgccatgaatttctcatgttcactgtggatgccatgaaaaaggca tgccttcccgggcacaagcaggtagatcatcactctaagyacaccaccctCatccaccaaatatttggaggctac tggagatctcaaatcaagtgtctccactgccacggcatttcagacacttttgacccttacctggacatcgccctg gatatccaggcagctcagagtgtccagcaagctttggaacagttggtgaagcccgaagaactcaatggagagaat gcctatcattgtggtgtttgtctccagagggcgccggcctCcaagacgttaactttacacacctctgccaaggtc ctcatccttgtat tgaagagattctccgatytgacaggcaacaagattgccaagaatgtgcaatatcctgagtgc cttgacatgcagccatacatgtctcagcagaacacaggacctcttgtctatgtcctctatgctgtgctggtccac gctgggtggagttgtcacaacggacattacttctcttatgtcaaagctcaagaaggccaatggtataaaatggat gatgc cgaggt ca ccgccgc tagc at cact tc tgt cctgag t caa caggcctacgt cct ct tt tacat ccagaag agtgaatgggaaagacacagtgagagtgtgtcaagaggcagggaaccaagagcccttggcgcagaagacacagac aggcgagcaacgcaaggagagctcaagagagaccacccctgcctccaggcccccgagttggacgagcacttggtg gaaagagccactcaggaaagcaccttagaccgctggaaattccttcaagagcaaaacaaaacgaagcctgagttc aacgtcagaaaagtcgaaggtaccctgcctcccgacgtacttgtgattcatcaatcaaaatacaagtgtgggatg aagaaccatcatcctgaacagcaaagctccctgctaaacctctcttcgtcgaccccgacacatcaggagtccatg aacactggcacactcgcttccctgcgagggagggccaggagatccaaagggaagaacaaacacagcaagaggyct ctgcttgtgtgccagtga hDUB4.3 deduced polypeptide sequence

MEDDSLYLGGEWQFNHFSKLTSSRPDAAFAEIQRTSLPEKSPLSCETRVDLCDDLAPVARQLAPREKLPLSSRRP

AAVGAGLQNMGNTCYVNASLQCLTYTPPLANYMLSRESQTCHR{KGCMLCTMQAH{ITR-ALHNPGHVIQPSQALA

AGFHRGKQEDAHEFLMFTVDAMKKACLPGHKQVDHHSKDTTLII4QIFGGYWRSQIKCLHCHGISDTFDPYLDIAL DIQAAQSVQQALEQLVKPEELNGENAYHCGVCLQRAPAS KTLTLHTSAKVL ILVLKRFSDVTGNKIAKNVQYPEC LDMQPYMSQQNTGPLVYVLYAVLVHAGWSCHNGHYFSYVKAQEGQWYKMDDAEVTAS

ITSVLSQQAYVLFYIQK

SEWERHSESVSRGREPRALGAEDTDRR-ATQGELKRDHPCLQAPELDEHLVERATQESTLDRWKFLQEQNKTKPEF

NVRKVEGTLPPDVLVIHQSKYKCGMKNHHPBQQSSLLNLS SSTPTHQESMNTGTLASLRGRARRS KGKNKMSKRA

LLVCQ

Nucleotide sequence for hDUB4 atgcgccagagagctcgtcatttgagactdctctcggaagggataYcgtctttctgcaacctgcggtcccagcag aaaaaccttgtgatccttgttccagtcgacatggaggaagactcactctacttgggaggtgagtggcagttcaac cacttttc&aaaactcacatcttctcggcccgatcactttttgctgaaatccagcggacttctctccctagaag tcaccactctcatgtgagacccgtgtcgacctctgtatgatttggctcctgtgcaagacacttgctcccagg gagaagcttcctctgagtaacaggagacctgctgcgtgggggctggctccagaatatgggaaatacctgctac gtgaacgcttccttgcagtgcctgacatacacaccgccccttgccaactacatgctgtcccgggagcactctcaa WO 031072724 PCT/US03105338 -61acgtgtcatcgtcacaagggctgcatgctctgtacgatgcaagctcacatcacacgggccctccacaatcctggc cacgtcatccagccctcacaggcattggctgctggcttccatagaggcaagcaggaagatgcccatgaatttctc atyt tcactgtggatgccatgaaaaaggcatgccttcccgggcacaagcaggtggatcatcactctaaggacacc accctcatccaccaaatatttggaggctactggagatctcaaatcaagtgtctccactgCCacggcatttcagac acttttgacccttacctggacatcgccctggatatccag9cagctcagagtgtccagcaagctttggaacagttg gtgaagcccgaagaactcaatggagagaatgcctatcattgtggtgtttgtctccagagggcgccggcctccaag acgttaactttacacacctctgccaaggtcctcatccttgtattgaagagattctccgatgtcacaggcaacaag attgacaagaatgtgcaatatcctgagtgccttgacatgaagcatacatgtctcagacgaactcaggacctctc gtctatgtcctctatgctgtgctggtccacgctgggtggagttgtcacaacggacattacttctcttatgtcaaa gctcaagaaggccagtggtataaaatggatgatgccgaggtcaccgcctctagcatcacttctgtcctgagtcaa caggcctacgtcctcttttacat ccagaagagtgaatgggaaagacacagtgagagtgtgtcaagaggcagggaa ccaagagcccttggcgcagaagacacagacaggcgagcaacgcaaggagagctcaagagagaccacccctgcctc caggcccccgagttggacgagcacttggtggaaagagccactcaggaaagcaccttagaccactggaaattcctt caagagcaaaacaaaacgaagcctgagttcaacgtcagaaaagcgaaggtaccctgctcccga.cgtacttgtg attcatcaatcaaaatacaagtgtgggatgaagaaccatcatcctgaacagcaaagctccctgctaaacctctct tcgacgaccccgacacatcaggagtccatgaacactggcacactcgcttccctgcaggagggccagaacc aaagggaagaacaaacacagcaagagggctctgcttgtgtgccagtggtctcagtggaagtaccgacccaca deduced polypeptide sequence

MRQRRHLKTLSEGIASFCNLRSQQKNLVILVPVDMEEDSLYLCCEWQFNHFSKLTSSRPDAAFAEIQRTSLPEK

SPLSCETRVDLCDDLAPVARQLAPREKLPLSNRRPAAVGAGLQNMGNTCYVNASLQCLTYTPPLANYMLSREHSQ

TCHRHKGCMLCTMQAIITRALHNPGHVIQPSQALAAGFHRGKQEDAHEFLMFTVDAMKKACLPGHKQVDHHSKDT

TLIHQI FGGYWRSQIKCLHCHGISDTFDPYLDIALDIQAAQSVQQALEQLVKPEELNGENAYHCGVCLQR-APASK

TLTLHTSAKVLILVLKRFSDVTNKIDKNVQYPECLDMKLYMSQTNSGPLVYVLYAVLVIAGWSCNTGHYFSYVK

AQEGQWYKMDDAEVTASS ITSVLSQQAYVLFYIQKSEWERHSESVSRGREPP-ALGAEDTDRRATQGELKRDHPCL QAPELDEHLVERATQESTLDHWKFLQEQNKTKPEFNVRKVEGTPPDVLVIHQSKYKCGMKN~HHPEQQS

SLLNLS

STTPTHQESMNTGTLASLRGRARRSKGKNKHSKRALLVCQWSQWKYRPT

Nucleotide sequence for hDUB4. 6 atggaggacg acatcttctc tcaccactct cagcttgctc gggctccaga acaccgcccc aagggctgta cacgtcatcc gcccatgaat aagcaggtgg tggagatctc ctggacatcg gtgaagcccg gcgccggcct aagagattct cttgacatgc gc bgtgctgg gctcaagaag tctgtcctga cacagtgaga aggcgagcaa gacgagcact caagagcaaa cccgacgtac gaacagcaa aacactggca cacagcaaga actcactcta ggcccgatgc catgtgagac ccagggagaa atatgggaaa ttgccaacta tgctctgtac agccctcaca ttctcatgtt atcatcactc aaatcaagtg ccctggatat aagaactcaa ccaagacgtt ccgatgtcac ag cc at ac a tccacgctgg gccagtggta gtcaacaggc gtgtgtcaag cgcaaggaga tggtggaaag acaaaacgaa ttgtgattca gCtCCCtgCt cactcgcttc gggctctgct cttgggaggt agcttttgct ccgtgtcgac gcttcctctg tacctgctac catgctgtcc gatgcaagct ggcattggct cactgtggat taaggacacc tctccactgc ccaggcagct tggagagaat aactttacac aggcaacaag gt ctcagacg gtggagttgt taaaatggat ctacgtcctc aggcagggaa gctcaagaga agccactcag gcctgagttc tcaatcaaaa aaacctctct cctgcgaggg tgtgtgccag gagtggcagt gaaatccagc ctctgtgatg agtagcagga gtgaacgctt cgggagcact cacatcacac gctggcttcc gccatgaaaa accctcatcc cacggcattt cagagtgtcc gcctatcatt acctctgcca attgccaaga aacacaggac cacaacggac gatgccgagg ttttacatcc ccaagagccc gaccacccct gaaagcacct aacgtcagaa tacaagtgtg tcgacgaccc agggccagga tga tcaaccactt ggacttctct atttggctcc gacctgctgc ccttgcagtg ctcaaacgtg gggccctcca atagaggcaa aggcatgcct accaaatatt cagacacttt agcaagcttt gtggtgtttg aggtcctcat atgtgcaata ctctcgtcta attacttctc tcaccgcctc agaagagtga ttggcgcaga gcctccaggc tagaccactg aagtcgaagg ggatgaagaa cgacacatca gatccaaagg ttcaaaactc ccctgagaag tgtggcaaga ggtgggggct cctgacatac tcatcgtcac caatcctggc gcaggaagat tcccgggcac tggaggctac tgacccttac ggaacagttg tctccagagg ccttgtattg tcctgagtgc tgtcctctat ttatgtcaaa tagcatcact atgggaaaga agacacagac ccccgagttg gaaattcctt taccctgcct ccatcatcct ggagtccatg gaagaacaaa hflUE4.6 deduced polypeptide sequence WO 03/072724 WO 0/072724PCT/USO3/05338

MEDDELYLGO

QLAPREKLPL

KGCMLCTMQA

KQVDHHSKDT

VKPEE.NGEN

LDMQPYMSQT

SVLSQQAYVL

DEHLVERATQ

EQQSSLLNLS

EWQFNI{FSKL

SSRRPAAVGA

HITRALHNPG

TLIHQI FGGY

AYHCGVCLQR

NTGPLVYVLY

FYIQKSEWER

ESTLDHWKFL

STTPTHQESM

TSSRPDAAFA

GLQNMGNTCY

HVIQPSQALA

WRSQIKCLHC

APASKTLTLH

AVL\THAGWS C

HSESVSRGRE

QEQNKTKPE F

NTGTLASLRG

Nucleotide sequence for hDUB4 .7 atggaggacg acatcttctc teaccactct cagcttgctc gggctccaga acaccgcccc aagggctgca cacgtcatcc gcccatgaat aagcaggta9 tggagatctc: ctggacatcg gtgaagcccg gcgoeggcct aagagattct cttgacatgc gctgtgctgg gctcaagaag tctgtcctga cacaytyaga aggcgagca gacgagcact caagagcaaa cccgacgtac gaacagcaaa aacactggca cacagcaaga actcactcta ggcccgatgc catgtgagac: ecagggagaa atatgggaaa ttgccaacta tgctctgtac agccctcaca ttctcatgtt atcatcactc aaatcaactg ccctggatat aagaactcaa ccaagacgtt ecgatgtcac agccatacat tccacgctgg gccagtggta gtcaacaggc gtgtgtcaag cgcaaggaga tggtggaaag acaaaacyaa ttgtgattCa gCtccctgCt cactcgcttc gggctctgct cttgggtggt agcttttgct ccgtgtcgac gettcctctg tacctgctac catgctgtcc tatgcaagct ggcattggct cactgtggat taaggacacc tctccactgc ceaggeagct tggagagaat aactttacac aggcaacaag gtctcagcag gtggagttgt taaaatggat ctacgtcctc aggcagggaa gctcaagaga agccactcag gcctgagttc tcaatcaaaa aaacctctct cctgcgaggg tgtgtgccag

EIQRTSLPEK

VNASLQCLTY

AGFHRGKQED

BGISDTFDPY

TSAKVLI LVL

HMGHYFSYVK

PRALCAEDTD

NVRKVEGTLP

RARRS KGKNK gagtggcagt gaaatccagc ctctgtgatg agtagcagga gtgaacgctt cgggagcact cacatcacac gctggcttcc gccatgaaaa accctcatac cacggcattt cagaytytc gcctatcatt acctctgcca attgccaaga aacacaggac cacaacggac gatgccgagg ttttacatcc ccaagagccc gaccacccct gaaagcacct aacgtcagaa tacaagtgtg tcgtcgaccc aggaccagga tga

SPLSCETRVD

TPPLANYMLS

AHE FLMFTVD

LDIALDIQAA

KRFSDVTGNK

AQEGQWYKMD

RRATQGELKR

PDVLVIHQSK

HSKRALLVCQ

tcaaccactt ggacttctct atttggctcc gacctgctgc ccttgcagtg ctcaaacgtg gggccctcca atagaggcaa aggcatgc at ace aa atat t cagacacttt aycaagcttt gtggtgtttg aggtcctcat atgtgcaata ctcttgtcta attacttctc tcaccgccgc ayaagagtga ttggcgcaga gcctccaggc tagaccactg aagtcgaagg ggatgaagaa cgacacatca gatccaaagg ttcaaaactc ccctgagaag tgtggcaaga gtggyct cctgacatac tcatcgtcac caatcctggc gcaggaagat tcccgggcac tggaggctac tgacccttac ggaacagttg tctocagagg ccttgtattg tcctyagtyc tgtcctctat ttatgtcaaa tagcatcact atgggaaaga agacacagac ccccgagttg gaaattcctt taccctgcct ccatcatcct ggaggccatg gaagaacaaa LCDDLAP VAR

REHSQTCHRE

AMKKACLPGH

QSVQQALEQL

IAKNVQYPEC

DAEVTASS IT

DNPCLQAPEL

YKCGMKNHHP

hDUE4.7 deduced polypeptide sequence

MEDDSLYLGG

QLAPREKLPL

KGCMLCTMQA

KQVDHHS KDT

VKPEELNGEN

LDMQPYMSQQ

SVLSQQAYVL

DEHLVERATO

EQQSSLLNLS

EWQFNHFSKL

S SRRPAAVGA

HITRALHNPG

TLIHQI EGGY

AYECGVCLQR

NTGPLVYVLY

FYIQKSEWER

ESTLDHWKFL

S STPTHQEAM TS SRPDAAFA

GLQNMGNTCY

HVIQPSQALA

WRSQINCLHC

APASKTLTLH

AVLVHAGWSC

IISEBS VS EGRE

QEQNKTKPEF

NTGTLASLRG

EIQRTSLPEK

VNASLQCLTY

AGFHRGKQED

HGISDTFDFY

TSAKVLILVL

HNGHYFSYVK

PRALGAEDTD

NVRKVEGTLP

RTRRSKGKNK

SPLSCETRVD

TPPLANYMLS

AHE FLMFTVD

LDIALDIQAA

KRFSDVTGNK

AQEGQWYKMD

RRATQGELKR

PDVLVIHQSK

BSKRALLVCQ

LCDDLAP VAR

REHSQTCHRH

ANKKACLPGH

QSVQQALEQL

TAKNVQYPEC

DAB VTAAS IT

DHPCLQAPEL

YKCGMKNHHP

Nucleotide, sequence for bDUB4 8 atgcgcCaga gagctcgtca tttgaagact ctctcggaag ggatagcgtc ttgctgcaaa ctgcggtccc agcagaaaaa ccttgtgatc cttgttccag tcgacatgga ggacgactca ctctaCttgg gatgcagctt gagacccgtg gaggtgagtg gcagttcaac cacttttcaa aactcacatc ttctcggccc ttgctgaaat coagoggact tctctccctg agaagtcacc actctoatyt tcgacctctg cgatgatttg gctcctgtgg caagacagct tgctcccagg WO 03/072724 WO 03/72724PCT[US03/05338 gagaagcttc ggaaatacct aactacatgc tytacyatgc tcacaggcat atgttcactg cactctaagg aagtgtctcc gatatccagg ctcaatggag acgttaactt gtgacaggca tacatgtctc gctgggtgga tggtataaaa caggcctacg tcaagaggca ggagagctca gaaagagcca acgaagcctg attcatcaat ctgctaaacc gcttccctgc ctgcttgtgt ctctgagtag gctacgtgaa tgtcccggga aagctcacat tggctgctgg tggatgccat acaccaccct actgccacgg cagctcagag agaatgccta tacacacctc acaagat tgc agcagaacac gttgtcacaa tggatgatgc tcctctttta gggaaccaag agagagacca ctcaggaaag agttcaacgt caaaatacaa tctcttcgtc gagggagggc gccagtga caggagacct cgcttcCttg gcactctcaa cacacgggcc cttccataga gaaaaaggca catccaccaa catttcagac tgtccagcaa tcattgtggt tgccaaggtc caagaatgtg aggacctctt cggacattac cgaggtcacc catccagaag agcccttggc CCCCtgcctc caccttagac cagaaaagtc gtgtgggatg gaccccgaca caggagatcc gctgcggtgg cagtgcctga acgtgtcatc CtcCacaatc ggcaageagg tgccttcccg atatttggag acttttgacc gctttggaac gtttgtctcc ctcatccttg caatatcctg gtctatgtcc ttctcttatg gccgctagca agtgaatggg gcagaagaca caggcccccg cactggaaat gaaggtaccc aagaaccatc catcaggagt aaagggaaga gggctgggCt catacacacc gtcacaaggg ctggc cacgt aagatgccca ggcacaagca gctactggag cttacctgga agttggtgaa agagggcgc c tattgaagag agtgccttga tctatgctgt tcaaagctca tcacttctgt aaagacacag cagacaggcg agttggacga tccttcaaga tgcctcccga atcctgaaca ccatgaacac acaaacacag ccagaatatg gccccttgcc ctgcatgctc catccagccc tgaatttctc ggtagatcat atctcaaatc catcgccctg gcccgaagaa ggcctccaag attctccgat catgcagcca gctggtccac agaaggccaa cctgagtcaa tgagagtgtg agcaacgcaa gcacttggtg gcaaaacaaa cgtacttgtg gcaaagctcc tggcacactc caagagggct hDUB4.8 deduced polypeptide sequence

MRQRARHLKT

DAAFAEIQRT

GNTCYVNASL

SQALAAGFHR

KCLHCHGISD

TLTLHTSAKV

AGWSCHNGHY

SRGREPRALG

TKPEFNVRKV

ASLRGRARRS

LSEGIASCCK

SLPEKSPLSC

QCLTYTPPLA

GKQEDAHEFL,

TFDPYLD TAL

LILVLKRFSD

FSYVKAQEGQ

AEDTDRRATQ

EGTLPPDVLV

KGKNKHS KRA

LRSQQKN~LVT

ETRVDLCDDL

NYMLSREHSQ

MFTVDAMKK1A DI QAAQSVQQ

VTGNKIAKN-V

WYKMDDAEVT

GELKRDHPCL

IHQSKYKCGM

LLVCQ

LVPVDMEDDS

APVARQLAPR

TCI{RHKGCML

CLPGHKQVDH

ALEQLVKPEE

QYPECLDMQP

AASITSVLSQ

QAPELDEHLV

KNI{HPEQQS S

LYLGGEWQFN

EKLPLSSRRP

CTMQAHITRA

HS KDTTLIHQ

LNGENAYHCG

YMSQQNTGPL

QAYVLFYIQK

ER-ATQESTLD

LLNLSSSTPT

HFSKLTSSRP

AAVGAGLQNM

LHNPGHVIQP

IFGGYWRSQI

VCLQRAPASK

VYVLYAVLVH

SE WERHSES V

HWKFLQEQNK

HQESMNTGTL

Nucleotide sequence for hDUB4. atgtgcatac actggcagac ccgatgccca aactgcaatt cgatcgatgc gggccagtat aggttatcgc ctcaggtcag gctgccaaaa ctcgttccag cacttttcaa tctctccctg gctcctgtgg gctgcggtgg cagtgcctga acgtgtcatc ctccacaatc ggcaagcagg tgccttcccg atatttggag gaacagggtc agcttatcga gggaacatgt ccaccataca gagaatccag taaaaatggt tggaagggaa aaagcgcact ggatagcgtc tcgacatgga aactcacatc agaagtcac caagacagct gggctgggct catacacaac gtcacaaggg ct ggcc acgt aagatgccca ggcacaagca gctactggag tccgtgtgac ttgggctccc ccactttcgg atgcgtaact gatatgcacg aatttcactc gaaaatacgc ttcgacttct tttctgcaac ggacgactca ttct cggccc actctcatgt tgctcccagg ccagaatatg gccccttgeC ctgcatgctc catccagccc tgaatttctc ggtagatcat atctcaaatc gtgtgtgaaa ctcaaaatcg cagcattaca ggaaatggag gcttattttg ggacagagaa tgtgctaaat tgtccttccg ctgcggtccc ctct act tgg gatgcaqctt gagacccgtg gagaagcttc ggaaa tacc t aactacatgc tgtactatgc tcacaggcat atgttcactg cactctaagg aagtgtctc actacagtgt gttatgagca attttggcac gcaacatcgc goat tt tCCC tcaataggct actatacttc tcgctgagag agcagaaaaa gaggtgagty ttgctgaaat tcgacctctg ctctgagtag gctacgtgaa tgtcccggga aagctcacat tggctgctgg tggatgccat acaccaccct actgccacgg gatgagcatg t t Caagc a ca caaatgtgct cgatcctgaa actgaaacaa caacgtggaa attgactatt gatgatggca ccttgtgatc gcagttcaac ccagcggact tgatgat ttg caggagacet cgcttccttg gcactctcaa cacacgggcc at t ccat aga gaaaaaggca catccaccaa catttcagac WO 03/072724 WO 03/72724PCTIUS03/05338 acttttgacc gctttggaac gtttgtctcc ctcatccttg caatatcctg gtctatgtcc ttctcttatg gccgctagca agtgaatggg acagaagaca caggcccccg cactggaaat gaaggtacc aagaaccatc catcaggagt aaagggaaga cttacctgga agttggtgaa agagggcgcc tattgaagag agtgccttga tctatgctgt tcaaagctca tcacttctgc aaagacacag cagacaggcg agttggacga tccttcaaga tgcctcccga atcctgaaca ccatgaacac acaaacacag catcgcccta gcccgaagaa ggcctccaag attctccgat catgcagcca gctggtccac agaaggccag cctgagtcaa tgagagtgtg agcaacgcaa gcacttggtg gcaaaacaaa cgtacttgtg gcaaagctcc tggcacactc caagagggct gatatccagg ctcaatggag acgttaactt gtcacaggca tacatgtctc gctgggtgga tggtataaaa caggcctacg tcaagaggca ggagagctca gaaagagcca acgaagcctg attcatcaat ctgctaaacc gcttccctgc ctgcttgtgt cagctcagag agaatgccta tacacacctc acaagattgc agcagaacac: gttgtcacaa tggatgatgc tcctctttta gggaaccaag agagagacca ctcaggaaag agttcaacgt caaaatacaa tctcttegtc gagggagggc gc cagtga tgtccagcaa tcattctggt tgccaaggtc caagaatgtg aggacctct cggacattac cgaggtcacc catccagaag agcccttggc cccctgcctc cacottagac cagaaaagtc gtgtgggatg gaccccgaca caggagatcc hDUB4.1O deduced polypeptide sequence

MCIRTGSPCD

NCNSTIQCVT

RLSLEGKKIR

LVPVDNIEDDS

APVARQLAPR

TCHRHKGCML

CLPGHKQVDH

ALEQLVKPEE

QYPECLDMQP

AASITSALSQ

QAPELDEHLV

KNI4HPEQQSS

VCENYSVMSM

GNGGNIADPE

CAKYYTSLTI

LYLGGEWQFN

EKLPLSSRRP

CTMQAHITR-A

HSKDTTLIHQ

LNGENAYHSG

YMSQQNTGPL

QAYVLFYIQK

ERATQESTLD

LLNLSSSTPT

TGRQLIDWAP

RSMRESRICT

LRSESALSTS

HFSKLTSSRP

AAVCAGLQNM

LHNPGHVIQP

IFGGYWRSQI

VCLQRAPAS K

VYVLYAVLVH

SE WERHSES V

HWKFLQEQNK

HQESMNTGTL

Nucleotide sequence for 1IDUB4. 11 atgtgcatac actggcagac ccgatgccca catgaaaaga tatacttcat gcggagagga ggtgagtggc gctgaaat~c gtggcaagac gtgggggctg ctgacataca catcgtcaca aatcctggcc caggaagatg cccaggcaca ggaggctact gaccctta~c gaacagttgg ctccagaggg cttgtattga cctgagtgcc gtcctctatg tatgtcaaag agcatcactt tgggaaagac gaacagggtc agcttatcga ggacacttta caagggaaag tgactattct tgatggcagc agttcaacca agcggacttc agcttgctcc ggctccagaa caccgcccct agggctgcat acgtcatcca cccatgaatt agcaggtaga ggagatctca tggacatcgc tgaagcccga cgccggCCtC agagattctc: ttgacatgca ctgtgctggt ctcaagaagg ctgtcctgag atagtgagag tccgtgtgac t tgggctCccc catccggcac aaacggggcc caggtcagaa tgccaaaatc cttttcaaaa tctccctgag cagggagaag tatgggaaat tgccaactac gctctqtact gccctcacag tctcatgttc tcatcactct aatcaagtgt cctggatatc agaactcaat caagacgtta cgatgtcaca gccatacatg cc acgc tgag ccagtggtat tcaacaggcc tgtgtcaaga

LKIGYEHSST

AYFGLFPLKQ

CPSVAERMMA

DAAFAE IQRT

GNTCYVNASL

SQALAAGFHR

KCLHCHGISD

TLTLHTSAKV

AGWSCHNGHY

SRGREPRALG

TKPEFNVRKV

ASLRGRARRS

gtgtgtgaaa ctcaaaatcg aggaagcctt aaagggaaga agcgcacttt gacatggagg ctcacatctt aagtcaccac cttcctctga acctgctacg atgctgtccc atgcaagctc gcattggctg actgtggatg aaggaCacca ctccactgc caggcagctc ggagagaatg actttacaca ggcaacaaga tctcagcaga tggagttgtc aaaatggatg tacgtcctct ggcagggaac

PMPREHVH'R

GPVLKMVI SL

AAKRIASFCN

SLPEKSPLSC

QCLTYTTPLA

GKQEDAHEFL

TFDPYLDIAL

LILVLKRFSD

FSYVKAQEGQ

TEDTDRRATQ

EGTLPPDVLV

KGKNKHSKRA

actacagtgt gttatgagca ctqatggagc aaatacgctg cgtcttcttg acgactcact CtcygCCaga tctcatatga gtagcaggag tgaacgcttc gggagcactc acatcacacg ctggcttcca ccatgaaaaa ccctcatcca acggcatttc agagtgtcca cctatcattg cctctgccaa ttgccaagaa acacaggacc acaacggaca atgccgaggt tttacatcca caagagccct

QHYNFGTKCA

GQRINRLNVE

LRSQQKNLVI

ETRVDLCDDL

NYMLSREHSQ

MFTVDANKKA

D IQAAQSVQQ

VTGNKIAKJV

WYKMDDAEVT

GELKRDHPCL

IHQSKYKCGM

LLVCQ

gatgagcatg ttcaagcaca aCdcctggcc tgctaaatac tccttccgtc ctacttggga tgcagctttt tttggctcct acctgctgcg cttgcagtgc tcaaacgtgt ggccctccac tagaggcaag ggcatgcctt ccaaatattt agacactttt gcaagctttg tggtgtttgt ggtcctcatc tgtgcaatat tcttgtctat ttacttctct caccgccgct gaagagtgaa tggcgcagaa WO 03/072724 WO 03/72724PCT11JS03/05338 gacacagaca cccgagt tgg aaattccttc aCCCtgCCtC Catcatcctg gagtccatga aagaacaaac ggcgagcaac acgagcactt aagagcaaaa ccgacgtact aacagcaaag acactggcac acagcaagag gcaaggagag 9gtggaaaga caaaacgaag tgtgattcat ctccctgcta actcgcttcc ggctctgctt ctcaagagag gccactcagg cctgagttca caatcaaaat aacctctctt ctgcgaggga gtgtgccagt hDUB4.2.1 deduced polypeptide sequence accacccctg aaagcacctt acgtcagaaa acaagtgtgg cgtcgacccc gggccaggag ga

PMPRTLYIRH

AERMMAA-KI

VARQLAPREK

HRHKGCMLCT

PRHKQVJDHHS

EQLVKPEELN

PECLDMQPYM

S ITSVLSQQA

PELDEHLVER

1{HPEQQS SLL cctccaggcC agaccactgg agt caaaggt gatgaagaac gacacatcag at cc aaaggg

MCIRTOSPCD

HEKTRERNCA

GEWQFNHFSK

VGAGLQNMGN

NPGHVIQPSQ

GGYWRSQIKC

LQRAPASKTL

VLYAVLVHAE

WERHSESVSR

KFLQEQNKT(

ESMNTGTLAS

VCENYSVMSM

KGKKIRCAKY

LTSSRPDAAF

TCYVNASLQC

ALAAGFHRGK

LHCHGISDTF

TLHTSAKVLI

WS CHNGHYFS GRE PRALGAE

PEFNVRKVKG

LRGRARRSKG

TGRQL IDWAP

YTSLTILRSE

AEIQRTSLPE

LTYTPPLANY

QEDAI{EFLMF

DPYLDIALDI

LVLKRFSDVT

YVKAQEGQWY

DTDRRATQGE

TLPPDVLVIH

ENKHSKRALL

LKIGYEHS ST SA.L S SSCPS V

KSPLSYDLAP

MLSREHSQTC

TVDAMKKACL

QAAQSVQQAL

GNKIAKNVQY

KDDDAEVTAA

LKRDHPCLQA

QSKYKCGMK<N

VCQ

RKPSDGAHLA

DMEDDSLYLG

LPLSSRRPAA

MQAHITRALH

KDTTL IHQI F

GENAYHCGVC

SQQNTGPLVY

YVLFYIQKSE

ATQESTLDHW

NLSSSTPTHQ

Nucleotide sequence for hDUB81 atgggggacgactcactctacttgggagytatycagtcaaccacttttcaaaactcacatcttctCggcca gatgcagcttttgctgaaatccagcggacttctctccctgagaagtcaccactctcatctgagacccgtgtcgac ctctgtgatgatttggctcctgtggcaagacagctcgct~ccagggagaagcttcctctgagtagcaggagacct gctgcggtgggggctgggctccagaatatgggaaatacctgctacgagaacgc2ttccctgcagtgcctgacatac acactgccccttgcaactacatgctgtccgggagcactCtcaaacatgtCagcgtcccaagtgctgcatgctc tgtactatgcaagctcacatcacatgggccctccacagtcctggccatgcatccagccctcacaggcattggct gctggcttccatagaggcaagcaggaagatgtccatgaatttctcatgtcactgtggatgccatgaaaaaggca tgccttcccggccacaagcaggtagatcatcatgaaggacaccacccatccaccaaatatttggaggctgc tggagatctcaaatcaagtgtctccactgCCacgggatttcagacacttttgacccttacctggacatcg~cctg gatatccaggcagct cagagtgtcaagcaagctttggaacagttggtgaagcccgaagaactcaatggagagaat gcctatcattgcggtctttgtctccagagggcgccggcctccaacacgtaactttacacacttctgccaaggtc ctcatccttgtcttgaaagatttccgatgtcgcaggcaacaaacttgccaagaatgtgcaatatcctgagtgc cttgacatgcagccatacatgtctcagcagaacacaggacctcttgtctatgtcctctatgctgtgctggtccac gctgggtggagttgtcacgacggacattacttctcctatgtcaaagctcaagaagtccagtggtataaaatggat gatgccgaggtcactgtctgtagcatcatttctgtcctgagtcaacaggCctatgtcctcttttacatccagaag agtgaatgggaaagacacagtgagagtgtgtcaagaggcagggaaccaagagccctcggcgctgaagacacagac aggcgagcaaagcaaggagagctcaagagagaccaccctgcctccaggcacccgagttggacgagcacttggtg gaaagagccactcaggaaagcaccttagaccactggaaattcctgcaagagCaaaacaaaacgaagcctyagttc aacgtcggaaaagtcgaaggtaccctgcctcccaacgcacttgtgattcatcaatcaaaatacaagtgtgggatg aaaaaccatcatcctgaacagcaaagctccctgctaaacctctcttcgacgacccggacagatcaggagtccatg aacactggcacactcgcttctctgcaagggaggaccaggagagcaaagggaagaacaaacaeagcaagagggct ctgcttgtgtgccagtga hDtIE8.1 deduced polypeptide sequence MGDDSLYLGGEWQFNHFSKLTSSRPDAAFAEIQRTSLPEKSPLS

SETRVDLCDDLAPVARQLAPREKLPLSSRRP

AAVGAGILQNMGNTCYENAS LQCLTYTLPLANYNILSREHSQTCQRPKCCMLCTMQAIITWALHSPGHVI

QPSQALA

AGFERGKQEDVHEFLMFTVDAMKKACLPGHKQVIDHHCKDTTL IHQJIFGGCWRSQI KCLHCHGISDTFDPYLDTAL D IQAAQSVKQALEQLVKPEELNGENAYHCGLCLQR-APASNTLTLHTSAKVL

ILVLKRFSDVAGNKLAKNVQYPEC

LDMQPYMSQQNTGPLVYVLYAVLVHAGWSCHDGHYFSYVKAQEVQWYMDDAEVTVCSI

ISVLSQQAYVLFYIQK

SEWERHSESVSRGREPRALGAEDTDRRAKQGELKRDHPCLQAPELDEHLVERATQESTLDHWKFLQEQNKTKPEF

NVGKVEGTLPPNALVIHQS KYKCGMKt'TI{PEQQSSLLNLS STTRTDQESMNTGTLASLQGRTRRAKG3KNK1{SKRA

LLVCQ

Nucleotide sequence for H1JUB823 WO 03/072724 PCT[US03/05338 -66- AtggaggacgactcactctacttgggaggtgagtggcagttcaaccacttttcaaaactcacatCttctcggcca gatgcagcctttgctgaaatccagcGgacttctctccctgagaagtcacaactctcaactgagacccgcgtcgac ttctgcgatgatttggcgcctgtggcaagacagcttgctcccagggagaa~cttcctctgagtagcaggagacct gctgcggtgggggctgggctccagaatatgggaaatacctgctacgtgaacgcttcccagcagtgtctgacatac AcaccgccccttgccaactacatgctgtcccgggagCactctcaaacatgtcatcgtcacaagtyctgcatgctc tgtaccatggaagctcacatcacatGgcccctccacattcctggccatgtcatccagccctcacaggcattggct gctggcttccatagaggcaagcaggaagctgcccttgaatttctcatgttCactgtggatgccatgaaaaagqca tgccttcccgggcacaagcaggtagatcatcactccaaggacaccaccctcatccaccaaatatttggagggtac TggagatctcaaatcaagtgtctccactgccacggcatttCagacacttttggcccttacctggacatcgccctg gatatccaggaagctcagagtgtcaAgcaagctttggaacagttggtgaagcccgaagaactcaatggagagaat gcctatcat tgtggcaacaaaattgccaagaatgtgcaatatcctqagtgCcttgacatgcagccatacatgtct cagcagaacacaggacctcttgtctatgtcctctatgctgtgctggtccacgccgggtggagttgtcacaacgga Cattacttctcttatgtcaaagttcaagaaggccagtggtataaaatggatyatgccgaggtcactgcctctggc atcacctctgtcctgagtcaacaggCctatgtcctcttttacatccacaagagtgaatgggaaagacacagtgag agtgtgtcaagaggcagggaaccaagagccctcggcgctgaagacacagaCaggcgagcaacgcaaggagagctc aagagagactacccctgcctccaggtacccgagttggacgagcacttggtggaaagagccactcaggaaagcacc TtagaccactggaaattcctccaagagcaaaacaaaaCgaagcctgagttcaacgtcagaaaacttgaaggtacc ctgcctcccaacgtacttgtgattcAtcaatcaaaatacaagtgtgggatgaaaaaccatcatcctgaacagcaa agctccctgctaaacctctcttcgacgaacccgaeagatcaggagtccatGaacactggcacactcgcttctctg caagggaggaccaggagagccaaagggaagaacaaacactgcaagagggctctgcttgtgtgccagtga HDUB8.3 deduced polypeptide sequence MEDDSLYLGGEWQFNHSKLTSSRPDAAFAEIQRTSLPEK9QLSTETRVDFCDDLAPVARQLAPREKLPLSSRRP

AAVGAGLQNMGNTCYVNASQQCLTYTPFLANYMLSREHSQTCHRHKCCMLCTMEAHITWPLHIPGHVIQPSQALA

AGFHRGKQEAALE FLPFTVDAMKKACLPGHKQVDHHSKDTTL IHQI FGGYWRSQI KCLHCHGISDTFGPYLD IAL

DIQEAQSVKQALEQLVKPEELNGENAYHCGNKIAKNVQYPECLDMQPYMSQQNTGPLVYVLYAVLVHAGWSCHNG

HYFSYVKVQEGQWYKMDDAEVTASGITSVLSQQAYVLFY I1KSEWER1HSESVSRGREPRALGAEDTDRRATQG2L

KRDYPCLQVPELDEHLVERATQESTLDHWKFLQEQNKTKPEFNVRKLEGTLPPNVLVIQSKYKCGMKNHHPEQQ

S SLLNLS STNPTDQESMNTGTLASLQGRTRRAKGKNKHCKRALLVCQ Nucleotide sequence for Atggaggacgactcactctacttgggaggtgagtggcagttcaaccacttttcaaaactcacatcttctcggcca gatgcagcttttgctgaaatccagcGgacttctctccctgagaagtcactactctcatctgaggcccgtgtcgac ctctgtgatgatttggctcctgtggcaagacagcttgctcccaggaaaaGcttctctgagtagcaggagacct gctgcggtgggggctgggctccagaatatgggaaatacctgctacgagaacgcttccctgcagtgcctgacatac AcaccgccccttgccaactacatgctgcccgggagcactctcaaacatgtcagcgtcccaagtgctgcatgCtc tgtactatgcaagctcacatcacatGggccctccacagtcctggtcatgtcatccagccctcacaggcattggct gctggcttccatagaggcaaycaggaagatgcccatgaatttctcatgttCactgtggatgccatgaaaaaggea tgccttcccggccacaagcaggtagatcatcactctaaggacaccaccctcatCCaccaaatatttggaggctgc Tggagatctcaaatcaagtgtctccactgccacgggatttcagacacttttgacccttacctggacatcgccctg gatatccaggcagctcagagtgtcaAgcaagctttggaacagttggtgaagcccgaagaactcaatggagagaat gcctatcattgcggtctttgtcttcagagggcgccagtctccaagacgttAactttacacacttttgccaaggaa cgcatacttgaaacgcagagaccatgggtggtcacacgccacaaactagccaagagtgtgcaatatgctgagagc CttgacatgcagccatacatgtctcagcagaacacaggacctcttgtctatgtCctctatgctgtgctggtccac gctgggtggagttgtcacgatggacAttacttc tc ttatgtcaaagctcaagaaggccagtggtataaaatggat gatgccaaggtcactgcctgtagcatcacttctgtcctgagtcaacaggcCtatgtcctcttttacatccagaag agtgaatgggaaagacacagtgagagtgtgtcaagaggCagggaaccaagagcctcggcgctgaagacacagac Aggcgagcaacgcaaggagagctcaagagagaccaccctgcctccaggcacccgagttggacgagcgcttggtg gaaagagccactcaggaaagcacctTagaccactggagattCccCcaagagcaaaacaaaacgaagcctgagttc aacgtcagaaaagtcgaaggtacctgcctcccaacgtacttgtgattcaTcaatcgaaatacaagtgtgggatg aaaaaccatcatcctgaacagcaaagctccctgctaaacctctcttcgacgaccggacagatcaggagtccgtg aacactggcaccctcgcttctc tgcaagggaggaccaggagatccaaagggaagaacaaacacagcaagagggct ctgc ttgtgtgc cagtga deduced polypeptide sequence WO 03/072724 PCT/US03/05338 -67- MEDDSLYLGGEWQFNHFSKLTSSRPDAAFAE IQRTSLPEKSPLSSEARVDLCDDLAPVARQLAPRKKLPLSSRRP AAVGAGLQNMGNTCYENAS LQCLTYTPPLANYMLSREHSQTCQRPKCCMLCTMQAHITWALHSPGHVIQPSQALA AGFHRGKQEDAHEFLMFTVDANMKKAC!LPGHKQVDHHSKDTTLIHQI FGGCWRSQIKCLHCHGISDTFDPYLDIAL D IQAAQSVKQALEQLVKPEELNGENAYH-CGLCLQRAPVSKTLTLHTFAKERILETQRPWVVTRHKLAKSVQYAES

LDMQPYMSQQNTGPLVYVLYAVLVHAGWSCHDGHYSYVKAQEGQWYKM~DDAKVTACSITSVLSQQAYVLFYIQK

SEWERHSESVSRGREPRALGAEDTDRRATQGELKRDHPCLQAPELDERLVERATQESTLDHWRFPQEQNKTKPEF

NVRKVEGTLPPNVLVIHQSKYKCGMK<NHHPEQQSSLLNJSSTTRTDQESVNTGTLASLQGRTRRS

KGKKSKRA

LLVCQ

Nucleotide sequence for HDUB8.6 Atggaagacgactcactctatttgggaggtgactggcagttcaatcacttttcaaaactcacatcttctcggcta gatgcagcttttgctgaaatccagc~gacttctctctctgaaaagtcaccactctatctgagacccgtt tcgac ctctgtgatgatttggctcctgtggcaagacagcttgctcccagggagaaGcttcctctgagtagcaggagacct gctgcggtgggggctgggctccagaagataggaaataccttctatgtgaacgtttccctgcagtgcctgacatac Acactgccgctttccaactacatgctgtcccgggaggactctcaaacgtgtcatcttcacaagtgctgcatgttc tgtactatgcaagctcacatcacat~ggccctctaccgtcctggccatgtcatccagccctcacaggtattygct gctgycttccatayaygtgagcaygaggatgcccatgaatttctcatgttTactgtggatgccatgaaaaaggca tgccttcccgggcacaagcagctagatcatcactccaaggacaccaccctcatccaccaaatatttggagcgtat Tggagatctcaaatcaagtatctccactgccacggcatttcagacacctttgaccttacctggacatcgcctg gatatccaggcagctcagagtgtcaAgcaagctttggaacagttggtyaagcccaaagaactcaatggagagaat gcctatcattgtggtctttgtctccagaaggcgcctgcctccaagacgttAactttacccacttctgccaaggtc ctcattcttgtattgaagagattctccgatgtcacaggcaacaaacttgccaagaatgtgcaatatcctaagtgc Cgtgacatgcagccatacatgtctcagcagaacacaggacctcttgtctattcctctatgctgtgctggtccac gctgggtggagttgtcacaacggacAttacttctcttatgtcaaagctcaagaaggccagtggtataaaatggat gatgccgaggtcactgcctctggcatcacctctgtcctgagtcaacaggcCtatgtcctcttttacatccagaag agtgaatgggaaagacacagtgagagtgtgtcaagaggcagggaaccaagagcccttggtyctgaagacacagac Aggccagcaacgcaaggagagctcaagagagaccacccttgcctccaggtacccgagttggacgagcacttggtg gaaagagccactcaggaaagcacctTagaccactggaaattcccccaaaagcaaaacaaaacgaagcctgagttc aacgtcagaaaagttgaaggtaccctgcctcccaacgtacttgtgattcaTcaatcaaaatacaagtgtggtatg aaaaaccatcatcctgaacagcaaagctccctgctaaacctctcttcgacgaaaccgacagatcaggagtccatg AacactggcacactcgcttctctgcaagggagcaccaggagatCCaaagggaataacaaacacagcaagagatct ctgcttgtgtgccagtga HDUB8.6 deduced polypeptide sequence

MEDDSLYLGGDWQFNHFSKLTSSRLDA-AFAEIQRTSLSEKSPLSSETRFDLCDDLAPVARQLAPREKLPLSSRRP

AAVGAGLQKIGNTFYVNVS LQCLTYTLPLSNYMLSREDSQTCHLHKCCMFCTMQAHiITWALYRPGHVIQPSQVLA AGFHRGEQEDA1HEFLMFTVDAMKKACLPGHKQLDHHSKDTTLIHQI FGAYWRSQI KYLHCHGISDTFDPYLDIAL D IQAAQS VKQALEQLVKPKELNGENAYHCGLCLQKAPASKTLTLPTSAKVL ILVLKRFSDVTGNKLAKNVQYPKC

RDMQPYMSQQNTGPLVYVLYAVLVHAGWSCHNGHYFSYVKAQEGQWYKMDDAEVTASGITSVLSQQAYVLFYIQK

SEWERHSESVSRGREPRALGAEDTDRPATQGELKRDHPCLQVPELDEHLVERATQESTLDHWKFPQKQNKTKPEF

NVRKVEGTLPPNVLVIHQSKYKCGMKNHEQQSS LLNLSSTKPTDQESMNTGTLASLQGSTRRSKGNNKHS KRS

LLVCQ

Nucleotide sequence for HDUB8.7 Atggaggacgactcactctacttgggagggagtggcagttcaaccacttttcaaaactcacatcttctcggcca gatgcaqcttttgctgaaatccagc~gacttctctccctgagaagtcaccactctcatctgaggcccgtgtcgac ctctgtgatgatttggctcctgtggcaagacagcttgctcccaggaagaaGCttcctctgagtagcaggagacct gctgcggtgggggctgggctccagaatatgggaaatacctgctacgagaacgcttccctgcagtgcctgacatac AcaccgccccttgccaactacatgctgtcccgggagcactctcaaacatgtCagcgt~ccaagtgctgcatgctc tgtactatgcaagctcacatcacatGggccctccacagtcctggtcatgtcatccagccctcacaggcattggct gctggcttccatagaggcaagcaggaagatgcccatgaatttctcatgttCactgtggatgccatgaaaaaggca tgccttcccggccacaagcaggtagatcatcactctaaggacaccaccctcatccaccaaatatttggaggctgc Tggagatctcaaatcaagtgtctccactgccacgggatttcagacacttttgacccttacctggacatcgccctg gatatccaggcagctcagagtgtCaAgcaagctttggaacagttggtgaagcccgaagaactcaatggagagaat gcctatcattgcggtctttgtctccagagggccagcctccaagaCgttAactttacacacttctgccaaggtc ctcatccttgtcttgaagagattctccgatgtcacaggcaacaaacttgccaagaatgtgcaatatcctgagtgc WO 03/072724 PCT/US03/05338 -68- CttgacatgcagccatacatgtctcagcagaacacaggacctcttgtctatgtcctctatgCtgtgctggtccac gctgggtggagttgtcacgatggacAttacttctcttatgtcaaagctcaagaaggccagtggtataaaatggat gatgccaaggtcactgcctgtagcatcacttctgtcctgagtcaacaggcCtatgtcctcttttacatccagaag agtgaatgggaaagacacagtgagagtgtgtcaagaggcagggaaccaagagccctcggcgctgaagacacagac Aggcgagcaacgcaaggagagctcaagagagaccacccctgcctccaggcacccgagttggacgagcgcttggtg gaaagagccactcaggaaagcacctTagaccactggagattcccccaagagcaaaacaaaacgaagcctgagttc aacgtcagaaaagtcgaaggtaccctgcctcccaacgtacttgtgattcaTcaatcgaaatacaagtgtgggatg aaaaaccatcatcctgaacagcaaagctccctgctaaacctctttcgacgacccggacagatcaggagtccgtg aacactggcaccctcgctt ctctgcaagggaggaccaggagatccaaagggaagaacaaacacagcaagagggc t ctgcttgtgtgccagtga HDUB8.7 deduced polypeptide sequence MEDDSLYLGGEWQFNHFSKLTSSRPDAAFAEI QRTSLPEKS PLS SEAPVDLCDDLAPVARQLAPRKKLPLS SRRP

AAVGAGLQNMGNTCYNASLQCLTYTPPLANYMLSREI{SQTCQRPKCCMLCTMQAHTTWALHSPGHVIQPSQALA

AGFERGKQEDAEEFLMFTVD)ANKKACLPGHKQVDHHSKDTTLIHQI FGGCWRSQIKCL1HCHGISDTFDPYLDIAL DIQAAQSVKQALEQLVKPEELNGENAYHCGLCLQRAPAS KTLTLHTSAKVL ILVLKRFSDVTGNKLAKNVQYPEC LDMQPYD4SQQNTGPLVYVLYAVLVHAGWSCH-DGHYFSYVKAQEGQWYKMDDAKVTACS

ITSVLSQQAYVLFYIQK

SEWERHSE9VSRGREPRALGAEDTDRRATQGELKRDHPCLQAPELDERLVERATQESTLDHWRFPQEQNKTKPEF NVRKVEGTLPPNVLVIHQSKYKCGMKNHHPEQQSSLLNLS STTRTDQESVNTGTLASLQGRTRRSKGKNKHSKRA

LLVCQ

Mucleotide sequence for HDUB8.8 Atggaagacgactcactctatttgggaggtgactggcagttcaatcacttttcaaaactcacatcttctcggcta gatgcagcttttgctgaaatccagcGgacttctctctctgaaaagtcaccactctcatctgagacccgtttcgac ctctgtgatgatttggctcctgtggcaagacagcttgctcccagggagaaGcttcctctgagtagcaggagacct gctgcggtgggggctgggctccagaagataggaaataccttctatgtgaacgt ttccctgcagtgcctgacatac AcactgccgctttccaactacatgctgtcccgggaggactctcaaacytgtcatcttcacaagtgctgcatgttC tgtactatgcaagctcacatcacatGggccctctaccgtcctggccatgtcatccagccctcacaggtattggct gctggcttccatagaggtgagcaggaggatgcccatgaatttctcatgttTactgtggatgccatgaaaaaggca tgccttcccgggcacaagcagctagatcatcactccaaggacaccaccctcatccaccaaatatttggagcgtat TggagatctcaaatcaagtatctCcactgccacggcatttCagacacctttyacccttacctggacatcgccctg gatatccaggcagctcagagtgtcaAgcaagctttggaacagttggtgaagcccaaagaactcaatggagagaat gcctatcattgtggtctttgtctccagaaggcgcctgcctccaagacgttAactttacccacttctgccaaggtc ctcattcttgtattgaagagattCtccgatgtcacaggcaacaaacttgccaagaatgtgcaatatcctaagtgc CgtgacatgcagccatacatgtctcagcagaacacaggacctcttgtctatgtcCtctatgctgtgctggtccac gctgggtggagttgtcacaacggacAttac ttctcttatgtcaaagctcaagaaggccagtggtataaaatggat gatgccgaggtcactgcctctggcatcacctctgtcctgagtcaacaggcCtatgtcctcttttacatccagaag agtgaatgggaaagacacagtgagagtgtgtcaagaggcagggaaccaagagcccttggtgctgaagacacagac AggccagcaacgcaaggagagctcaagagagaccaccttgcCtccaggtacccgagttggacgagcacttggtg gaaagagccactcaggaaagcacctTagaccactggaaattcccccaaaagcaaaacaaaacgaagcctgagttc aacgtcagaaaagttgaaggtaccctgcctcccaacgtacttgtgattcaTcaatcaaaatacaagtgtggtatg aaaaaccatcatcctgaacagcaaagctccgtgctaaacctctcttcgacgaaaccgacagatcaggagtccatg aacactggcacactcgcttctctgcaagggagcaccaggagatccaaagggaataacaaacacagcaagagatct ctgcttgtgtgccagtga HDUB8.8 deduced polypeptide sequence MEDDSLYLGGDWQFNHFS KLTS SRLDAAFAE IQRTSLSEKS PLS SETRFDLCDDLAPVARQLAPREKLPLS SRRP

AAVGAGLQKIGNTFYVNVSLQCLTYTLPLSNYMLSREDSQTCHLHKCCMFCTMQAHITWALYRPGHVIQPSQVLA

AGFHRGEQEDAHEFLMFTVDANKKACLPGHKQLDHHSKDTTLTHQTFGAYWRSQIKYLHCHGISDTFDPYLDIAL

DIQAAQSVKQALEQLVKPKELNGENAYHCGLCLQKAPASKTLTLPTSAKVLILVLKRFSDVTGNKLAKNVQYPKC-

RDMQPYMSQQNTGPLVYVLYAVLVRAGWS CHNGHYFSYVKAQEGQWYKMDDAEVTASGI TSVLSQQAYVLFYIQK

SBWERHSESVSRGREPRALGAEDTDRPATQGELKRDHPCLQVPELDEHLVERA~TQESTLDHWKFPQKQNKTKPEF

NVRKVEGTLPPNVLVIHQSKYKCGMKNHHPEQQSSVLNLSSTKPTDQESMNTGTLASLQGSTRRSKGNNKHSKRS

LLVCQ

WO 03/072724 PCT/US03/05338 -69- Nucleotide sequence for HDUB8.11 Atggaggacgactcactctacttgggaggtgagtggcagttcaaccacttttcaaaactcacatcttctcggcca gatgcagcctttgctgaaatccagcGgacttctctccctgagaagtcacaactctcaactgagacccgcgtcgac ttctgcgatgatttggccgctqtggcaagacagctcgctcCagggagaaCttcctctgagtagcaggagacct gctgcggtgggggctgggctccagaatatgggaaatacctgctacgtgaacgcttcccagcagtgtctgacatac AtaccgccccttgccaactacatgctgtcccgygagcactatcaaacatgtCatcgtcaCaagtgctgcatgatc tgtaccatggaagctcacatcacatGgcccctccacattcctggccatgtcatccagccctcacaggcattggct gctggcttccatagaggcaagcaggaagctgccttgaatttctcatgttCactgtggatgccatgaaaaaggca tgccttcccgggcacaagcagatcctcatcctcgtatggaagagattctccgatgtcacaggcaacaaaattgcc AagaatgtycaatatcctgagtgccttgacatgcagccatacatgtctcagcagaacaggacctCttgtctat gtcctctatgctgtgctggtccacgCcgggtggagttgtcacaacggacattacttctcttatgtcaaagttcaa gaaggccagtggtataaaatggatgatgccgagaagagtgaatgggaaagAcacagtgagagtgtgtcaagaggc agggaaccaagagccctcggcgctgaagacacagacaggcgageaacgcaaggagagctcaagagagactacccc Tgcctccaggtacccgagt tggacgagcacttggtggaaagagccactcaggaaagcaccttagaccactggaaa ttcctccaagagcaaaacaaaacgaAgcctgagttcaacgtcagaaaacttgaaggtaccctgCC tcccaacgta cttgtgattcatcaatcaaaatacaagtgtgggatgaaaaaccatcatccTgaacagcaaagctccctgctaaac ctctcttcgacgaacccgacagatcaggagtccatgaacactggcacactcgcttctctgcaagggaggaccagg agatccaaagggaagaacaaacactgcaagagggctctgcttgtgtgccagtga HDUB8.11 deduced polypeptide sequence MEDDSLYLGGEWQFNHFSKLTS SRPDAAFAE IQRTSLPEKSQLSTETRVDFCDDLAAVARQLAPREKLPLS SRRP AAVGAGLQNMGNTCYVNASQQCLTYI PPLANYMLSREHSQTCHRHKCCMLCTMEAHITWPLHIPOHVIQPSQALA AGFHRGKQEAALEFLMFTVDANKKACLPGHKQI LI LVWKRFSDVTGNKIAKNVQYPECLDMQPYMSQQNTGPLTY

VLYAVLVHAGWSCHNGHYFSYVKVQEGQWYKMDDAEKSEWERHSESVSRGREPRALGAEDTDRRATQGELKRDYP

CLQVPELDEHLVERATQESTLDHWKFLQEQNKTKPEFNVRKLEGTLPPNVLVIHQSKYKCGMKNHHPEQQSSLLN

LSSTNPTDQESMNTGTLASLQGRTRRSKGKNKHCKRALLVCQ

Nucleotide sequence for HDUB4 .4 sequence atggaggagg acatcttctc tcaccactct c agcttgct c gggctccaga acaccgcccc aagggctgca cacgtcatcc gcccatgaat aagcaggtag tggagatctc ctggacatcg gtgaagcccg gcgccggcct aagagattct cttgacatgc gctgtgctgg gctcaagaag atctgtcctg acacagtgag caggcgagta ggacgagcac tcaagagcaa tcccgacgta tgaacagcaa actcactcta cttgggtggt gagtggcagt tcaaccactt ttcaaaactc ggctcgatgc agcttttgct gaaatccagc: ggacttctct ccctgagaag catgtgagac: ccgtgtcgac ctctgtgatg atttggttcc tgaggcaaga ccagggagaa gcttcctctg agtagcagga gacctgctgc ggtgggggct atatgggaaa tacctgctac gtgaacgctt ccttgcagtg cctgacatac ttgccaacta catgctgtcc cgggagcact ctcaaacgtg tcatcgtcac tgctctgtac tatgcaagct cacatcacac gggccctcca caatcctggc agccctcaca ggcattggct gctggcttcc atagaggcaa gcaggaagat ttctcatgtt cactgtggat gccatgaaaa aggcatgcct tcccgggcac atcatocctc taaggacacc accctcatcc accaaatatt tggaggctac aaatcaagtg tctccactgc cacggcattt cagacacttt tgacccttac ccctggatat ccaggcagct cagagtgtcc agcaagcttt ggaacagttg aagaactcaa tggagagaat gcctatcatt gtggtgtttg tctccagagg ccaagacgtt aactttacac acttctgcca aggtcctcat ccttgtattg ccgatgtcac aggcaacaag attgccaaga atgtgcaata tcctgagtgc agccatacat gtctcagcag aacacaggac ctcttgtcta tgtcctctat tccatgctgg gtggagttgt cacaacggac attacttctc ttatgtcaaa gccagtggta taaaatggat gatgccgagg tcaccgcctc ttagcatcac agtcaacagg. cctacgtcct cttttacatc cagaagagtg aatgggaaag agtgtgtcaa gaggcaggga accaagagcc cttggcgcag aagacacaga acgcaaggag agctcaagag agaccacccc tgactccagg cccccgagtt ttggtggaaa gagccactca ggaaagcacc ttagaccact ggaaattcct aacaaaacga agcctgagtt caacgtcaga aaagtcgaag gtaccctgcc cttgtgattc atcaatcaaa atacaagtgt gggatgaaga accatcatcc agctccctgc taaacctctc ttcgacgacc ccgacacatc agcagtccat WO 03/072724 PCT[US03/05338 gaacaatggc acactcgctt ccctgcgagg gagggccagg agatccaaag ggaagaacaa acacagcaag agggctctgc ttgtgtgcca gtga hDUB4.4 Deduced polypeptide sequence

MEEDSLYLOG

QLAPREK.PL

KGCMLCTMQA

KQVDHPSKDT

VKPEELNGEN

LDMQPYMSQQ

EWQFN1HFSKL TSSRLDAAFA EIQRTSLPEK SPLSCETRVD LCDDLVPEAR SSRRPAAVGA GLQNMGN'TCY VNASLQCLTY TPPLANYMLS RERSQTCHRH HITRALHNPG HVIQPSQALA AGFI-RGKQED AHEFLMFTVD ANKKACLPGH TLIHQIFGGY WRSQTKCLHC HGTSDTFDPY LDIALDIQAA QSVQQALEQL AYHCGVCLQR APASKTLTLH TSAKVLILVL KRFSDVTGNK IAKNVQYPEC NTGPLVYVLY AVLVHAGWS C HMGHYFSYVK AQEGQWYKMD DAEVTAS Nucleotide sequence for hDUB4 9 atggaggacg acatctcctc tcaccactct cagcttgctc gggctccaga acaccgcccc aagggctgca cacgtcatcc gcccatgaat aagcaggtgg tggagatctc ctggacatcg gtgaagcccg gcgccggcct aagagattCt cttgacatgc gctgtgctgg gctcaagaag tctgtcctga cacagtgaga actcactcta cttgggaggt gagtggcagt tcaaccactt ttcaaaactc ggcccgatgc agcttttgct gaaatccagc ggacttctct ccctgagaag catgtgagac ccgtgtcgac ctctgtgatt atttg~ctcc tgtggcaaga ccagggagaa gcttcctctg agtagcagga gacctgctgc ggtgggggct atatgggaaa tacctgctac gtgaacgctt ccttgcagtg cctgacatac ttgccaacta catgctgtcc cgggaqcact ctcaaacgtg tcatcgtcac tgctctgtac tatgcaagct cacatcacac gggccctcca caatcctggc agccctcaca ggcattggct gctggctztcc atagaggcaa gcaggaagat ttctcatgtt cactgtggat gccatgaaaa aggcatgcct tcccgggcac atcatcactc taaggacacc accctcatcc accaaatatt tggaggctac aaatcaagtg tctccactgc cacggcattt cagacacttt tgacccttac ccctgyatat ccaggcagct cagagtgtcc agcaagcttt ggaacagttg aagaactcaa tggagagaat gcctatcatt gtggtgtttg tctccagagg ccaagacgtt aactttacac acctctgcca aggtcctcat ccttgtatty ccgatgtcac aggcaacaag attgccaaga atgtgcaata tcctgagtgc agccatacat gtctcagcag aacacaggac ctcttgtcta tgtcctctat tccacgctgg gtggagttgt cacaacggac attacttctc ttatgtcaaa gccagtggta taaaattgat gatgccgagg tcaccgcctc tagcatcact ctcaacaggc ctacgtcctc ttttacatcc agaagagtga atgggaaaga gtgtgtcaag aggcagggaa ccaagagccc ttggctctga agactaa hDUB4.9 deduced polypeptide sequence

MEDDSLYLGG

QLAPREKLPL

KGCMLCTMQA

KQVDHHSKDT

VKPEELNGEN

LDMQPYMYSQQ

SVLTQQAYVL

EWQFNHFSKL TSPRPDAAFA EIQRTSLPEK SPLSCETRVE LCDYLAPVAR SSRRPAAVGA GLQNMGNTCY VNASLQCLTY TPPLANYMLS REHSQTCHRH HITRAIA{NPG HVIQPSQALA AGFHRGKQED AEEFLMFTVD AMKKACLPGH TLTHQIFGGY WRSQIKCLHC HGISDTFDPY LDIALDIQAA QSVQQALEQL AYHCGVCLQR APASKTLTLH TSAKVLILVL KRFSDVTGNK IAKNVQYPEC NTGPLVYVLY AVLVHAGWSC HNGH-YFSYVK AQEGQWYKID DAEVTASSIT FYIQKSEWER HSESVSRGRE PRALGSED Nucleotide sequence for hDUB8 .2 sequence atgcggccag cggtcccagc tacttgggag gcagcttttg acccgcgtcg aagcttcctc aatacctgct tacatgctgt actatgcaag Caggtgttgg agagcccgtc~ atttgaagac tcggaagaga tagcgtcttt ctgcaacctg cgaaaaacct tgtgatcctt gttccgggcg acatggagga cgactcactc gtgagtggca gttcaaccac ttttcaaaac tcacatcttc tcggccagat ctgaaatcca gcggacttct ctctctgaga agtcatcact ctcatctgag acctctgtga tgatttggct cctgtggcaa gacagctcgc tcccagqgag tgagtagcag gagacctgct gcggtggggg ctgggctcca gaatatggga acgtgaacgc ttccctgcag tgcctgacat acacaccgcc ccttgccaac cccgggagca ctctcaaacg tgtcatcgtc acaagtgctg catgctctgt ctcacatcac atggcccctc cacagtcctg gccatgtcat ccagccctca ctgctggctt ccatagaggc gagcaggaag atgcccatga atttctcatg WO 03/072724 PCT/US03/05338 ttcactgtgg tctaaggaca tgtttccact atccaggcag aatggataaa ttaactttac acaggcaaca atgtctcagc gggtggagtt ataaaatgga cctatgtcct taggcaggga tcatgaataa tttaaccaat gtgtaaccat tttcagaatc ctcttcactc aagaa ttccc gattgcccct -71atgccatgaa aaaggcattc cttcccgggc acaagcattt agataatcac ccaccctcat ccaccaaata tttggagggt actggagatc tcacatcaac gccacgggat ttcagacacc tttgaccctt acctggacat cgccctggat ctcagagtgt caagcaagct ttgtaacagt tggtgaagcc cgaagaactc atgcctatca ttgtggtctt tgtctccaga aggcgcctgc ctccaygacg acacttctgc caaggtcctc atccttgtat tgaagagatt ctctgaggtc aacttgccaa gaatgtgcaa tatcctgagt gccttgacat gcagccatac agaacacagg acctcttgtc tatgtcctct atgctgtgct ggtccacgct gtcacaacgg acattactta tcttatgtca aactcaagaa ggccattggt tgatgccgag gtcactgcct ccggtatcac ttctgtcctg agtcaacagg cttttacatc cagaagaatg aatttggaag acccagttac agtgtgtcca accaagagct ctttgcgtga aggcaagtga attgtgtgtg aaataaaatg atcttycayt ggagtattta tttgtctcac tttgtaatca gtgaatgagc atcaatgcct agtgcctacc ccccagagat aagaacttcc actctcttat ggcctctgga ttgcttatga ctctgaagat aattctcctt tcccccaacg acttcaggtg gtggtaacag ataacacatc agtccctttc tctctctttt aggaaaactc tcactgagac aaaggaaaat cctatggttt actggggagg tcaggagtga aattggtggc tccttcctcc ctgtcaagtc tcttcctcag ttgtctcttc aggact hDUB8. 2 dedeuced polypeptide sequence MRPESPS FED

AAFAEIQRTS

NTCYXTNAS LQ

Q)VLAAGFHRG

CFHCAGISDT

SEEIASFCNL RSQPKNLVIL VPGDMEDDSL YLGGEWQFNH PSKLTSS1RPD LSEKSSLSSE TRVDLCDDLA PVARQLAPRE KLPLSSRRPA AVGAGLQNMO CLTYTPPLAN YMLSREHSQT CHRHKCCMLC TMQAHITWPL HSPGHVIQPS EQEDAI{EFLM FTVDAMKKAF LPGHKHLDN- SKDTTLIHQI FGGYWRS-IN PDPYLDIALD IQAAQSVKQA L Nucleo tide sequence for hDUB B 9 atggaggaag acatcttctc tcaccactct cagct tgc tc ggtctccaga acaccgcccc aagtgctgca ccatgtcatc tgcccatgaa caagcagcta ctagagatct cctggatatc ggtgaagccc ggcgcctgcc gaagagattc cgttgacatg tgctgttctc actcaagaag tctccttaga cccagttaca attgtggtga taatcagtga acttccagtt ctcctgt CCC cctttctctc actcactcta cttgggaggt gagtggcagt tcaaccactt ttcaaaactc agccagatgc agcttttcct gaaatccagc ggacttctct ccctgagaag catcggagac ccgtgtcgac ctctgtgacg atttggctcc tgtgacaaga ccagggagaa gcttcctccg agtagcagga gacctgctgc ggtgggagct atatgggaaa tacctgccac ttgaatgctt ccctgcagtg cctgacatac ttgccaacta catgctgtcc tgggagctct ctcaaatgtg tcatcgtccc tgctctgtat tatggaagct cacagcacac gggcacctcc accgtcctgg cagccctcac aggcattggc tgctgacttc catagagaca agcaggaaga tttctcatat tcactgtgga tgccattaga aaggcatgcc ttcccgggca gatcatcact gcaaggacac catcctcatc caccaaatat ttggagggta caaatcaagt gtctctactt ccacggcatt tcagacacct tcgaccctta gccctggata tccaggcagc tcagagtgtc aagcaagctt tggaacagtt gaagaactca atggagagaa tgcctatcat tgtggtcttt gtctccagaa gccaagacgt taactttacc cacttctgcc aaggtcctca tccttgtctt tccgatgtca caggcaacaa acttgccaag aatctgcaat atcctgagtg cagccataca tgtctcagca gaacacagga cctcttttct atgtcctcta qtcatcaccg ggtggagttg tcacaacgga cattacttct cttgtgtcaa gccagtggta taaaatggat gatgccgagg tcactgcctc tggtatcact gtcaacaggc ctatgtcctc ttttacatcc agaagaatga atttggaaga gggtgtccgc aggcagagaa ccaagagctc tttgtgctga agacaattga aataatatgt catgaataaa tcttgcagca gatttatttg tctcacttitg atgagcttta acgaatatca atgcctagtg cctacccccc agagataaga tctcatgtgt aatcatggca tctggattgc tcatgattct gaagataatt ccaaagtttc agaatcactt caggtggtag aaacagataa cacatcagtc tcttttctct tca hDUBS.9 Deduced polypeptide sequence WO 03/072724 WO 03172724PCT/US03/05338

MEDDSLYLGG

QLAPREKLPL

KCCMLCTMQA

KHLDNHSKDT

EWQFNHFSKL

S SRRPAA'VGA

HITWPLHSPG

TLIHQI FGGY

TSSRPDAAFA

GLQNMGNTCY

HVIQPSQVLA

WRSHINCFHC

EIQRTSLSEK SSLSSETRVD LCDDLAPVAR XTNASLQCLTY TPPLANYMLS REHSQTCHRH AGF}{RGEQED AHEFLMFTVD ANKKAFLPGH HGISDTFDPY LDIALDIQAA QSVKQALEQL VKPEELNG Nucleotide sequence for hDuB 8.10o atggaggacg acatcttctc tcatcactct cagctc9Ctc gggctccaga acaccgccca aagtgctgca catgtcatcc gcccatgaat aagcatttag tggagatctc ctggacatcg gtgaagccc~g gcgcctacct aagagattct cttgacatgc: gctgtgctgg ctcaagaagg CtgtCCtgag ccagttacag tgtgtgtgaa tgtaatcayt gaacttccac ttctcctttc tccctttctc t atggtt ta c gtcaagtctc agatgccccc actcactcta cttgggaggt yagtggcagt: Lcaaccactt ttcaaaactc ggccagatgc agcttttgct gaaatccagc ggacttctct ctctgagaaq catctgagac ccgcgtcgac ctcctgatg atttggctcc: tgtggcaaga ccagggagaa gcttcctctg agtagcagga gacctgctgc ggtg9ggggct: atatgggaaa tacctgctac gtgaacgctt ccctqcagtg cctgacatac ttgccaacta catgctgtcc cgggagcact ctcaaacgtg tcatcgtcac tctctgtac tatgcaagct cacatcacat ggccccteca cagtcctggc agccttcaca ggtgttgyct gctggcttcc atagaggcga gcaggaagat ttctcatgtt cactgtggat gccatcgaaaa aagcattcct tcccgggcac ataatcactc taaggacacc accctcatcc accaaatatt tggagggtac acatcaactg tttccactgc catgggattt cagacacctt tgacccttac ccctggatat ccaggcagct cagagtgtca agcaagcttt ggaacagttg aagaactcaa tggataaaat gcctatcatt gtggtctttg tctccagaag ccaggacgtt aactttacac acttctgcca aggtcctcat ccttgtattg ctgatgtcac aggcaacaaa cttgccaaga atgtgcaata tcctgagtgc agccatacat gtctcagcag aacacaggac: ctcttgtcta tgtcctctat tccacgctgg gtggagttgt; cacaacggac attacttatc ttatgtcaaa ccattggtat aaaatggatg9 atgccgaggt cactgcctcc ggtatcactt tcaacaggcc tatgtcctct tttacatcca gaagaatgaa tttggaagac tgtgtccata ggcagggaac cgagagctct ttgcgtgaag gcaagtg9aat; ataaaatgtc atgaataaat cttgcagtgg agtatttatt tgtctcactt gaatgagctt taaccaatat caatgcctag tgcctacccc ccagagataa tctcttatgt gtaaccatgg cctctggatt gcttatgact ctgaagataa ccccaacgtt tcagaatcac ttcaggtggt ggtaacagat; aacacatcag tctcttttct cttcactcag gaaaactctc actgagacaa aggaaaatcc tggggaggaa gaattccctc aggagtgaaa ttggtggctc cttcctccct ttcctcagga ttgccccttt gtctcttcag gactctgctc atcaggcccg tggttgtgca tacctggcct: gtgaagaaat a hDETB8.10 Deduced polypeptide sequence

MEEDSLYLGG

QLAPREKL PP

KCCMLCIMEA

EWQFNHFSKL

S SRRPAAVGA

HSTRAPPPSW

TSSQPDAAFP EIQRTSLPE( SPLSSETRVD LCDDLAPVTR GLQNMGNTCH LNASLQCLTY TPPLANYMLS WELSQMCHRP PC1HPALTGIG C Table 24. Deduced aAminc, acid alignment of hDUB4. 10 and hDUB4.1 1.

hDUB4 .10 MCIRTGSPCDVCENYSVMSM~TGRQLDWAPLKIGYEHSSTPMPREHVHFRQHYNFGTKCA hDUB4 .11 MCIRTGSPCDVCENYSVMSMTGRQLIDWAPLKIGYEHSSTPMPRT-LYIRHRK 52 hDUB4 .10 NCNSTIQCVTGNGGNIADPERSMRESRICTAYFGLFPLKQGPVLKMVISLGQRINRLNVE 120 hDUB4.11 TRE 66 hDJB4 .10 RLSLEGKKIRCAKYYTSLTILRSESALSTSCPSVAERMMAAAKRIASFCNLRSQQKNLVI 180 hDUB4.11 RNGAKGKKIRCAKYYTSLTILRSESALSSSCPSVAERMMAAAK-------------------109g hDIJB4. 10 LVPVDMEDDSLYLGGEWQFNHFSKLTSSRPDAAFAEIQRTSILPEKSPLSCETRVDLCDDL 240 WO 03/072724 PCT/US03/05338 -73hDJJE4.11 -IDMEDDSLYLGGEWQFNHFSKLTSSRFDAAFAEIQRTSLPEKSPLS--------- YDL 158 hDUB4. NMLSREHS 300 hDtJB4 .10 APVARQLAPREKLPLSSRRPAAVGAGLQNMGNTCYVNASLQCLTYTTPLANYMLSREHSQ 300 hDJB4 .10 TCHRHIKGcMLCTMQAIIITRALHNDCHVIQPSQALAAQFHRGKQEDAHEFLMFTVDAMKKA 360 hDJB4 .11 TCHRHKGCMLCTMQAHITRALHNPGHVIQFSQALAAGFHRGKQEDkHEFLMFTVDAMKKA 278 hDUB4 .10 CLPCHKQVDHHSKDTTLIHQIFCCYWRSQIKCLHCHCISDTFDPYLDIALDIQAAQSVQQ 420 hDUE4 .11 CLPRHKQVDHHSKDTTLIHQIFGGYWRSQIKCLHCHGISDTFDPYLDIALDIQAAQSVQQ 338 hDUB4 .10 ALEQLVKPEELNGENAYHSGVCLQRAPASKTLTLHTSAKVLILVLKRFSDVTGNKIAKNV 480 hDUB4 .11 ALEQLVKPEELNGENAYHCGVCLQRAPASKTLTLHTSAKVLILVLKRFSDVTGNKIAK<NV 398 hDUB.10 YELDM*YM**NTG***VY***H**S*1*GHY*YVKQE **YKMDAE 54 hDUB4 .10 QYPFCLDMQPYMSQQNTGPLVYVLYAVLVHEWSCHNGHYFSYVKAtQEGQWYKMDDAEVT 450 hDIJB4. 10 AISITSALSQQAYVLFYIQKSEWERHSESVSRGREPRALGTEDTDRRATQGELKRDHPCL 600 lDUB4 .11 AASITSVLSQQAYVLFYIQKSEWERIISESVSROREPRALCAEDTDRRATQGELKRDHPCL 518 hDUB 66 hDUB4 .10 QAPELDEHLVERATQESTLDHWKFLQEQNKTKPEFNVRKVEGTLPPDVLVTHQSKYKCGM 660 hDUB4. 10 KNHHPEQQS SLLNLS SSTPTHQESMNTGTLASLRGRARRS KCKNKHSKRALLVCQ 715 hDUB4 .11 KNHHPEQQSSLLNLSSSTPTHQESMNTGTLASLRGRARRSKGKUKHSKRALLVC- 632 Table 25. Nucleotide sequence alignment of hDUB4.5, hDUJB4.8 and hDUBS.2 In frame termination codons in hDIJBS.2 are underlined hDLJB4.5 hIDTJ4 8 hDtJB8 .2 hDIJS4 hDtB4 8 1IDLB8 .2 hDUB4.5 hDJB4 8 hDUB8 .2 hDtJB4.5 hDUB4 B hDUB8. .2 hDtJS4.5 hDU 4. .8 hDJ 8. .2 ATCO- CCAGAGAGCTCGTCATTTGAAGACTCTCTCGGAAGGGATAGCGTCTTTCTGCAA ATOC CCAGAGAGCTCGTCATTTGAAGACTCTCTCGGAAGGGATAGCGTCTTGCTGCAA ATGCCGCCAAGACCCCGTCATTTGAACA CTCGGAAOAGATAGCGTCTTTCTGCAA

CCTGCGGTCCCAGCAGAAAAACCTTGTGATCCTTGTTCCAGTCGACATGGAGGAAGACTC

ACTGCGGTCCCAGCAGAAAAACCTTGTGATCCTTGTTCCGTCGACATGGAGGACGACTC

ACTCTACTTGGGAGGTGAGTGGCAGTTCAACCACTTTTCAAAACTCACATCTTCTCCGCC

ACTCTACTTGOGAGGTGACTGGCAGTTCAACCACT2'TTCAAAACTCACATCTTCTCGGCC

ACTCTACTTGGGAGGTGAGTGGCAGTTCAACCACTTTTCAAAACTCACATCTTCTCGCC

CGATGCAGCTTTTGCTGAAATCCAGCGGACTTCTCTCCCTGAGAAGTCACCACTCTCATG

CGATGCAGCTTTTGCTOAAATCCAGCCCACTTCTCTCCCTGAGAAGTCACCACTCTCAT

TGAGACCCGTGTCGACCTCTGTGATGATTTCCGCTCCTTGCAAGACAGCTTGCTCCCAC

TGAGACCCGTGTCGACCTCTGTGATGATTTGGCTCCTGTGGCA.AGACAGCTTGCTCCCAG

TGAGACCCGCGTCGACCTCTSTGATGATTTGGCTCCTGTGGCAAGACAGCTCGCTCCCAG

WO 03/072724 PCT/US03/05338 -74hDUB4 .5 GGAGAAGCTTCCTCTGAGTrAACAGGAGACCTGCTGCGGTGGGGGCTGGGCTCCAGAATAT 359 h0U24 .8 GGAGAAGCTTCCTCTGAGTAGCAGGAGACCTGCTSCGGTGGGGGCTGGGCTCCAGAATAT 359 hEUB8 .2 GGAGAAGCTTCCTCTGACTAGCAGGAGACCTGCTGCGGTGCGGCTGGGCTCCAGAATAT 356 hDtIB4 .5 GGGAAATACCTGCTACOTGAACGCTTCCTTGCAGTGCCTGACATACACACCGCCCCTTGC 419 hIYIB4.8 GGGAAATACCTGCTACGTGAACCCTTCCTTGCAGTGCCTGACATACACACCGCCCCTTGC 419 hDUB8 .2 GGGAAATACCTGCTACGTGAACGCTTCCCTGCAGTGCCTGACATACACACCGCCCCTTGC 416 h0UB4 .5 CAACTACATGCTGTCCCGGGAGCACTCTCAAACGTGTCATCGTCACAAGGGCTGCATGCT 479 hDUB4 .8 CAACTACATGCTGTCCCCGGGAGCACTCTCAAACCTGTCATCGTCACAAGGGCTGCATGCT 479 hDUR8S.2 CAACTACATGCTGTCCCGGGAGCACTCTCAAACGTGTCATCGTCACAAGTGCTGCATGCT 476 hDUB4 .5 CTGTACGATGCAAGCTCACATCACACGGGCCCTCCACAATCCTGGCCACGTCATCCAGCC 529 hDUB4 .8 CTGTACGATGCAAGCTCACATCACACGGGCCCTCCACAATCCTGGCCACGTCATCCAGCC 539 hEUBS .2 CTGTACTATGCAAGCTCACATCACATGGCCCCTCCACAGTCCTGGCCATGTCATCCAGCC 536 hDIJB4 .5 CTCACAGCCATTGGCTGCTGGCTTCCATAGAGGCAAGCAGGAAGATGCCCATGAATTTCT 599 hDUB4 .8 CTCACAGGCATTGGCTGCTGGCTTCCATAGAGGCAAGCAGGAACATGCCCATGAATTTCT 599 hDUBS .2 CTCACAGGTGTTGGCTGCTGGCTTCCATAQAGGCGAGCAGGAAGATGCCCATGAATTTCT 596 hDUB4 .5 CATJGTTCACTGTGGATGCCATGAAAAAGGCATGCCTTCCCGGGCACAAGCAGGTGGATCA 659 hDUS4 .8 CATGTTCACTGTGGATGCCATGAAAAAGGCATGCCTTCCCGGGCACAAGCAGGTAGATCA 659 hDU98 .2 CATGTTCACTGTGGATGCCATCAAAAAGGCATTCCTTCCCGGGCACAAGCATTTAGATAA 656 hDUB4 TCACTCTAAGGACACCACCCTCATCCACCAAATATTTQCAQCCTACTGGAGATCTCAAAT 719 hDUB4 .8 TCACTCTAAGGACACCACCCTCATCCACCAAATATTTGGAGGCTACTGGAGATCPCAAAT 719 hDUB8 .2 TCACTCTAAGGACACCACCCTCATCCACCAAAWATTTGGAGGGTACTOGAGATCTCACAT 716 hDUB4 CAAGTGTCTCCACTGCCACGGCATTTCAGACACTTTTGACCTTACCTGGACATCGCCCT 779 hDUB4 .8 CAAGTGTCTCCACTGCCACGGCATTTCAGACACTTTTGACCCTTACCTGGACATCGCCCT 779 hDUB8 .2 CAACTGTTTCCACTGCCACGGGATTTCAGACACCTTTGACCCTTACCTCCACATCCCCCT 776 hDUB4 .5 GGAFATCCAGGCAGCTCAGAGTGTCCAGCAAGCTTTGGAACAGTTGGTGAAGCCCGAAGA 839 hDUB4 .8 GGATATCCAGGCAGCTCAGAGTGTCCAGCAAGCTTTGGAACAGTTGGTGAAGCCCGAAGA 839 hDLTB8 .2 GGA'PATCCAGGCAGCTCAGAGTGTCAAGCAAGCTTTGTAACAGTTGGTGAAGCCCGAAGA 836 hDIJB4 .S ACTCP-ATGGAGAGAATGCCTATCATTGTGGTGTTTGTCTCCAGAGGGCGCCGGCCTCCAA 899 hDtJB4 .8 ACTCAATCGAGAGAATGCCTATCATTGTOGTGTTTGTCTCCAGAGGGCGCCGGCCTCCAA 899 bDLB8 .2 ACTCAATGGATAAAATGCCTATCATTGTGGTCTTTGTCTCCAGAAGGCGCCTGCCTCCAG 896 hDUB4 .5 GACGTTAACTTTACACACCTCTGCCAAGGTCCTCATCCTTGTATTGAAGAGATTCTCCGA 959 hDU84 .8 GACGTTAACTTTACACACCTCTGCCAAGGTCCTCATCCTTGTATTGAAGAGATTCTCCGA 959 hDJ28 .2 GACGTTAACTTTACACACTTCTGCCAAGGTCCTCATCCTTGTATTGAAGAGATTCTCTGA 956 hDtJE4 TCTCACAGGCAACAAGATTGACAAGAATGTGCAATATCCTGAGTGCCTTGACATGAAGCT 1019 h0184 .8 TGTGACAGGCAACAAGATTGCCAAGAATGTGCAATATCCTGAGTGCCTTGACATGCAGCC 1019 hDtD8 .2 GGTCACAGGCAACAAACTTGCCAAGAATCTCCAATATCCTCAGTGCCTTGACATGCAGCC 1016 hDJB4 .5 ATACATGTCTCAGACGAACTCAGGACCTCTCGTCTATGTCCTCTATGCTGTGCTGGTCCA 1079 hDUB4 .8 ATACATGTCTCAGCAGAACACAGGACCTCTTGTCTATGTCCTCTATGCTGTGCTGGTCCA 1079 hDUB8 .2 ATACATGTCTCAGCACAACACAGGACCTCTTGTCTATGTCCTCTATGCTGTGCTGGTCCA 1076 hDUB4. 5 h~t.14 5CGCTGGGTGGAGTTGTCACAACGGACATTACTTCTCTTATGTCAA.AGCTCAAGAACGCCA 1139 WO 03/072724 PCT/US03/05338 lDUB. .2 hDUB4. S hDUB. .2 hDIB4 .5 10184 .8 101328. 2 hDUB4. 5 hDUB4 8 bDUB4.5 hDJ 8. .2 hDUB4.5 hDUB4 8 h1U38. .2 hDUB4.5 10T84 8 hDTBS 2 101324.5 hOUJB4 8 hDJ 8. .2 101384.5 10184 8 hDUB8. .2 hID1B4.S hD13B4 8 hDU 8. 2 101324.5 hDUB4 8 hDJB8 .2 CGCTGGGTGGAGTTGTCACAACGGACATTACTTCTCTTATGTCAAAGCTCAAGAAGGCCA 1139 CGCTGGGTGGAGTTGTCACAACGGACATTACTTATCTTATGTCAAA- CTCAAGAAGGCCA 1135 119 GTGGTATAAAAIGGATGATGCCGAGGTCACCGCCTCTAGCATCACTTCTGTCCTGAGTCA 1199 ATGGTATAAAATGGATGATGCCGAGOTCACTCCCCTATCACTTCTGTCCTGAGTCA 1199 ACAGGCCTACGTCCTCTTTTACATCCAGAAGASTGAATGGGAAAGACACAGTGAGAGTGT 1259 ACAGGCCTACGTCCTCTTTTACATCCAGAAGASTGAATGGGAAAGACACAGTGAGAGTGT 1259 ACAGCCCTATGTCCTCTTTTACATCCAGAAGAATGAATTTGGAAGACCCAGTTACAGTGT 1255 C* 131 GTCAAGAGGCAGCGAACCAACACCCCTTGGCGCAGAAGACACAGACAGGCGAGCA-ACGCA 1319 GTCCATAGGCAGGGAACCAAGAGCTCTTTGCGTCAAGGCAACTGAATTGTGTGTGAAATA 1315 *GGT 137 AGGAGAGCTCAAGAGAGACCACCCCTGCCTCCAGGCCCCCGAGTTGGACCAGCACTTGGT 1379 AAATG- TCATGA- -ATAAATCTTGCACTCGAGTATTT-ATTTGTCTCACTTTGTAAT 1368 *TTA-AAGCAAAA-A143 GGAAAGAGCCACTCAGGAAAGCACCTTAGACCACTGGAAATTCCTTCAAGAGCAAAACAA 1439 CAGTGAATGAGCTTTAACCAATATCAATGCCTAGTGCCTACCCCCCAGAGATAAGAACTT 1428 AGGTCCCGCCCCCACGA G 1499 AACCAAGCCTGAGTTCAACGTCAGAAAAGTCGAAGGTACCCTGCCTCCCGACGTACTTGT 1499 CCACTCTCTTATGTGTAAC- -CATGCCCTCTGGATTGCTTATGACTCTGAAGATAATTCT 1486 *CTGAACGCAAGCT155 GATTCATCAATCAAAATACAAGTGTGGGATGAAGAACCATCATCCTG-AACAGCAAAGCT 1558 CCTT- -TCCCCCA-ACGTTTCAGAATOACTTCAGGTGGTCGTAACAGATAACACATCAGTC 1544 **GATCCTGACATGCACC 61 CCCTGCTAAACCTCTCTTCGACCAC-CCGACACATCAGCAGTCCATGAACACTGGCACAC 161B CCTTTCTCTCTCTTTTCTCTTCACTC-AGOAAAACTCTCACTGAGACAAAGCAAAATCCTA 1604 TCGCTTCCCTGCGAGGGAGGGC--CAGGAGATCCAAAGGGAAGAACAAACACAGCAA 1673 TCGCTTCCCTCCGAGGG3AGGGC--CAGGAGATCCAAAGGGAAGAACAAACACAGCAA 1673 TGGTTTACTGGGGAGGAAGAATTCCCTCAGGAGTGAAATTGGTGGCTCCTTCCTCCCTGT 1664 CACCGCTCTGCTTCTGTG- -CCAGTGGTCTCAGTGGAAGTACCGACCCACA 1722 1698 CAAGTCTCTTCCTCAGGATTGCCCCTTTGTCTCTTCAGGACT------------ 1706 Table 26. Deduced amino acid alignment of hDUB4.5, IiDUB4.8 and hDUBS.2.

N-terminal potential mitoehondrial targeting sequences are underlined.

01384 5 hD13B4 .8 hDU8. .2 hD3B4 5 101384.8 h-DUBD8 .2 MRQRARHLKTLSEGIASFCNLRSQQKNLVI LVPVDMEEDSLYLGGEWQFNHFSKLTSSRP MRQRARHLKTLSEGIASCCKLRSQQKNLVI LVPVDMEDDSLYLGGEWQFNHFSKLTSSRP MRPESPSFED- SEEIASFCNLRSQPKNLVILVPGDMEDDSLYLGGEWQFNHFSKJTSSRP D*AF.E.Q.TSLP*** DAAFAE TQRTSLPEKSPLSCETRVDLCDDLAPVARQLAPREKLPLSRRPAAVGAGLQNJ CAAFAE IQRTSLPEKSPLSETRVDLCDDLAPVARQLAPREKLPLSSRRPAAVGAGLQNN WO 03/072724 PCTIUSO3/05338 -76hDUB4 .5 GNTCYVNASLQCLTYTFFLANYMLSREHSQTCHRHKGCMLCTMQA4ITRALNPG4VIQP 180 hDUB4 .8 GNTCYVNASLQCLTYTPPLANYMLSREHSQTCHRHKGCMLCTQA{ITRALJHNPGHVLQP 180 hDJB8 .2 GNTCYVNASLQCLTYTPPLANYMLSREHSQTCHRIKCCMLCTMQA4ITWPLHSPGHVIQP 179 hDUB4 .5 SQALAAGFHRGKQEDAtE FLMFTVDAMKKACLPGHI{QVDHHS KDTTL TI-QI PGGYWRSQ I 240 hDUB4 .8 SQALAAGFHRGKQEDAI{EFLMFTVDANKKACLPGHKQVDMNISKDTTLIHQIFGGYWRSOT 240 hDUB8 .2 SQVLAAGFHRGEQEDAHEFLMFTVDAI4KKAFLPGHKHLDNHSKDTTLII4QIFGGYWRSHI 239 hDtJB4 KCLHCHGISDTFDPYLDIALDIQAAQSVQQALEQLVKPEELaNGENAYHCGVCLQRAPASC 300 hDUB4 .8 KCLHCNCISDTFDPYLDIALDIQAAQSVQQALEQLVKPEELNGENAYHCGVCJQRAPASK 300 htflB8 .2 NCFHCHGISDTFDFYLDIALDIQAAQSVKQAL------------------------------ 271 hDuB4 .5 TLTLHTSAKVLITJVIKRFSDVTGNKDKNVOYPECLDMKLYMSQTNSGPLVYVLYAVLVH 360 hDUB4 .8 TLTLHTSAKVLILVLKRFSDVTGNKIAKNVQYPECLDMQPYMSQQNTGPLVYVLYAVLVH 360 hSXTBS.2 hDUB4 .5 AGWSCHNGHYFSYVKAQEGQWYKMDDAEVTASSITSVLSQQAYVLFYQKSEWEI-SESV 420 hDUB4 .8 AGWSCHNGHYFSY-VKAQEGQWYKMDDAEVTAASITSVLSQQAYVLFYIQKSEWERHSESV 420 hDUD S .2 hDUB4 .5 SRGREPRALGAEDTDRRATQGELKRDNPCLQAPELDERLVERATQESTLDHWKFLQEQNK 480 hDUB4 .8 SRGREPRAIJGAEDTDRRATQGELKRDHPCLQAFELDEHLVERATQESTLDHWKFLQEQNK 480 hDLJE8.2 hDUE4 .5 TKPEENVRKVEGTLPPDVLVIHQSKYKCCM<NHPEQSSLLLSSTTPT4OESMNTGTL 540 hDUE4 .8 TKPEFNVRKVEGTLPPDVLVIHQSKYKCGMKNHHPEQQSSLLNLSSSTPTHQESMNTGTL 540 h O U B8 .2 hfltB4 .5 AST.RGRARRSKGKNKHSKRALLVCQWSQWKYRPT 574 h01394.8 ASLRGRARRSKGKNKHSKRALLVCQ 565 hID IB8.2 Table 27. Upstream of initiation codon nucleotide sequence (putative promoter region) alignment of hDUB4.5, hDUB4.S and hDUBS.2 Numbering is initiated from initiation ATG.

h0124 .5 CACACGAACACAATCACACACACACACTCACACGGTTTCCTACGTAAACATTTCTTCCCT -278 hEIE4 .8 CACACGAACACAATCACACACACACACTCACACGGTTTCCTACGTAAAGATTTCTTCCCT -276 hEUBS .2 GGGAGAAAAACACACACACACACACACACACACCGTTTCATAGGTAAAGATTTCTTCCCT -276 hiDtE4 GCCATTGCTTTACCTAAAATAAGGCAACTGTGTGGCCACTGTCCCAACCCGGTTACACTC -216 hDUB4 .8 GCCATTGCTTTACCTAAAATAAGGCAACTGTGTGGCCACTGTCCCAACCCGGTTACACTC -216 hDUS8 .2 QACATTGTTTTACCTAAAATAAGGCAACTGTGTGGCCACTGTCCCA-CCCGGTTACACTC -216 hDtJB4 .S CTATTATATGTGCCTATCATCCTGAGOAGTAATTTGATICAGGTGTTCTGGAAGTCATGC -156 hDIJB4 .8 CTATTATATGTGCCTATCATCCTGAGCAGTAATTTGATTCAGGTGTTCTGGAAGTCATGC -156 hDtS8 .2 ATATTACATGTGTCTATCAGCCTGAGGAGTAGTTTGATTCAGGTGTTCTAGAAGTCATCA -156 hDtE4 .5 TGTGGGCTGTGTCTGTTGAATTCCCAGCGATGCAAGGGGACACACCCTGTGACTCCTTCC -96 hDtJB4 .8 TGTGGGCTGTGTCTGTTGAATACCCAGCGATGCAAGGGGACACACCCTGTGACTCCTTCC -96 hDtJB8 .2 TGTGGGCTGTGTCTGTTGAATTCCCAGCGATGCAAGCACACACCCTGTGACTCATTCC -96 hDUB4. 5 h~tJB 5TGAATTGAGTGCTGATATTTGATTGGCTTATCGCGCACCTGATGAGTGGGTGGGGTGTTC -36 WO 03/072724 PCT/US03105338 -77hDUTB4 .8 TGAATTGAGTGCTGATATTTGATTGGCTTATCGCGCACCTGATGAGTGGGTGGGGTGTTO -36 hDUBa .2 TTAATTGAGTGCTGATATTTGATTGGTTTATCGCGCACT3ATGGGTGGGTGGGGTGTTC -36 hDUB4 .s GCGGTTGGTGGGOTGACTTACAGAAGGGCTGATG 0 hDUnS .2 GCGGTTGGTGGGGGTGAGTTATATAAGGGCTGATG 0 Table 28 CLUSTAL W (1.81) multiple sequence alignment of core amino acids of hDUBs MEDUSLYLCCEWQFNHFSKLTSSRPDAAFAEIQRTSLPEKSPLSSEARVDLCDDLAPVAR 8 .7 MSDDSLYIJGGEWQFNHFSKLTSSRPDAAPAEIQRTSLPEKSPLSSEARVDLCDDLAPVARZ 8.1 MGDDSLYLGGEWQFNHFSKLTSSRPDAAFAEIQRTSLiPEKSPLSSETRVDLCDDaAPVAR 4.2 MEDDSLYLGGEWQFNHFSKLTSSRPDAAFAEIQRTSLPEKSPLSCETRVDLCDDLAPVAR 4.3 MEDDSLYLGGEWQFNHFSKLTSSRPDAAFAEIQRTSLPEKSPLSCETRVDLCDDLAPVAR 4 .S MEEDSLYLGCEWQFNHFSKLTSSRPDAAFAEIQRTSLPEKSPLSCETRVDLCDULAPVAR 4 .1 MEDDSLYLGGEWQFNHFSKLTSSRPDAAFAEIQRTSLPEKSPLSCETRVnLCDCLAPVAR 8.3 MEDDSLYLGGEWQFNHFSKLTSSRPDAAFAEIQRTSLPEKSOLSTETRVDFCDDLAFVAR 8. 11 MEDDSLYLGOEWQFNUFSKLTSSRPDAAPAEIQRTSLPEKSQLSTETRVDFCDDLAAVAR 8-8 MEDDSLYLGGDWQFNHFSKLTSSRLDAAFAEIQRTSLSEKSPLSSETRFDLCDDLAPVAR 8.6 MEDDSLYLGGDWQFNHFSKLTSSRLDAAFAEIQRTSLSEKSPLSSETRFDLCDOLAPVAR QLAPRKKLPLSSRRPAAVGAGLQNNGNTCYENASLQCLTYTPPLANYMLSREHSQTCQRP 120 8 .7 QLAPRKKLPLSSRRPAAVGAGLQNMGNTCYFNASLQCLTYTPPLANYMLSREHSQTCQR? 120 8 .1 QLAPREKLPLSSRRPAAVGAGLQNNGNTCYENASLQCLTYTLPLANYMLSREHiSQTCQR? 120 4.-2 QLAPREKLPLSSRRPAAVCAQLQNNGNTCYVNA-SLQCLTYTTPLANYMLSREHSQTCHRH 120 4 .3 QLAPREILPLSSRRPAAVOAOLQNMGNTCYVNASLQCLTYTPPLANYMLSREE4SQTCNRM 120 QLAPREKLPLSNRRPAAVGAGLQNMGNTCYVNASLQCLTYTPPLANYMLSREESQTCHRH 120 4 .1 QLAPREKPPLSSRRPAAVGAGLQNMGNTCYVNASLQCLTYKPPLANYMLFREESQTCHRH 120 8 .3 QLAPREKLFLSSRRPAAVGAGLQNMGNTCYVNASQQCLJTYTFFLANYMLSREHSQTCHRH 120 8 .11 QLAPREKLPLSSRRPAAVOAGLQN?4GNTCYVNASQQCLTYIPPLANYMLSREHSQTCHRH 120 8 .8 QLAPREKLPLSSRRPAAVOAGLQKIGNTFYVNVSLQCLTYTLPLSNYMLSREDSQTCHLH 120 8 .6 QLAPREKLPLSSRRPAAVGAGLQKIGNTPYVNVSIJQCLTYTLPLSNYMLSREDSQTCHLH 120 18 8.5 KCCMLCTMQAHITWALHSPCI-VIQPSQALAAGFNROKQEDAnEFLMFTVDAMKKACLPGI4 180 8.1 KCCMLCT-MQABITWALHSPGHVIQPSQALAAGFHRGKQEDAHEFLMFTVDANKKACLPGH 180 8.21 KCMLcrMQAHITWALHSPGHVIQPsQALAAGFERGKQEDvHEELMFTVDAMKKACLPGH 180 4 .2 KGCMLCTMQAIIITR-ALHNPGUVIQPSQALAAGFHRGKQEDAHEELMFTVDANKKACLPGH 180 4 .5 KGCMLCTMQAIITRALHNPGHVIQPSQALAAGFI4RGKCEDAI{EFLMFTVDANKKACLPGH 180 4.5 KGCMLCTMQAJ-ITRALHNPGHVIQPSQALAAGFHRGKQEDAIIEFLMFTVDAMKKACLPGH 180 8.3 KGCMLCTMQAHITRALHIPG-IVIQPSQALAAGFHRGKQEDAALEFLMFTVDAMRKACLPGH 180 8.11 KOCMLCTMEAHITWPLHIPOI4VIQPSQALA.AGFHRGKQEAALEFLMFTVL1ANKKACLPGH 180 8 .61 KCCP4CTMAHITWPLHIPGHVIQPSQALAAGFHRGKQEDAEFLMFTVDAMKKACLPGH 180 8.68 KCCIFCTMQAHITWALYRPGHVIQPSQVLAAGFHRGEQEDAHEFIJMFTVDAMKKACLPGH 180 KQVIHSKDTTLIHQIFGGCWRSQIKCLNCHGTSDTFDPYLDIALDIQAAQSVKQALEQL 240 8.7 KQVnDHSKDTTLIHQIFGCCWRSQIKCLHCHGISDTFDPYLDIALDIQAAQSVKQALEQL 240 8.1 KQVDEHCKDTTLINQIFGGCWRSQIKCLHCHGISDTFDPYLDTALDIOAAOSVKQALEQL 240 4.2 K0VD1HHSKDTTLI11IFGYWRSQIKCLUC1GISDTFDPYLDIALDIQAAQSVQQALEQL 240 4.3 KQVDHHSKDTTLIHQIFGGYWRSQIKCLHCHGISDTPDPYLDIALDIQAAQSVQQALEQL 240 KQVDHHSKDTTLIHQIFGGYWRSQTKCLHCHGTSDTFDPYLDTALOIQAAQSVQQALEQL 240 4 .1 KQVURHSKIJTTLIHQIFGGYWRSQIKCLHCI-GISDTFDPYLDIALDIQAAQSVQQALEQL 240 8.3 KQVDNI-SKTTLIHQIFGGYWRSQIKCLHCIGISDTFGPYLDIALDIQEAQSVKQALEQL 240 8.11 196 8.8 KOLDHHSKDTTLIHOIFGAYWRSQIKYLHCHGISDTFDPYLDIALDIQAAQSVKQALEQL 240 8 .6 KOLIHHSKDTTLIHOIFGAYWRSQIKYLHCHGISDTF'DPYLDIALDIQAAQSVKQALEQL 240 WO 03/072724 PCT/US03/05338 -78- VKPEELNGENAYHCGLCLQRAPVSKTIJTLHTFAKERILETQRPWVVTREKLAKSVQYAES 300 8.7 VKPEELNGENAYHCGLCLQRAPASKTLTLHTSAKVLILVLKRFSDVTGNK±AKNVQYFEC 300 8 .1 VKPEELNGENAYHCGLCLQPAPASNTLTLHTSAKVLILVLKRFSDVAGNKLAKNVQYPEC 300 4.2 VKPEELNGENAYHSGVCLORAPASKTLTL-TSAKVLILVLKRFSDVTGNKIAKNVQYPEC 300 4.3 VKPEELNGENAYHCGVCLQR-APASKTLTLHTSAKVLILVLKRFSDVTGNKIAKNVQYPEC 300 4 .5 VKPEELNGENAYHCGVCLQR-APASKTLTLHTSAKVLILVLKRPSDVTGNKIDKNVOYPEC 300 4 .1 VKPEFLNGENAYNCGVCLQR-APASKTLTLHNSAKVLILVLKRFPDVTQNKIAKNVQYPFC 300 8.3 267 NKIAKNVQYPEC 208 8 .8 VKPKEIJNGENAYHCGLCLQKAPASKTLTLPTSAKVLILVLKRFSDVTGNKLAKNVQYPKC 300 8.6 VKPKELNGENAYHCGLCLQKAPASKTLTLPTSAKVLILVLKRFSDVTGNKLAKNVQYPKC 300 ***YSQTPVYLALKGSHGHFYKQGWKMDKTC 6 8.5 LDMQPYMSQONTGPLVYVLYAVLVHAGWSCHDGHYFSYVKAQEGQWYKMDDAKVTACSIT 360 8.17 LDMQPYMSQQNTGPLVYVLYAVLVHAGWSCHDGI4YPSYVKAQEGOWYKM4DDAKVTACSIT 360 8.21 LDMQPYMSQQNTGFLVYVLYAVLVHAGWSCMDGHYFSYVKAQEVQWYKMDDAEVTVCSII 360 4 .2 IDMQPYMSQQNTGPLVYVLYAVLVHAGWSCHNGHYFSYVKAQEGQWYK<MDDAEVTAASIT 360 4.53 LDMQPYMSQQNTGPLVYVLYAVLVHAGWSCHINflHYFSYfVKAQEGOWYK<MDDAEVTAASIT 360 4 .1 LDMKLYMSQTGPLVYVLYAVLVHAGWSCHNGHYFSYVKAQEGOWYKMDDAEVTASSIT 360 48.1 LDMQPYMSQQNTcPLVYVLYAVLVHAGWSCHNGHYSSYVKAQEGQWYKMDDAEVTASSIT 360 8.11 LDMOPYMSQQNTGPLVYVLYAVLVHAGWSCHNGHYFSYVKVQEGQWYKMDDAE--------- 261 8 .8 RDMQPYMSQQNTGPLVYVLYAVLVI4AGWSCaNGNYFSYVKAQEGQWYK<MDDAEVTASGIT 360 8.6 RDMQPYMSQQNTGPLVYVLYAVLVHAGWSCHNG}TYFSYVKAQEGQWYKMDDAEVTASGIT 360 r* 42 SVLSQQAYVLFYIQKSENER-HSESVSRGREPRALGAEDTDRRATQGELKRDHPCLQAPEL 420 8.7 SVLSQQAYVLFYIQKSEWERHSESVSRGREPRALGAEDTDRRATQGELKRDHPCLQAPEL 420 4.1 SVLSQQAYVLFYIQKSEWER-HSESVSRGREPRALGAEDTDRRAKQGELKRDHPCLQAPEL 420 4 .2 SALSQQAYVLFYIQKSEWERHSESVSRGREPRALGTEDTDRRATQGELKRDHPCJQAPEL 420 4.3 SVLSQQAYVLFYIOKSEWER-HSESVSRGREPRALGAEDTDRRATQGELKR-DHPCLOAPEL 420 4 .1 SVLSQQAYVLFYIQKSEWERIISESVSRGRFPRALGAEDTDRFATQGELKRDHPCLQAPFL 420 8 .3 SVISQQAYVIFYIHKSEWER-HSESVSRGREPRALGAEDTDRRATQGELKDYPCJQVPEL 387 8.11 KSEWERHSESVSRGREPR-ALGAEDTDRRATQGELKRDYPCLQVPEL 307 8.8 SVLSQQAYVLFYIQKSEWERHSESVSRGREPRALGAEDTDRPATQGELKRDHPCJQVFEL 420 8.6 SVISQQAYVLFYIQKSENERHSESVSRGREPR-ALCAEDTDRPATQGELKRDHPCLQVPEL 420 DERLVER-ATQESTLDHWRFPQEQNKTKPEFNVRKVEGTLPPNVJVIHOSKYKCGMKNHHP 480 8 .7 DEaLVERATQESTLDHNRFPQEQNKTKPEFNVRKVECTLPPNVLVIQSKYKCGMKNHHP 480 8 .1 DEHLVERATQESTLDHWKFLQEQMKTKPEPUVGKVEGTLPPNALVIHQSKYKCGMKNIIHP 480 4 .2 DEHLVERATQESTLDHNKFLQEQNKTKPEFNVRKVEGTTJPPDVIJVIHQSKYKCGMKNHHP 480 4 .3 DEHLVERATQESTLDRNKFI.QEQNKTKPEFNVRKVSGTLPPDVLVIHQSKYKCGMK4HHP 480 4 .5 DEI-LVEATQESTLDHKFLQEQNKTKPEFNVRKVEGTLPPDVLVTHQSKYKCG?4KNHHP 480 4 .1 DEHLVERATQESTLDUWKFLQEQNKTKPEFNVRRVEGTVPPDVLVIHQSKYKCRMKNHHP 480 8 .3 DEHLVERATQESTLDHWKFLOEQNKTKFEFNVRKLEGTLPPNVLVIHQSKYKCGMC4HHP 447 8.11 DEHLVERAVQESTLDHWKFLQEQNKTKPEFNVRKLEGTLPPNVLVIHQSKYKCGMKNH4P 367 8 .81 DEHLVERZATQESTLDHWKFPQKQNKTKPEFNVRKVEGTLPPNVLVIHQSKYKCGMKNHHP 480 8 .6 DEHLVEPATQESTLDHNKPPQKQNKTKPEFNVRKVEGTLPPNVLVIHQSKYKCGMKNHHP 480 WO 03/072724 PCT/US03105338 -79- EQQSSLLNLSSTTRTDQESVNTGTLASLQGRTRRSKGKNKHSKRALLVCQ 530 6.7 EQQSSLLNLSSTTPTDQESVNTGTTJASLQGRTRRSKGKNKHSKPALLVCQ 530 8B.1 EQQSSLLNLSSTTRTDQESMTGTLASLQGRTRPAKGKNKHSKRALLVCQ 530 4 .2 EQQSSLLNLSSSTPTHQESMNTGTLASLRGRARRSKGKNKHSKRALLVCQ 530 4.3 EQQSSLLNLSSSTPTHQESMNTGTLASLRGRARRSKGKNKHSKRALLVCQ 530 4 .5 EQQSSLLNLSSTTPTHQESMNTGTLASLRGRARRSKGKNG{SKRALLVCQ 530 4 .1 EQQSSLLNLSSTTPTDQESMNTGTLASLRRTRRSKKJKHSKRALLVCQ 530 8.3 EQQSSLLNLSSTNPTDQESMNTGTLASLQGRTRRAKGKNKECKSAJLVCQ 497 B .11 EQQSSLLNLSSTNPTDQESMNTGTLASLQGRTRRSKGKNKHCKRALLVCQ 417 8.8 EQQSSVLNLSSTKPTDQESMNTGTLASLQGSTRRSKGNNKHSKRSLLVCQ 530 8.6 EQQSSLLNLSSTKPTDQESMNTGTLASLQGSTRRSKGNNKHSKRSLLVCO 530 WO 03/072724 PCT[US03/05338 Table 29 GLUSTAL W 81) multiple sequence alignment of putative promoter sequences of hDUBs (upstream of ATG initiation codon) 8.9 8.10 8.3 8.11 4 .2_a 4.3 4.2_b 4.4 4.1_b 8.1 8.7 8.6 8.8 8.2 4. 1a 8.9 8.10 8.3 8.11 4.2_a 4.3 4 .2-b 4.4 4. 1_b 8.1 8 .7 8.6 88 3.2 4. 1_a B .9 8.10 8.3 8.11 4.2_a 4.3 4.2_b 4.4 4.1_b B.1 B.7 8.6 B8 8.2 4. 1_a

TGACGTGTGTGAAA-ACTACAGTGTGATGAGCATGACTTGCAGACAGGTTATCGATTGGGC

GACGTGTGTGAAAACTACAGTGTGACGAGCATGACTCGCAGACAGGTTATCGATTGGGC

GATATCAATACGGC

GATATCAATACGGC

TTATCGATTGGGC

fGAGCAT'GACTGGCAGACAGCTTATCGATTGGGC

GATGAGCATGACTGGCAGACAGCTTATCGATTGGGC

GTGATGAGCATGACTGGCAGACAGCTTATCGATTGGGC

GTGATGAGCATGACTCGCAGACAGCTTATCGATTGGGC

AfTGCAATGAGCATGACACGCAGGCAGGATATCAATTCGGC

CAATGAGCATGACACGAAGACAGAATATCAATTCGGC

CAATGAGCATGACATGCAGGCAGGACATCAATTCGGC

TGTGATGAGCATGACTCGCAGACAGGTTATCGATTGGGC

TGTGATGAGCATGACTCGCAGACAGGTTATCGATTGGGC

TCTCTGTCAGAACCATGGTACTCTGTTGTGGTGTGAAAGTAGC

TCACATCTTCTCGGCCAGATGCAGCCTTGCTGAAATCCAGCCGGACTTCTC

AGTATAGCASAGCAGAGAGCTG-GAAGGGACC

T-CCCCTCAAAAT- TAGTTATGCATTAAAGGACACCGATGCCC- -AGGTCCCGGCTO T- CCCCTCAAAAT- CAGTTATGAGCATTAAAGCACACCGATGCCC -AGGTCCCGGCTC T-CACCTCAAAAG-CAGTTATG-AGCATTAA.AGGACACCCATGCCT- -AGGTCCCGCTTA T-CACCTCAAAAG- CAGTTATGAt3CATTAAAt3GACACCCATGCCT- -AGGTCCCGGTTA T- CCCCTCAAAAT- CGGTTATGAGCATTCAAGCACACCGATGCCC -AGGTCCCGGCTG T- CCCCTCAAAAT-CGGTTATC-AGCATTCAAGCACACCGATGCCC- -AGGTCCCGGCTC T- CCCCTCAAAAT- CGGTTATG-AGCATTCAAGCACACCGATGCCC -AGGTCCCGGCTG T- CCCCTCAAAAT- CGGTTATC-AGCATTCAAGCACACCGATGCCC AGGTCCCGGCTC T-CCCCTCAAAAT-CGGTTATO-AGTATTCAAGCACACCGATGCCC- AGGTCCCGGCTG T -CCCCTCAAAAG- CTGTTATC.AGCATTAAAGGACACCAATGCCT AGTTCCCGGTTA T-CACCTCAAAT- -CAGTTGTC.AGCATTAAAGAAAACCAATTCCT AGGTCCC3CTTA T -CACCTCAAAAG- CAGTTATC-AGCATTAAAGGACAACAATTCCT AGGTCCCGCTTA T-CCCCTCAAAAT-CAGTTAGGAACATGAAAGCACACCGATGCCC- AGGTCCTGGCTG T-CCCCTCAAAAT- CAGTTAGGAACATGAAAGCACACCGATGCCC- AGGTCCTGGCTG3 CACAGATCATCTG- TAGAT -TAAGGGGTGTGGCTTTGTTCCAACA- -AAGCTTTATTTA

TCCCTGAGAAGTCACAACTCTCAACTGAGACCCGCGTCGACTTCTGCGATGATTTGGCGC

TGCATCCCTAAT GATATAAGAAAGTATCTGTACTAGCCCTGA- -ATGGTATAACTA

*-CTCAGTTGGGAGCCGC-TCGATGTAG

CAGGAATAAGAC- CCTCCGCGTCTTGTGTGAAGCCACGGC- -ATCTGGATTGCTCATGC CAGGATAAGAC CTCCACGCTTGTGTGAAGCCACGGC- -ATGTGGATTGCTCATGC AAGAGATAAGAC- TCTCCCACACCCTGTGTGAAGCCACGGC- -ATGTGGATTGCTCATGC AAGGATAAGAC- TCTCCCACACCCTGTGTGAAGCCACGGC- -ATGTGGATTGCTCATGC CAGGAATAAGAC- CCTCCAGGGTCTTGTGTGAAGCCTCGGC- -ATCTGCATTGCTCATGC CAGGAATAAGAC-CCTCCAGGGTCTTGTGTGAAGCCTCGGC- -ATCTGCATTGCTCATGC CAGGAATAAGAC- CCTCCAGGGTCTTGTGTGAAGCCTCGGC- -ATCTGCATTGCTCATGC CAGGAATAAGAC-CCTCCAGGGTCTTGTGTGAAGCCTCGGC- -ATCTGCATTGCTCATGC CAGGATAAGAC- CCTCGACGCTTGTGTGAAGCCTCGGC- -ATCTGCATTGCTCATGC AAAGATAAGAC-CTCCACACCCTGTGGGAAGCCACGGC- -ATCTGGATTGCTCATGC AAGAGATAAGAC- CATCCAACAACCTGTGTGAAGCCACCGC- -ATCTGGCTTGCTCATGA AAGGATAAGAC- CATCCAACATCCTGTGTGAAGCCACGGC- -ATCTGGATTGCTCATGT CAGGAATAAGAT- CCTCCGACGTCTTGTGTGAAGCCACGAC- -ATCTGCATTGCTCATGC CAAACACAGGCTGTGGGCTGGATTTGGCCTGCAGCTGTAGT- -TTGTG3 ATCCTTGA CTGTGGCAAGAC AGCTTGCTCCCAGGGAGAAGCTTCCTCTGAGTAGCAGGAGACCTGC CAG -GTTAAATT TACGTGAAAAAGAAATCAACTTCTGCCTTGTTTAAGCAAACTTA- WO 03/072724 PCT[US03/05338 8.9 8.10 8.3 8.11 4 .2_a 4.3 4.2_b 4.4 4.1lb 8.1 8.7 8.6 8.8 8.5 8.2 4 .1 a 8.9 8.10 8.3 S .11 4 .2_a 4 .5 4.3 4.2_b 4.4 4.1_b 8.1 8.7 8.6 8.8 8.2 4.1_-a 8.9 8.10 8.3 8.11 4 .2_a 4.3 4 .2_b 4.4 4.1_b 8.1 8.7 8.6 8.8 8.2 4. 1_a TTCTG-G-GGATCATTCTCCTC-AAAATG- -GTGGCTCCTTCCTGCCTGTGGAGCACCTCT TTCTG- G- GGATCATTCTCCTC-AAAACG- -GTGGCTCCTTTCTCCCTGTGGAGCACCTTT TTCTG-G-GGATCATTCTCCTC-AAAATG- -GTGGCTCCTTTCTCACTGTGGAGCATCTTT TTCTG-G- GGATCATTCTCCTGAAAATG- -GTGGCTCCTTTCTCACTGTGGAGCATCTTT TTCTG-G-GGATCATTCTCCTGAAAATG- -GTGGCTCCTTTCTCCCTGTGGAGCATCTTT TTCTG- G- GGATCATTCTCCTGAAAATG- -GTGGCTCCTTTCTCCCTGTGGAGCATCTTT TTCTG-G-GGATCATTCTCCPQAAAATG- -GTGGCTCCTTTCTCCCTGTGGAGCATCTTT TTCTG-G-GGATCATTCTCCTGAAAATG- -GTGGCTCCTTTCTCCCTGTGGAGCATCTTT TTCTG-G-GGATCATTCTCCTGAAAATG- -GTGGCTCCTTTCTCCCTCTGGAGCATCTTT TTCTG-G- GGATCATTTTCCTGAAAATC- -GTGGCTGCTTTCTCCCTGTGTAGCATCTTT TTCTG-G-GGATCATTCTCCAGAAAATG- -GTGGCTCCTTTCTCCCTGTGGAGCATCTTT TTCTG- G- GGAACATTCTTCFGAAAATG- -GCGGCTCCTTTCTCCCTGTGGAGCATCTTT TTCTG-G- CGATCATTCTCCTGAAAATG- -GTGGCTTCTTTCTCCCTGTGGAGCATCTTT TTCTG- G- GGATCATTCTCCTG-AAAATG- -GTGGCTTCTTTCTCCCTGTGGAGCATCTTT TTCAG- ACAGTTTAGCAAGGCTGAAAAG -AACACCCACACCCCCTTGTTACCCACAGAT TGCGGTGGGGGCTGGGCTCCAC-AATATG GGAAATACCTGCTACGTG AACQCTTCC TTCAG GCATTAATTTTATAAATATGTAGAGAATACATACTCCTTAT- GAGCAGA--

*ACCGACCTTAACAGCCAAAGCTC

CTA-AGCA-GTGC- CCTTTCTTCACCCAGGACACTTTACATCAGGCACAGAAAGCCTTCT CTA-AGCA-GTGC- CCTTTCTTCACCCAGGACACTTTACATCAGGCACAGAAAGCCTTCT GTA- ACCA- GTGT -CCTTTCTTCCCCCAGGACACTTTACTTCAGGCACAGGAAGCCTTCT

CTA-AGCA-GTGTCTTTTCTTCCCCCAGGACACTTTACTTCAGGCACAGGAAGCCTTCT

CTA- ACCA- CTGCTCTTTTCTTCCCCCAGGACACTTTACATCCGGCACAGGAAGCCTTCT CTA- AGCA- GTGCTCTTTTCTTCCCCCAGGACACTTTACATCCGGCACAGGAAGCCTTCT CTA-AGCA- GTGCTCTTTTCTTCCCCCAGGACACTTTACATCCGGCACAGGAAGCCTTCT CTA-AGCA- GTGCTCTETTTCTTCCCCCAGGACACTTTACATCCGGCACAGGAAGCCTTCT CTA-AGCA- (T'GCTCCTTTCTTCCCCACAGGAAACTTTACATCAGGCACAGGAAGCCTTCT CTA- AGCA- GTGCTCCTTTCTTCCCACAGGAAACTTTACATCAGGCACAGGAAGCTTTCT CTA-AGCA-GTGC- CCTTTCTTCCCCCAGGACACTTTACATGAGGCTAGGAAGCCTTCT

CTA-AGCA-GTGCTCCTTTCTTCCCCCAGGACACTTTACATCAGCGCAAGAAGCCTTCT

CTA- AcCA-GcTGCTCCTTTCTTCCCCCAGGACACTTTACATCAGGCGCACGAAG.CCTTCT GGGTGGGA- CTGTGTTGGCCACAGACCGAGAGACGGGTGCTCACAGGGGAACGTACAGCA

CAGCAGTGTCTGACATACACACCGCCCCTTGCCAACTACATGCTGTCCCGGGAGCACTCT

AACAATGTTTGCGCCATATGGTCCATGATGGGTGTTCAATAATGTGTGATGATGATAAT

GAGACAACGGCAGAA*CAGGT*GACGGCAACTAA

GATGGAGCACACCTGGCCCATGAAAAGACAAGGGATAAGAAACGGGGCCAAAGATCACAG

GATGGAGCACACCTGGCCCATGAAAAAACAAGGGA-A-AGAAACGGGGCCAAAGGTCACAG

GATCGAGCACACCTGGCCCATGAAAAGACAAGGGA- AAGAAATGGGGCCAAAGGTCACAG GATGGAGCACACCTG7GCCCATGAAAAGACAAGGGA- AAGAAACGGGCCCAAAGGTCACA(C GATGGAGCACACCTGGCCCATGAAAAGACAAGGGA- AAGAAACGGGGCCAAAGGTCACAG GATGGAGCACACCTGGCCCATGAAAAGACAAGGGA- AAGAAACGGGGCCAAAGGTCACAG GATGGAGCACACCTGGCCCATGAAAAGACAAGGGA- AAGAAACGGGGCCAAAGGTCACAG GATGGAGCACACCTGGCCCAPGAAAAGACAAGGGA -AAGAAACGGGCCAAAGGTCACAG

GATGGAGCACACCTGGCCCATGAAAAGACAAGGGA-AAGAAACGGGGCCAAAGGTCACAC

GATGGAGCACACCTGGCCCATGAAAAGACAAGGGA- AAGAAATGAGGGCCAAAGGTCACAC GATGAAGCACACCTGG3CCCATGAAAAGACAAAGGA- AAGAAACAOGCCAAAGGTCACAG GATcIAAGTACACCTGGCCCATGAAAAACAAAGGA-AAGAAACAGGGCCAALAGGTCACAG GATGGAGCACACCTGGCCCATGAAAAGACAAGGGA- AAGAAACCGGGGCCAAAGGTCACAG TGTAGAGGCCGGAAGGTGCTCCAGGGCACAAGTGT -GGGAAAGTGGGACATACGGGGAAG CAAACATGTCATC- -GTCACAAGTGCTGCATGCTCTGTACCATGGAAGCTCACATCACAT AATGAAGACAATAGTGACAAATAAAAGAAAATAAA- AAGCAGTGAAACAAAGTGGTTTAA WO 031072724 8.9 8.10 8.3 8.11 4. 2_a 4 .5 4.3 4.2_b 4.4 4.1lb 8.1 8.7 8.6 8.8 8.5 8.2 4. 1_a 8.9 8.10 8-3 8.11 4.2_a 4.5 4.3 4.2_b 4.4 4.1_b 8.1 8.7 8.6 8.8 8.2 4 .1_a 8.9 8.10.

8 .3 5.11 4 .2_a 4.3 4 .2_b 4.4 4 .1_b 8 .1 8.7 8.6 8.8 8.2 4 .l1a PCT/US03I05338 -82- TCCTCTCATTCCACCGTCCTCCTTAAAATCATCCTAATTTCATGGGCTCT-GCGGCCACG 404 TCCTCTCATTCCATCATCCTCCTTAAAATCATCCTAATTTCATGGGCCCT -GAGGCCACG 402 TCCTCTCATTCCATCATCCTCCTTAAAATCATCCTAATTTCATGGGCCCT-GAAGCCAGG 357 TCCTCTCATTCCATCATCCTCCTTAAAATCATCCTAATTTCATGGGCCCT-GAGGCCACG 357 TCCTCTCATCCCATCATCCTCCTTAAAATCATCCTAATTTCATGGGCCCT-GAAGCCAGG 357 TCCTCTCATCCCATCATCCTCCTTAAAATCATCCTAATTTCATGGGCCCT-GAAGCCAGC 378 TCCTCTCATCCCATCATCCTCCTTAAAMJCATCCTAATTTCATGGGCCCT-AAGCCAGG 380 TCCTCTCATCCCATCATCCTCCTTAAAATCATCCTAATTTCATGCCCCT-GAACCAGG 382 TCCTCTCATCCCATCATCCTCCTTAAAATCATCCTAATTTCATGGGCCCT-GAAGCCAGG 382 TCCTCTCATTCCATCATACTCCTTAAAATcATCCTAATTTCATGGGTCCT-GAAGCCAGG 385 TCCTCTCATTACATCATCATCCTTAAAATCATCCTAATTTCATGAGCCCT-GAAGACAGG 379 CCCACTCATTTCATCACCATCCTTAAAATCATCCTAATTTCATGGGCCAT -GAAGCCAGG 381 TCCTCTCATTCCATCATCCTCCTTAAAATCATCCGAATTTCATGAGCCCTTGAAGCCAGG 384 TCCTCTCATTCCATCATCCTCCTTAAAATCATCCGAATTTCATGAGCCCTTGA.AGCCAGG 384 TTTCCAGAAAGCATGATGTCAAGTTGGAG-GTGGAGCGCTGCTGcGCTTaTGAAGrnTCT 386 GGCCCC- -TCCA-CATTCCTGGCCATGTCATCCAGCCCTCACAGGCATT---------- G 389 TAGCTATACATAGTTATT -TTGTTGAAAGATTCTGCTGCTAATATTATTCAATATTTTTG 370 GCGTTTTACCTCAACTTGGCAGCTCATCGCCGGGT*C 46 GCTGTTTCTTTACACCTCGAGACCTTGGCGCCAGGCCTCAATTCTGCCCGGTGCTTACT 464 GCTGTTTCTTTACACCTCGAGACCTTGGCGCCGGGCCTCAATTCTGCTCCAGTGCCTTACT 412 GCTGTTTCTTTAAA-ACTAGAGGCCTTGGCGCCGTGCCTCAATTCTGCCCTGTTCCTTACT 417 GCTGTTTCTTTAPCACCTAGAGGCCTTGGCGCCGGGCCTCAATTCTGCCCTGTTCCTTACT 417 GCTGTTTCTTTACACCTAGAGGCCTTGGCGCCGGGOCTCAATTCCGCCCTGTTCCTTACC 417 GCTGTTTCTTTACACCTAGAGGCCTTGGCGCCGGGCCTCAATTCCOCCCTGTTCCTTACC 438 GCTGTTTCTTTACACO 1'AGAGGCCTTGGCGCCGGGCCTCAATTCCGCCCTGTTCCTTACC 440 GCTGTTTCTTTACACTAGAGGCCTTGGCGCCGGGCCTCAATTCCGCCCTGTTCCTTACC 442 GCTGTTTCTTTACACTAGAGGCCTTGGCGCCGGGCCTCAATTCCGCCCTGTTCCTTACC 442 GCTGTTTCTTTACACCTAGAGGCCTTGGCGCCGGGCCTCAATTCTGCCCTGTTCCTTACT 445 GCTGTTTCTTTACACCCAGAGGCCTTGGCGCCGGGCCTCAATTCTGCCCTGTTCCTTACT 439 GCTGTTTCTTTACACCCAGAGGCCTTGGCGCCGGGCCTCAATTCTGCCCTGTTCCTTACT 441 GCTGTTTCTTTACACCCAGAGGCCTTGGCGCCGGGCCTCAATTCTGCCCTGTTCCTTACT 444 CGAGTCCAAGTGAGGGCGGGTTGTGAAGGGTCTCCTCTCAAAGCTGACCGACTTCGGGAC 446 GCTGCTGGCTTCCATAGAGGCAAGCAGGAAGCTGCCCTTGAATTTCTCATGTTCACTGTG 449 TATGCTGGC- -GCAAATAAGGAAATTTACATCGTCTAATAAAAATTATTTATCAATTTAT 428 *TTAAATTOAATCTGGCCGACTATCGTACAA 523 GTCTAAGACATTTTGGGAAAATCCCTAGAGC- CTAGATCTTCAATCCTGGTAAGCCAGAG 523 GTCTAAGAATTTTGGGAAATCCCTAGAGC CAGATCTTCAATCCTGGTAAGCCAGAG 521 GTCTAAGAAAGGTTGGGAAAATCCCTAGAGC- CAGGATCTTCATTCCTGGTAAGCCAGAG 476 GTCTAAGAAGTTGGGAAAATCCCTAGAGC- CAGGATCTTCATTCCTGGTAAQCCAGAG 476 GTCTAAGACATGTTGGGAAAATCCCTAGAGC- CAGGATCTTCATTCCTGCTAAGCCAGAC 497 GTCTAAGACATGTTGGGAAAATCCCTAGAGC -CAGGATCTTCATTCCTGCTAAGCCAGAC 497 GTCTAAGACATGTTGGGAAAATCCCTAGAGC -CAGGATCTTCATTCCTGCTAAGCCAGAC 491 GTCTAAGACATGTTGGGAAAATCCCTAGAGC -CAGGATCTTCATTCCTGCTAAGCCAGAC 501 CTCTAAGACATGTTGGGAAAGTCCCTAGAGC -CAGGATCTTCATTCCTGCTAAGCCAGAC 501 GTCTAAGACATGTTTGGGAAAGTCCAGAGC -CAGGATCTTCATTCCTGc3TAAGCCAGAC 54 GTCTAAGACATTTTGGGAAAATCCCTAGAGC -CAGGACCTTCATTCCTGGTAAGCCAGAG 498 GTCTAAGACATTTTGGGAAAATCCCTAGAGC- CAGGATCTTCATTCCTGGTAAGCCAGAG 500 GTCTAAGACATTTTGGGAAAATCCCTAGAGC AGGATCTTCATTCCTGGTAAGCCAGAG 503 TTCCCAGGGATTGTTGTTGAGTCCACGGCTCACGTCGTCCACACTC -TGAGGTCCCATGG 505 GATGCCATGAAAAAGGCATGCCTTCCCGGGCA 'AAGCAGGTAGATC -ATCACTCCAAGG 507 AAAACAGTAAAAA'rTTCATAG- -AATGGGGCTAAGAATCTGCACTGCAAACTAACTCTTT 488 WO 03/072 724 8. 9 8. 10 8.3 8.11 4. 2_a 4 .5 4 .3 4 .2 b 4.4 4.1lb 8.1 8.7 8.6 8.8 8.5 8.2 4 1a 8.9 8 .10 8 .3 8.11 4.2 a 4.5 4.3 4 .2_b 4 .4 4.1_b 8.1 8.7 8.6 8.8 8.2 4 .1la 8.9 8.10 8.3 8.11 4 .2_a 4.3 4.2_b 4.4 4. 1_b 8.1 8.7 8.6 8.8 8.2 4.1 la PCT/USO3/05338 -83- AGccTGc3AGA:-AcACCCAAATTATGTCCCTCTTAGTTCAGGGAACATGTCCATTTTCGTC 583 AGCCTGAAGA:-ACACCCAAATTATGTCCCTCTTAGTTCAGGGAACATGTCCATTTTCGTC 581 AGCCTGAAGAC ACACCCAAATTCTGTCCCTCTTACTTCACGCAACATGTCCACTTTCGTC 56 AGCCTGAAGACACACCCAAATTCTGTCCCTCTTACTTCAGGGAACATGTCCACTTTCGTC 536 AGCCGOAACACACACCCAAATTCTGTCCCTCTTACTTCAQGGAACATQTCCACTTTCGGC 526 AGCCGGAAGAC'ACACCCAAAPTCTGTCCCTCTTACTTCAGGGAACATGTCCACTTTCGGC 557 AGCCGGAAGACACACCCAAATTCTCTCCCTCTTACTTCAGGC3AA!2ATGTCCACTTTCGCC 559 AGCCGGAAGACACACCCAAATTCTGTCCCTCTTACTTCAGGGAACATGTCCACTTTCGGC 561 AGCCGGAAGACACACCCAALATTCTGTCCCTCTTACTTCAGGGAACATGTCCACTTTCGGC 561 AGAATGAAGACACACCAAAATTCTGTCCCTCTTAATTCAGGGAACGTGTCCACTTTCGTC SE64 AGCCGAAAGACACACCCAAATTCTL3TCCCTCTTAGTTCAGGGAACAGGTCTACTTTCGTC 558 AGCCTGAAGACACACCCAAA EGCTTCCCTCTTAGTTCAGGGAACATGTCCACTTTCGTC 560 AGCCTGAAQACACACCCAAAVGCTGTCCCTCTTAGTTCAGGGAACATGTCCACTTTCGTC 563 AGCCTGAAGACACACCCAAATGCTCTCCCTCTTAG3TTCAGGGAACATGTCCACTTTCGTC 563 ATTCGCCACCCACATTCATCTACTCTCCTCTCTCTCTTCCTTACCTCCTTTGATCCCCTC 565 ACACCACCCTCATCCACCAAATATTTGGAGGGTACTGGAGATCTCAAATCAAGTGTCTCC 567 CAGTTGATTTTATGCACAGAAATTATTGAGAATCCCCTTATCTAGATCCAACAGATCTGG 546 AGATAATTGCCAATTCAATCATCACTCATC*AT 643* AGCATTAAAATTTTCGCACCAAATGTGCTAACTGCAATTCCACCATACAATGCATAACTG 643 AGCACTAAAATTTTTGCACCAAATGTGCTAACTGCAATTCCACCATGCAATGCGTAACTG 56 At3CATTACAATTTTTGCACCAAATGTGCTAACTGCAATTCCACCATACAATGCATAAATG 596 AOCATTACAATTTTTGCACCAAATGTGCTAACTGCAATTCCACCATACAATGCATAAC~TG 596 AGCATTACAATTTTGGCACCAAATGTGCTAACTGCAATTCCACCATACAATGCGTAACTG 56 AGCATTACAATCTTTGGCACCAAATGTGCTAACTGCAATTCCACCATACAATGCGTAACTG 617 AGCATTACAATTTTGGCACCAAATGTGCTAACTGCAATTCCACCATACAATGCGTAACTG 621 AGCATTACAATTTTGGCACCAAATGTGCTAACTGCAATTCCACCATACAATGCGTAACTG 621 AGCATTACAATTTTGGCACCAALATGTGCTAACTGCAATTCCACCATACAATGCGTAACTG 621 AGAATTAAAATTTTTGCACCAAATGTGCTAACTGGAAFTCCACCATACAATGCATAACTG 624 AGCATTACAATTTTTQCACCAAATGTCCTAACTCCAATTCCACCATACAATGCATAACTG 618 AGCATTACAATTTTTGCACCAAATGTACTAACTGCAATTCCACCATACAATGCATAACTG 620 AGCATTACAATTTWTGCACCAAATGTACTAACTGCAATTCCACCATACAATGCATAACTG 623 CCCA- TATGCTACCCCCCGCTACCAAACCTCTGCCA-AGCATACCACCCTATCGGCAGCTA 624 ACTGCCACGGCATTTCAGACACTTTTGGCCCTTACCTGGACATCGCCCTGGATATCCAGG 627 GCTTACATAGGTGCTATCAAGACTTAAGGAAGAAAATTTTCCTGACTCTATCCATACCTC 606 GAAATACAGGCAACATCTCATATCCTCAACAATTCAThTG AGAATCTX3GAGAC 697 TAAATGGAGCCAACATCTCAGATCCTGAACAATCGATGCG AGAATCCAGGAGAC 695 GAAATGGAGGGAACATCTCAG3ATCCTGAACAATCGATGCG--- ACAATCCACGAGAT 650 GAAATGGAGGGAACATCTCAGATCCTGAACAATCGATGCG AGAATCCAGGAGAT 650 GAAATGGAGGCAACATCTCCGATCCTGAACGATCGATGCG AGAATCCAGGATAT 650 GAAATGGAGGCAACATCTCCGATCCTGAACGATCGATGCG AGAATCCAGGATAT 671 GAAATGGAGCCAACATCTCCGATCCTGAACGATCGATGCG AGAATCCAGGATAT 673 GAAATGGAGGCAACATCGCCGATCCTGAACGATCCATCCG AGAATCCACGATAT 675 GAAATGGAGGCAACATCTCCGATCCTGAACGATCGATGCG AGAATCCAGGATAT 675 GAAATGGAGCGAAAATCCCAGATCATOAACAATCAA.AGCG AGAATCCACGAQAC 678 GAAATGGAGGGAACATCTCAQATCATGAACAATCGATGAG AGAATCCAGGAGAW 672 GAAATGGAGGGAACATCTCAGAGCATGAACAACTGATGCG AGAATCCAGGAGAT 674 GAAATGGAGGGAACATCTCAGACCATGAACAATCGATG3AG AGAATCCAGGAGAC 677 GAAATGCAGGGAACATCTCAGACCATGAACAATCGATGAG AGAATCCAGGAGAC 677 CTCTTCACTCCCA-ACTACATCGGCCGCATCNNNNNNNNN NNNNNNNNNNNNN 677 AAGCTCAGAGTGTCAAGCAAGCTTTGGAACAGTTGGTGAAGCCCGAAGAACTCAATGGAG 687 CAATTAGTAATAGATCTAGAGATTTAAAACTGAAATCCAGACCTC -CTGCTTCCATGTGC 665 WO 031072724 8.9 8.10 8.3 8.11 4-2_a 4.3 4 .2_b 4.4 4.1lb 8.1 8.7 8.6 8.8 8.5 8.2 4 .1la 8.9 8.10 8.3 8.11 4.2a 4.5 4.3 4.2 b 4.4 4.1_b 8.1 8.7 8.6 8.8 8.2 4 .1_a 8.9 8.10 8.3 8.11 4.2_a 4.3 4 .2_b 4.4 4 .1_b 8.1 8.7 8.6 8.8 8.2 4.1la PCT/US03I05338 -84- AOACCGCTTATTTTTGCCTTTTCCCACTGAAACAATGGCTAGTATTAACAATGTTATGCT 757 ACACGGCTTATTTTTGCCTTTTCCCAOTGAAACAAGGGCCAGTATTAACAATCTTATGCT 755 ACACGGCTGATTTTTGCGTTTTCCCTGTGAAACAAGGGCCAGTATTAAAAATGGTATGCT 710 ACACGGCTGATTTTTGCGTTTTCCCTCTGAAACAACCGCCACTATTAAAAATGGTATGCT 710 GCACGGCTTATTTTGGCCTTTTCCCACTGAAACAAGGGCCAGTATTAAA4ATGGCACGCT 710 QCACGGCTTATTTTCGCCTTTTCCCACTAAACAAGGGCCAGTATTAAAAATGGCACGCT 731 GCACGGCTTATTTTGGCCTTTTCCCACTGAAACAAGGGCCAGTATTAAAAATGQCACGCT 733 GCACGGCTTATTTTGGCCTTTTCCCACTCAAACAAGGGCCAGTATTAAAAATGGTACGCT 735 GCACGGCTTATTTTGGCCTTTTCCCACTGAAACAAGGGCCAGTATTAAAAATGGCACGCT 735 ACACGGCTTATTTTGGCCTTTTCCCACTGAAACAAGGACCAGTATTAAAAATGGTATGCT 738 ACACGGCTTATTTTTGCCTTTTCCCTTGAAACAAGGGCAAGTATTAAAAACTTTATGCT 732 ACACGGTTTATTTTTGCCATTTCCCAGTGAA-ACAAAAGCCAGTATTAAAAAGGTTATGCT 734 ACACGGCTTATTTTTGCCTTTTCCCTGTAAACAAGGGCCAGCATTAAAAAGGTTATGCT 737 ACACGGCTTATTTTTGCCTTTTCCCTGTGAAACAAGGGCCAGCATTAAAALAGGTTATGCT 737 NNNNNNN 737 AGAATGCCPATCATTGTGGTCTTTGTCTCCAGACGGCGCCGGCCTCCAAGACGTAAACTT 747 AGTGTCCTTTCACTGTCCTGTTTTGCTTCACTTGATGAAGAGATTTAGAATAAATGAC 725S ATCCTTGGTTTCACTCCCCACTTTTAAATCTCTCGGATGTTTACTTCT -TGAGACAGG- 814 ATCCTGGGTTTCACTCTCTGCTTTTAAATCTCTCCAATGTTTTCTTCT-TGAGACAGG-- 812 ATCCTCTGPTTCACTCCCTGCTTTTAAGTCTCC- -GAPCTTT-CTTCT-TAAGACACG- 764 ATCCTCTGTTTCACTCCCTGCTTTTAAGTCTCC- -GATGTTT-CTTCT-TAAGACAGG- 764 ATCCTCTG VTTCACTZCCTCCTTTTAAACCTCTCCGATGT-TTCTCCC-TGAGACAGC 766 ATCCTCTGTTTCACTOCCTGCTTTTAAACGTCTCCGATGT-TTCTCCC-TGAGACAGG- 787 ATCCTCTGTTTCACTCCCTGCTTTTAAACGTCTCCGATGT-TTCTCCC-TGACACAGG- 789 ATCCTCTGrTTCACT:-CCTGCTTTTAAAOGTCTCCGATGT-TTCTCCC-TGACACAGG- 791 ATCCTCTGI'TTCACT:-CCTGCTTTTAAACGTCTCTGATGT-TTCTCCC-TGAGACAGG- 791 ATACTCTGTTTCACTCCCTGCTTTTAAACGTCTCCCATGT-TTCTTCT-TGAGACAGG-- 794 GTCTTCTATTTCACTGCCTGCTTTTAAACGTCTCCGATGTATTCTTCTTGAGAAAGG-- 789 ACCCTCTG'FTTCACTCACTGCTTTTAAACGTCTCCGATGTTTTCTTCF-TCAGACAGG- 791 ATCTTCTGPTTTCACTCCCTGCTTTTAAACGTCTCCGATGTTTTCTICT-TCAGACAGG- 794 ATCTTCTGTTTCACTOCCTGCTTTTAAACCTCTCCCATCTTTTCTTCT-TCAGACACG- 794 NNNNNNNNNNNINNNNCTGCTTTTAAACGTCTCCGATGTTTTCTTCT-TCAGACAGG-- 794 TACACAOTTCTGCCAAGATCCTCATCCTCGTATTGAAGAGATTCTCCGATGTCACAGGCA 807 CACATGATTCAACTCCTCCTCAGCTCTGAGCAAT-ATAGCCCTGTCCTGGCAAACAAGAA 784 GCCTC-ACTGCCGTCACCCACGCTTTTCTACGGT GTAATTTTTGTTGTTCGCTT 867 GCCTC-ACTCCCGTCACCACGGCTTTTCTACGGT GCAATTTTCGGTGTTTGCTT 865 GCCTC-ACTTCOTTCCCCCTGACTTTTCTACGGT ATAATTTTCGTTGTTTGCTT 817 GCCTC-ACTTCCTTCCCCCTGACTTTTCTACGCT ATAATTTTCGTTGTTTGCTT 817 GCCTC-ACTTCCGTCAGCCGGGCTTTTCCACGGT ATAATTTTCCTTGTTTGCTT 819 GCCTC-ACTTCCGTCAGCCGGGCTTTTCCACGGT ATAATTTTCCTTGTTTGCTT 840 GCCTC-ACTTCCGTCAGCCGGGCTTTTCTACGGT ATAATTTTOCTTGTTTGCTT 842 GCCTC-ACTTCCGTCAGCCGGGCTTTTCTACGGT ATAATTTTCCTTGTTTGCTT 844 GCCTC-ACTTCCGTCAGCCGGGCTTTTCTACGGT ATAATTTTCCTTGTTTGCTT 844 GCCTC-ACTGCCGTCCGCCGGGC'2AT-CTAGAGT ATA.ATTTTCAGTGTTTGCTT 846 GCCTC-ACTACTGTCACCTGGCPTTTCTAAGCT ATAATTTTCCTTGTTTCCTT 842 GCCTC-ACTCCCGTCACCCGGGC -TTTCTACGGT ATAATTTTCCTTGTTTGCTT 844 GCCTC-ACTCCCGTCACCCGGGC2TTTCTACGGT ATAATTTTCCTTGTTTGCTT 847 GCCTC-ACTCCCGTCACCCGGGCCTTTCTACGGT ATAATTTTCCTTGTTTGCTT 047 GCCTC-ACTCCCGTCACCCGGGCTTTTCTACGGT ATAATTTTCCTTGTTTGCTT 847 ACAAA-ATTGCCAAGAATGTGCAATATCCTGAGTGCCTTGACATGCAGCCATACATGTCT 866 GCTCCTGCACTAGTAGAGCAGGCAAATATACGTT CACTAATCTAACATACAAG- 837 WO 03/072 724 8.9 8.10 8.2 8.11 4.2_a 4.3 4.2 b 4.4 4.1lb 8 .1 8.7 8.6 8.8 8.5 8.2 4 .1 a 8.9 8.10 8.3 8.11 4.2_a 4.5.

4.3 4.2 b 4.4 4.1_b 8. 1 8.7 9.6 8 .8 8.2 4 .1-a 8.9 8.10 B.2 8.11 4.2_a 4.3 4.2_b 4.4 4. 1_b 8.1 8.7 8.6 8.8 8.2 4.1la PCT11JS03105338 TTGTCAAATTTAGAAATTTTCATTTCA- -TCTCTATCAAATGTTGCTCCATT---- -ATCA 921 TTGTCAAATTTAGAACTTTTCATTTCA- -TCTCTATCAAATGTTGATCCATT---- -ATCA 919 TTGTCAAAATTAGAACTTTTTATTTCA- -TCTCTATGAAATGTTGATCCATT---- -ATCA 871 TTGTCAAAATTAGAACTTTTTATTTCA--TCTCTATGAAATGTTCATCCATT--- -ATCA 871 TTGTCCAAATTAGAACTTTTTATTTCA- -CCTCTAGGAAACGTTGATCCATT- -ATCA 873 TTGTCCAAATTACAACTTTTTATTTCA- -CCTCTAGGAAACGTTGATCCATT- -ATCA 894 TTGTCCAAATTAGAACTTTTTATTTCA- -TCTCTAGGAAACGTTGATCCATT- -ATCA 896 TTGTCCAAATTAGAACTTTTTATTTCA- -TCTCTACGAAACGTTGATCCATT---- -ATCA 898 TTGTCCAAATTAGAACTTTTTATTTTA- -TCTCTAGGAAACGTTGATCCATT- -ATCA 090 TTGTCAACCTTAGAACATTTTATTTCG- -TCTCTATGAAATGTTGATCCATT -ATCA 900 TTGTCAAAATTAGAACATTTTATTTCA- -TATCTATGAAATGTTGATCCATT -ATCA 896 TTGTCAAAATTAGAACTTTTTATTTCA- -TCTCTATGAAATGTTGATCCATT- ATCA 898 TTGTCAAAATTAGAACTTTTTATTTCA- -TCTCTATGAAATGTTGAGCCATT- -ATCA 901 TTGTCAAAATTAGAACTTTTATTTCA- -TCTCTATGAAATGTTGAGCCATT- -ATCA 901 TTGTCAAAATTAGAACTTTTTATTTCA- -TCTCTATGAAATGTTGATCCATT---- -ATCA 901 CACCAGAACACAGGACCTCTTGTCTATGTCCTCTATGCTGTGCTGGTCCACGCCGGGTGG 926 -GCAGTAGGCACTGTACCATAAACAAG-ACACTGTGGGGGTTCAGACCACG- -GCCAA 891 CAAGAG-A*ATTAGGGTTAAAGTTTTTTCTA 980* CATACGTATGA-AAATATTATCACCGTGCTGTGAGAThCGTTGTTTTTATTTTCATCAA 978 CATACGTATGA-AAATATTATCACCCATGCTGTGAGATACGTTGTTTTTATTTTCATCAA 978 CATACGTAPGG -AAAGACTATCACCCATGCTGTCAGATACGTTGTTTTTATTTTCATCAA 930 CATACGTATGG-AAAGACTATCACCCATGATGTGAGATACGTTGTTTTTATTTTCATCAA 930 CATACGTA2'GG -AAATATTATCACACATGCTGTCACATACGTTCTTTTTATTTTCATCAA 953 CATACGTATGG-AAATATTATCACACATGCTGTGAGATACGTTGTTTTTAITTTCATCAA 953 CATACGTATGG -AAATATTATCACACATGCTGTGAGATACGTTGTTTTTATTTTCATCAA 955 CATACGTATGG -AAATATTATCACACATGCTGTGA3AThCGTTGTTTTTATTTTCATCAA 957 CATACGTATGC -AAATATTATCACACACCTGTGAGATACGTTGTTTTTATTTTCATCAA 957 CATACACATGG- AAATATTATCACCCATCGTGTCAGATACGTTGTTTTTATTTTCATCACA 959 CATACGTATGG -AAATAGTATCAGCCAATGCTGTGAGATAAGTTGTTTTTATTTTGGTCAA 955 CGTAAGTATGG -AAATAG'JATCACCAGCTGTGAGATACGTTGTTTTTATTTTCATCAQ 957 CATACCTATGG -AP.ACAGTATCACCCATGCTGTGAQATACGTTGTTTTTATTTTCATCAG 960 CATACGTATGO-AAACAGTATCACCCATOCTGTCAGATACGTTGTTTTTATTTTCATCAG 960 AGTTGTCACAACGGACATTACTTCTCTTATGTCAAAGTTCAAGAAGGCCAGTGGTATAAA 986 AGTGGGGATTG- -ATAGGGCTAGTAAAGTCTAGGAAGTGTTCACTAACAAAATGTCTAA 948 *TTTGAAAAAGTTGTGAACTTATCCATTTGT 10*40* TTCTTTTGTAAAACAAAGGTTATAGTTGGGATACCTTCTGATTTCTCAAGTTTTTTGTTT 1040 TTCTTTAATAAACCAAAGGTTATAGTTGGGATACCTTCTGATTTCTCAAGTTTTTTCTTT 190 TTCTTTAATAA.ACCAAAGGTTATAGTTOGGGATACCTTCCGATTTCTCTAGTTTTTTGTTT 990 TTCTTTAATAAACCAAAGGTTATAGTTGGGATACCTTCCGATTTCTCTAGTTTTTTGTTT 990 TTCTTTAATAAACAAACGGTTATAGCTGGGATACCTTCTGAGTTCTCAAGTTTTTTGTTT 9923 TTCTTTAATAAACAAACGGTTATAGCTGGGATACCTTCTGAGTTCTCAAGTTTTTTGTTT 1013 TTCTTTAATAAACAAAAGGGTATAGCTGGGATACCTTCTGAGTTCTCAAGTTTTTTGTTT 1015 TTCCTTAATAAACAAAAGGTTATAGCTGGGATACCTTCTGAGTTCTCAAGTTTTTTGTTT 1017 TTC AATAAAAAAAGGTTATAGCTGGGATACCTTCTGAGTTCTCAAGTTTTTTGTTT 1016 TTC- AAGAAAAAAAGQGTATACTTGGGATACCTTCTGATTTCTCAAGATPTTTCTTT 1016 TTCTTrTAATAAACAAAAGCTTATAGTTGGGATACCTTTGATTTCTCAACGTTTTTTGTTT 1015 TTATTTAATAAACAAA.AGCTTATAGTTGCGATACCTTTGGATTTCTCAAGTTTTTTGTTT 1017 TTCTTTAATAAACAAAAGCTTATAGTTTGGGATACCTTTGGATTTCTCAAGTTTTTTCTTT 1020 TTCTTTAATAA.ACAAAAGCTTATAGTTTGGATACCTTTGGATTTCTCAAGTTTTTTGTTT 1020 ATGGATGATGCCGAGGTCACTGCCTCTGGCATCACCTCTG- -TCCTGAGTCAACAGGCC 1043 TTATTAACTAAACTAAATGGTTTC -TCAACATGACCTAATTAATTGTA-ACTTACTATAAA 1007 WO 03/072724 PCTUS03105338 8.9 8.10 8.3 8.11 4.2_a 4.S 4.3 4.2 b 4.4 4 -lb 8.1 8 .7 8.6 8 .8 8 .5 8.2 4 1a 8.9 8.10 8 .3 8.11 4-2_a 4 .5 4 .3 4 .2_b 4.4 4 1_b 8. 1 8.7 8.6 8.8 8.2 4 .1la 8.9 8 -10 8.3 82-11 4.2_a 4 .3 4.2_b 4.4 4 .1-b 8.1 8.7 8.6 8.8 8.2 4 .lIa CAGGTTTCTT CATGTTTTCTTTCTTTTTTTTTTTTTTTTTTTT GAGACGGGGTCTCGCTCT

CATGTTTTCTTTCTTTTTTTTTTTTTTTTTTTTTTTTTTTTTGAGACGGGGTCTCGCTCT

CGTGTTTTCTT CGTGTTTTCTT CATATTTTCTT CATGTTTTCTT CAAGTTTTCTT-- CATGTTTTCTT CATGTTTTCTT 1051 1049 1041 1050 1003 1024 1026 1028 1027 1027 1026 1028 1031 1031 1031 1062 1021 GTCGCCCAGGCCGGACTGCGGACTGCAGTGGCGCAATCTCGGCTCACTGCAAGCTCCGCT 1101 GTCGCCCAGGCCGGACTGCGGACTGCAGTGGCGCAATCTCCGCTCACTGCAAGCTCCGCT 1110 TCCCOGGTTCACGCCATTCTCCTGCCTCAGCCTCCCGAGTAGCTGGGACTACAGGCGCCC 1161 TCCCGGGTTCACGCCATTCTCCTGCCTCAGCCTCCCGAGTAGCTGGGACTACAGGCGCCC 1170 WO 03/072724 PCT111S03105338 8.9 8.10 8.3 8.11 4.2_a 4.3 4.2 b 4.4 4.l b 8 .1 8.7 8.6 8 .8 8.2 4. 1_a 8.9 8 8 .2 8 .11 4.2_a 4.3 4.2 b 4.4 4.1_b 8 .1 8.7 8 .6 8.8 8.2 4 .1la 8.9 8.10 8 .3 8 .11 4.2_a 4 .3 4 .2_b 4 .4 4 .1-b 8.1 8.7 8.6 8.8 8.2 4 .lIa 1052 1050 GCCACCGCGCCCGGCTAATTTTTTGTATTTTTAGTAGAGACGGGGTTTCACTTTGTTAGC 1221 C-ACCGCGCCCGGCTAATTTTTTGTATTTTTAGTAGAGACGGGGTTTCACCTTGTTAGC 1229 AA T C C C C C 1 6 AA T C G C C C 16 AAA T C G C C C 1 1 T G AC 1 3 AA T C T G AC 1 4 TC AC 1 4 T G AC 1 4 C TC AC 1 4 G C AC 1 4 CC AC 1 4 C C AC 1 4 AA T C CC AC 1 4 C C AC 1 4 TA A C T A C TT 13 WO 03/072724 PCTIUS03/05338 8.9 8.10 8.3 8.11 4-2_a 4.3 4. 2_b 4.4 4.l b 8.1 8.7 8.6 8.8 8.5 8.2 4 .1_a 8.9 8.10 8.3 2.11 4.2_a 4.5 4.3 4.2_b 4.4 4.1_b 8.1 8. 7 8.6 8.8 8.2 4. 1_a 2.9 8.10 2.3 8.11 4 .2_a 4.3 4.2_b 4.4 4.1_b 8.1 8.7 8.6 8.8 8.2 4.l a GTCCAAAACCACTCGCTATGCAATGTCTTG -ACCATCTCTCTTTTCTGGCAAATATAAAT GTCCGAAACCATTCACTATACAATGTCATT- TTCATCTCTCTTTTCTGGCACACATAAAT ATCCGAAATCATTCACTLATACAATGTCATG- ACCATCTCTCTTTCCTGGCAAACAIAAAT

ATCCGAAATCATTCACTATACAATCTCATG-ACCATCTOTCTTTTCTGGCAAACAAAAT

GTCCGAAACCCCTCACTATGCAGTGTCATG-ACCGTCTCTCTTTTCTGGCAAACAIAAAT

GTCCGAAACCGCTCACTATGCAGTGTCATC -ACCOTCTCTCTTTTCTGGCAAACATAAAT

GTCCCAAACCGCTCACTATGCAGTGTCATIG-ACCGTCTCTCTTTTCTGGCAA-ACATAAAT

GTCCGAAACCGCTCACTATGCAGTGTCATG-ACCGTCTCTCTTTTCTOCCAAACATAAAT

GTCCGAAACCGCTCACTATGCAGTGTCATG-ACCGTCTCTCTTTTCTGGCAAACAIAAAT

GTCAGAAACTACTCACTATACAATGTCGTG-ACAATCTACATTTTCGGGCAAACACAAAT

GTCCGAAACCACTCACTATACAATGTCAt2G-ACCATCTCTCTTTTCTGGCACACATAAAT

GTCCGAAACCACTCACTATACAATGTCAGG-ACCATCTCTCTTTTCTGCACACATAAAT

GTCCGAAACCACTCACTATACAATGTCAGG -ACCATCTCTCTTTTCTGGTACACATAAAT

GTCCGAAACCACTCACTATACAATGTCACG-ACCATCTCTCTTTTCTGGTACACATAAAT

GTCCCAAACCACTCACTATACAATGTCAGG -ACCATCTCTCTTTTCTGGCACACATAAAT AGTGAGAGTGTGTCAAGAGGCAGGGA- ACC -AAOAGCCCTCCGCCCTGA- AGACACAGAC

GCCAAAATATTTGTAGCTTATGTTCCCATTTAACAAGGTTTTCTGGTCAAAACTGTGCAC

1125 1123 1400 1408 1077 1098 1100 1102 1101 1101 1100 1102 1105 1105 1105 1142 1097 TTTCGGAATC-TCATCAATTASTCTCTCCGTGATTGCATTATTTCCCCAAAGTCTTTTACA 1185 TTGCGGA-ATGTCATCAATTAGTCTCTCGGTGATTGCATGATTTCCCCAAAGTCTTACACA 1183 TTGGGGATTGTCATCAATTAGTCTCTCAGTGACTGCATGATTTCCACAAAGTCTTTCACA 1460 TTGGGGATTCGTCATCAATTACTCTCTCGGTGACTGAATGATTTCCACAAAGTCTTTCACA 1468 TTGGGGATTGTCATCAATTACTCPCPCCCCGATTGCATCATTTCCCCAAAGGCTTTCACA 1137 TTGGGGATTGTCATCAATTAGTCTCTCGGGGATTGCATCATTTCCCCAAAGGCTTTCACA 1158 TTGGGATTGTCATCAATTAGTCTCTCGGGGATTGCATCATTTCCCCAAAGGCTTTCACA 1160 TTGGGGATTGTCATCAATCAGTCTCTCGGGGATTGCATGATTTCCCCAAAGGCTTTCACA 1182 TTGGGGATTGTCATCAATTAGTCTCTCGGCGATTGCATCATTTCCCCAAAGGCTTTCACT 1161 TTGGGGAATGTCATCAAATAGTCTCCCGCTGATTGCATGATT -CCACAAAGTCCTACACA 1180 TTGGGGAATGTCATCAATTAGTCTCTCCGTGATTGCATCATTTCCCCAAAGTCTTTCACA 1160 TTGGGGAATGTCATCAATTAGTCTCTCGGTGATTGCATGATTTCCCCAAAGTCTTTCACA 1162 TTGGGGAAAGTCATCAATTAGTCTCTCCGTGATTCCATCATTTCCCCAAAGTCTTTCACA 1165 TTGGGGAAAGTCATCAATTACTCTCTCCGTGATTGCATGATTTCCCCAAAGTCTTTCACA 1165 TTGGGGAATGTCATCAATTAGTCTCTCGGTGATTGCATCATTTCCCCAAAGTCTTTCACA 1165 A- GGCGAGCAACG- CAAGGAGAGCTCAAGAGAGACTACCCCTGCCTCCAGG- -TACCCGA 1198 CCACATCATTCTAATGAACTTAGTGTCCAATAAAACATGGACTCTCAGTCGTCCCACGGA 1157

GTCTAGTTTGTGCACTGAGTATCTCTTCAAACTTCAGTGCATGTTTCTACGACTTAATGC

CTCTACATTGTGCACTGAGTATCTCTTCAGACTTTAGTCCATCTTTCTACCACTTGATGC

GTCTACTTTCTGCACTGAGTATCTCTTCAALACTTCAGTGT GTTTCTACCATATGATGC

GTCTACTTTATGCACTGAGTATCTCTTCAAACTTCAGTGTATGTTTCTACCATTTGATGC

GTCTACTTTGTGCACTGAGTATCTCTTCAALACTTCAGTGCATGTTPCTACCATTTGATTC

GTCTACTTTGTGCACTGAGTATCTCTTCAAACTTCAGTGCATGTTTCTACCATTTCATGC

GTCTACTTTGTGCACTGAGTATCTCTTCAAACTTCAGTGCATGTTTCTACCATTTGATTC

GTCTACTTTGTGCACTGAGTATCTCTTCAAACTTCACTCCATGTTTCTACCATTTGATGC

GTCTACTTTGTGCACTGAGTATCTCTTCAAACTTCAGTGCATGTTTCTACCATTTGATGC

GTCTACATTGTGCACTGAGTATCTCTTCAALACTTCAGTGCTTCTTTCTACCATATGATGC

GTCTACTTTGTGCAATGAGTATCTCTTCAAACTTCAGTGCATATTTCTACCATTTGATGC

GCCTACTTTGTGCACTGAGTATCTCTTCAAACTTTAGTGCATGTTTCTACCATTTGATGC

GTCTACTTTGTGCACTGAGTAACTCTCCAALACTTCAGTGCATGTTTCTACCATTTGATGC

GTC EACTTTGTGCACTGAGTAACTCTCCAAACTTCAGTGCATGTTTCTACCATTTGATGC

GCCTACTTTGTGCACTGAGTATCTCTTCAAACTTTAGTGCATGITTCTACCATTTGATGC

GTTGGACGAGCACTTGGTGGAAAGAGCCACTCAGGAAAGCAC-

CTTAGACCACTCGAAAT

AGTTATTTTGTGTGCATAGTACATCTCTGTGAATATGCCTAATGAGGTATGGAAGGACAC

1245 1243 1518 1528 1197 1218 1220 1222 1221 1220 1220 1222 1225 1225 1225 1257 1217 WO 03/0172724 PCT1US03105338 8.9 8.10 8.3 8-11 4 .2_a 4.3 4.2_b 4.4 4 .l1b 8.1 8.7 8.6 8.8 8.5 8.2 4 1a 8.9 8.10 8.3 8.11 4.2a 4.5 4.3 4.2_b 4.4 4.1_b 8.1 8.7 8.8 8.8 8.2 4 1a 8.9 8.10 8.3 8.11 4 .2_a 4.3 4.2_b 4.4 4.1_b 8.1 8.7 8.6 8.8 8 .2 4 .1 a -89- TTTATTATTCAGCAATCTAGCTTCCACAAGAGCATTTAATGTAAAGACTTGTCT-

TTTTC

TTTATTACTT- GCCATCTAGCTTCCACAAGAGCATTTCATGCAAAGACTTCTCT- TGTTC TTTATTATTTGGCAACCTAGCTTCCAAAAGAGCATTTCATGCAAAGACTTGTCT-

TGTTA

TTTATTATTTCGCAACCTAGCTTCCAAAAGAGCATTTCATGCAAAGACTTGTCT-

TGTTA

TTTCTTATPTGGCAATCTAGCTTCCACAAGAGCATTTCACGCAAAQACTTOTCT

-TGTTC

TTTCTTATTTGGCAATCTAGCTTCCACAAGAGCATTTCATGCAAAGACTTGTCT

TTTC

TTTCTTATTTGGCAATCTAGCTTCCACAACAGC-ATTTCATGCAAAGACTTGTCT-

TOTTC

TTTATTATTTGGCAATCTAGCTTCCACAAGAGCATTTCATGCAAAGACTTGTCT-

TGTTC

TTTATTATTTGGCAATCTAGCTTCCACAAGAGCATTTCATGCAAAGAGTTGTCT

-TCTTC

TTTATCATTTGGCAATCTAGCTTCCACAAGAGCATTTCATGCAAACACTTGTCT-

TGTTG

TTTATTATTTGGCAACCTAGCTTCCACAAGAGCATGTCAGGCAAAGAGTTCTCT-

TGTTC

TTTATTATTTGGCAGCCTAGCTTCCACAAGAGC-ATTTCATGCAAAGACTTGTCT

-TGTTC

TTTATT- TGGCAGCCTAGCTTCCACAAGAGTATTTCATGCAAAGACTTGTCT- TGT TC TTTATT- TGGCAGCCTAGCTTCCACAAGAGTATTTCATGCAAAGACTTGTCT- TGTTC TTTATTATTTGGCAGCCTACCTTCCACAACAGCATTTCATGCAAAGACTTGTCT

-TG:TC

TCCTCCAAGAGCAAAACAAAACGAAGCCTGAGTTCAACGTCAGAAAACTTGAAGGTACCC

TT-ATTATCCAAACAGAGACATTCCACTGGTGCTAGAGAGCCACAGAC- -GGAAGTTrTC

*TCGAAAGACATAGTGAATGAAGTA

TCCACTGGCAGGTAATTTCACTCGGATATAGAATCATTAGGCTGAACATGGAAAGGTTAT

TCCACTGGCAGGTAATTTCACTCGGATAGAGAATCAATAGGCTGAACGTGGAAAGGTTAT

TCCACTGGCAGCTAATTTCATTOGGATAGAGAATCAATACCCTGAACGTCCAAAQCTTAT

TCCACTGGCAGCTAATTTCATTCGGATAGAGAATCAATAGGCTGAACGTGGAAAGCTTAT

TCCACTGGCAGGTAATTTCACTCGGACAGAGAATCAATAGGCTCA.ACGTGCAAAGCTTAT

TCCACTGGCAGGTAATTTCACTCAGATAGAGAATCAATAGGCTCA.ACGTGGAAAGCTTAT

TCCCCTGGCAGGTAATTTCACTCGGACAGAGAATCAATAGGCTCAACGTGGAAAGGTTAT

TCCACTGGCAGGTAATTTCACTCGGACAGAGAATCAATAGGCTCAACGTGGAAAGGTPAT

TCCACTGGCAGGTAATTTCAACTCGGACAGAGAATCAATAGGCTCAACGTGGAAAGGTTAT

TCCACTGGCAAGTA-ATTCACACGGATAGAGAATCAATACGCTCAACGTGGAAAGCTTAT

TCCACTGGAAGTAATTTCATTCGCACAGAGAATCAATAGGCTGA.ACGTAGAA-AGGTTAT

TCCACTGGCAGTAATTTCACTCGGATAGACAGTCAATAGCTGAACGTGGAAAGOTTAT

TCCACTGGCAGGTAATTTCACTCGGATAGAGAATCAATAGTCTGAACGTGGAAAGGTTAT

TCCACTGGCAGTAATTTCACTCGGATAGAGAATCAATAGTCTGAACGTGGAAAGGTTAT

TGCCTCCCAACGTACTTGTGATTCATCAATCAAAATACAAGTGTGGGATGAAAAA-COAT

TCTGCCTACTGGAAATAAAGC--CAAGCTTTCTTCTTTCCTCAGCCCTGACGATTC

CCCTGGGACCTCTGTTTCATTCCACQGATCTCTCCTTTTTTATTGAGGAAAAAAATATSC

CGCTGCAACCTCTOTTTCATTCCACGCATCTCTCCTTTCTTATTAAGGAAAAAGATACAC

CGCTGGAAGGTTTGTTTGTTTCCACGGATCTCTCCTTTCTTATTAGGGAAAAAAATACGC

CGCTGGAAGGTTTGTTTGTTTCCACGGATCTCTCCTTTCTTATTAGGGAAAAAAATACGC

CGCTGGAAGGTCTGTTTGATTCCACGGATCTCTCCTTTCTCATTAGCGAAGAAATACGC

CQCTCGAAGGTCTGTTTGATTCCACGGATCTCTCCTTTCTCATTAGGGAAGAAAATACGC

CGCTGGAAGGTCTGTTTGATTCCACGGATCTCTCCTTTCTCACTAGGGAAGAAAATACGC

CGCTGCAAGGTCTGTTTGATTCCACGGATCTCTCCTTTCTCACTAGGGAAGAAAATACGC

CGCTGGAACCTCTGTTTCATTCCACJCATCTCTCCTTTCTCACTACGAAGAAAATACGC

CCCTCCAACGTCTGTTTGATTCCACGGATCTCTCCTTTCTCATTAGGGAAGAAAATACGC

CGCTGGAAGCTCTGTTTCATTCCACSGATCTCTCCTTTCTTATTAAAGAAAAAAATACC

CCCTGGAAGGTCTGTTTGATTCCACSGATCTCTCCTTTATTATTAAGGAAGAAAATACGC

CGCTGGAAGGTCTGTTTGATTCCACSGATCTCTCCTTTATTATTAAGGAAAAATATACGC

CGCTGGAAGGTCTGTTTGATTCCACGGATCTCTCCTTTATTATTAAGGAAAAATATACGC

CCCTGGAAGGTCTGTTTGATTCCACGGATCTCTCCTTTATTATTAAGGAAGAAAATACC

CATCCTGAA- -CAGCAAACCTCCCTOCTAAACCTCTCTTCGACCAACCCGACACATCAGG TOACCTCC- -TCTTTATCATTCTCTCTCTCTCTTTTTTTTTAATGAGCCAAGCTCCACCA 1304 1301 1577 1587 1256 1277 1279 1281 1280 1279 1279 1281 1281 1281 1284 1317 1274 1364 1361 1637 1647 1316 1337 1339 1341 1340 1339 1339 1341 1341 1341 1344 1376 1329 1424 1421 1697 1707 1376 1397 1399 1401 1400 1399 1399 1401 1401 1401 1404 1434 1387 WO 03/072724 PCT/US03/05338 8. 9 8 .10 8.3 4.2_a 4 .3 4 .2 -b 4,4 4. I.b 8 .1 8.7 8.8 a8- 8. 5 8.2 4. 1_a 8.9 8 .10 8 .3 8 .11 4 .2 -a 4 .5 4 .3 4 .2_b 4.4 4-1_b 8.1 8.7 8.8 8.8 8.2 4.-1_a 8.9 8.10 8.3 8.11 4 .2_a 4.3 4.2_b 4.4 4.1_b 8.1 8.7 8.6 8 .8 8.2 4 .lIa 1'GTGCTAATTACTGTACTTCATTGCCTATTCTCAGGTCAGAAAG--CGCACTTCAGA TGCGCTAATTACTATACTTCATTGACTATTCTCAGGTCAGAAAG

GCACTTCCGA

TGTGCTAAATACTATACTTCATTGACTATTCTCAGGTCAGAAAG

CGCACTTCCGA

TGTGCTAAATACTATACTTCATTGACTATTCTCAGGTCAGAAAG--CGCACTTCCGA

TGTGCTAAATACTATACTTCATTGACTATTCTCAGGTCAGAAAG--CGCACTTTCGT

TGTGCTAALATACTATACTTCATTGACTATTCTCAGGTCAGAAAG--CGCACTTTCGA

TGTGCTAAATACTATACTTCATTGACTATTCTCAGGTCAGAAAG--CGCACTTTCGA

TGTGCTAAATACTATACTTCATTGACTATTCTCAGGTCAGAAAG--CGCACTTTCGA

TGTGCTAAATACTATACTTCATTGACTATTCTCAGGTCAGAAAG--CGCACTTTCGA

TGTGCTAAATATTATACTTCATTGACTATTCTCAGGTCAGAAAG--CACACTTCCGA

TGTGCTAAATACCATACTTCATTGACTAATCTCAGGTCAGAAAG--CACACTTCCGA

TGTGCTAAATACTATACTTCATTCACTATTCTCAGGTCAGAAAG--CGCACTTCAGA

TGTGCTAAATACTATACTTCATTGACTATTCTCAGGTCAGAAAG--TGCACTTCAGA

TGTGCTAAATACTATACTTCATTGACTATTCTCAGGTCAGAAAG--TGCACTTCAGA

TGTGCTAAATACTATACTTCATTGACTATTCTCAGGTCAGAAAG---CGCACTTCAGA

AGT-CCATGAACACTGGCACACTCGCTTCTCT- GCAAGGGAG-3-AC- CAGGAGA

AATAATAAGATAAACTTTGTGCAAGACTTGGTAAGAGTAGAGTGTCTGACACCTTATGGT

CTC CCTT* *AGT-AGTACGCAAGCCTC *CG CTTCT- -CCTTCTATCGCTGAAAGGAT-GATGGTATCTGCCAAAAGCACATAC-

TCGGA

CTTCTTCTCCTTCCGTCGCTGAGAGGAT ATGGTATCTGCCAAAAGCACATAT- TTGGA

CTTCTTCTCTTTCCGTCGCTGAGAGGAT-GATGGTAGCTGCCAAAAGCACATAC-TTGGA

CTTCTTCTCTTTCCGTCGCTGAGAGGAT -GATCCAGCTGCCAAAAGCACATAC- TTGGA

CTTCTTGTCCTTCCGTCGCGIGAGAGGAT-GATGGCAGCTGCCAAALAGTACATAC-TTGGA

CTTCTTGTCTTTCCGTCGCTGAGAGGAT-GATGGCAGTCTGCCAAAAGTACATAC-

TTGGA

CTTCTTGTCCTTCCGTCGCTGAGAGGAT -GATGGCAGCTGCCAAAAGTACCTAC- TTGGA CTTCTTGTCCTTCCGTCGCTGAGAGGAT -GATGGCAGCTGCCAAAAGTACCTAC- TTGGA ATTCTTGTCCTTCCGTCGCTGAGAGGAT -GATGGCAGCTGCCAAAAGTACATAC- TTGGA ATTCTTGTCCTTCTGTCACTGAGAGGAT -GATGGTAGCTGCCAAAAGTACATAC- TTGGA CTTCTTGTCCTTCCGFTGATGAGAGGAT -GACGGTAGCTGCCAAAACTACATAC- TTGGA CTTCTTGTGCTTCCATCGCTGAGAGGAT-GATGG3TA3CTGCCAAAAGTACATAC-TTGGA CTTCTTGTGCTTCCATCGCTGAGAGGAT -GATGGTAGCTGCCAAAAGTACATAC- TTGGA CTTCTTGTCCTTCCGTTGATGAGAGGAT -GACGGTAGCTGCCAAAAGTACATAC- TTGGA GCCAAAGGGAAGA- -ACAAACACTGCAAGAGGGCTCTGC- TTGTG

GCTATAATACTCAAAGCAAAAGCAAAATCGCCTAGGACCAGAAAAGGGAGTCACATAGGA

AGT~ *CTCACCACCCCCCC *CAC AGT ACATCCCGCACAAACACACACACACACA-----------------

CACACACACA

AGT- -ACATCCCGGCACAAACACACACACACAA-----------------

CACACACACA

GGT- TCATCCCAGCP.CAAACACACACACACAA.A-----------------

CACACAAACA

AGT TCATCCCAGCACAAACACACACACACACG---------------CACACACACA TCATCCCAGCACAAACACACACACACACGC- -CCCCCCCCACACACACACACACA GGT TCATCCCAGCACAAACACACACACACACGCGCCCCCCCC

CACACACACACA

GGT- -TCATCCCAGCACAAACACACACACACACACGCCCCCCCC--

-CACACACACACA

GGT- -TCATCCCAGCACAAACACACACACACACACCCCCCCCCC-

CACACACACA

GGT- -TCATCCCAGCACAAACACACACACACACACCCCCCCCC-

-ACACACACACA

AGT- -TCATCCCAGCACCAAACACACATAACACACACACCC

-CACACACACA

TCATCCCAGCACGAGCACACACACACACAAACACACACA--CACACACACA

-TCATCCCAGCACAAGCACACACACACACA-- CACAAACA--CACACACACA AGT TCATCCCAGCACAAGCACACACACACACA- -CACAAACA--CACACACACA AGT- -TCATCCCAGCACAAGCACACACACACACA- -CACAAACA--CACACACACA TGCCAGTGATCTCAGTGGAAGTGCCGACCCACACGTAGGGGAGAA

AAACACACA

AATCTAGAAGACCTATTGGCTGAGAGACCTGCAGCCTCATAGTTCATTAGCTCTC

-CATA

1479 1476 1752 1762 1431 1452 1454 1456 1455 1454 1454 1456 1456 14S6 1459 1484 1447 1534 1534 1810 1820 1489 1510 1512 1514 1513 1512 1512 1514 1514 1514 1517 1526 1507 1576 1S78 1852 1862 1544 1567 1566 1566 1566 1564 1564 1564 1564 1564 1567 1580 1566 WO 03/072724 PCTIUSO3/05338 8.9 8.10 8.3 8.11 4.2 _a 4.3 4 .2-b 4.4 1_U 8 .1 8.7 8.6 8.8 8.5 8.2 4 .1-a 8.9 8.10 8.3 8 .11 4.2 a 4.5 4.3 4.2_b 4.4 4.1_b 8.1 8.7 8.6 8.8 8.2 4.-1_a 8.9 8.10 8.3 8.11 4. 2_a 4.3 4.2_b 4.4 4.1_b 8.1 8.7 8.6G 8.8 8.2 4 .1I8 -91- AACACACATACTCACAC-------------- GGTTTCA- -TAGGTAAACATTTCTTCCCTGA CACACACACACACACAC------------- GGTTTCA- -TAGGTAAAGATTTCTTCCCTGA CACACACA GGCTTCA--TAGGTAAAfJATTTCTTCCCTGA CACACACA GGCTTCA--TAGGTAAAGATTTCTTCCCTGA AACACACTCACACACACACACGCACAC- -GGTTTCC -TACCTAAACATTTCTTCCCTGC AACACAATCACACACACACACTCACAC- -GGTTTCC- -TACGTAAAGATTTCPTCCCTGC AACACACTCACACACACACACCCACAC- -GGTTTCC- -TAGGTAAAGATTTCTTCCCTGC AACACACTCACACACACACACGCACAC -GGTTTCC -TAGGTAAAGATTTCTTCCCTGC AACACACTCACACACACACACOCACAC- -CGTTTCC- -TAGGTAAACATTTCTTCCCTC AACACACTCACACACACACACACACACACGGTTTCC AAGGTAAAGATTTCTTCCCTGC CACACACACACACACACAGACACACACAGGGTTTCA- -TAGGTAAAGATTTCTTCCCTGA CACACACACACAGAGAGAGATrACACACACGGTTTCA- -TAGGTAAAGATTTCTTCCCTGA CACACACACACACACACAGACACACACACCGTTTCA- -TAGGTAAAGATTTCTTCCCTGA CACACACACACACACACAGACACACACACCGTTT CA- -TAGGTAAAGATTTCTTCCCTCA CACACACACACAGAGAGAGATACACACACGGTTTCA- -TAGGTAAAGATTTCTTCCCTGA

CACACACACACACACAC--------------CGGTTTCA--TAGCTAAAGATTTCTTCCCTGA

GCAACTCTCACATGAAATGAAGTCAGTGGTGTTTCAAGTGCTTCAAACCCTCTTTACT-

C

CATTTTCTA*''A **CCCGTTCCR CATTCTTTTACCTAAAA1'AAG GCAACTGTGTGGCCACTGTCCCAACCCGGTTACCT CATTGTTTTACCTAAAATAAC -GCAACTCTCTGGCCACTGTCCCAACCCGGTTACACT CATTGTTTTACCTAAAATAAG--- -GCAACTGTGTGGCCACTGTCCCAACCTGGTTACACT CATTGTTTTACCTAAAATAAG--- -GCAACTGTCTGGCCACTGTCCCAACCTGGTTACACT CATTGCTTTACCTAAAATAAG--- -GCAACTGTGAGGCCACTGTCCCAACCCGGTTACACT CATTGCTTTACCTAAAATAAG- -CCAACTGTGTGGCCACTGTCCCAACCCCGTTACACT CATTGCTTTACCTAAAATAAG- -CCAACTGTGAGCCACTGTCCCAACCCGCTTACACT CATTGCTTTACCTAAAATAAG- -GCAACTGTGAGTCCACTGTCCCAACCCGGTTACACT CATTGCTTTACCTAAAATAAG- -GCAACTGTGAGGCCACTGTCCCAACCCGGTTACACT CATTCTTTTACCTAAAATAAG GCAACTGTGTGGCCACTGTCCCAAACCCGGTTACACT CATTCTTTTACCTAAAATAAG--- -GCAACTCTGCGGCCACTGCCCAACCCCGTTACACT CATTCTTTTACCTAAAATAAG--- -GCAACTGTGTGGCCACTGTCCCAACCCGGTTACACT CATTCTTTTACCTAAAATAAG GCAACTGTGTGGCCACTGTCCCAACCCGGTTACACT CATT-CTTTACCTAAAATAAG GCAACTGTGTGGCCACTGTCCCAACCCGGTTACACT CATTG-TCTTACCTAAAATAAG GCAACTGTGTGG-CCACTGTCCCAACCCC -TTACACT TACTTCTAAATGTGAATTAATTATGCAAATTTACTAGCAGTTGCTAGACCT -CAAAAGC CATATTATATGTGCCTATCATCCTGAGGAGTAATTT- GATGAAGGTGTTTTAGAAGT CATATTACATGTGTCTATCAGCCTGAGGAGTAGTTT- GATTCAGGTGTTCTAGAAGT CATATTACATCTCCCTATCATCCTGACCAGTAATGT-- -ATTCAGGTGTTCTAGAAGT CATATTACATCTGCCTATCATCCTGAGGAGTAATGT GATTCACGTCTTCTAGAACT CCTATTATATGTGCCTATCATCCTGAGGAGTAATTT GATTCACCTGTTCTGGAAGT CCTATTATATGTGCCTATCATCCIGAGGAGTAATTT- GATTCAGGTGTTCTGGAAGT CCTATTATATGTGCCTATCATCCTGAGGAGTAATTT- GATTCAGGTGTTCTGGAAGT CCTATTATATGTCCCTATCATCCTGAGGAGTAATTT GATTCAGGTGTTCTGGAAGTf CCTATTATA2'GTGCCTATCATCCTGAGGAGTAATTT- GATTCAGGTGTTCTGGAAGT CCTATTATATGTGCTTATCATCCTGAGGAGTAATCT GATTCAGGTGTTCTGGAAGT CATATTATATGTSCCTATCACCCTGAGGAGTAATTT- GATTCACGTGTTCTAGAAGT CATATTATATCTGCCTATCACCCTGACGAGTAATTT- GATTCAGQTCTTCTAGAAGT CATATTACATGTGTCTATCACCCTCACCAGTAATTT CATTCACGTGTTCTAGAAGT CATATTACATGTGTCTATCAGCCTGAGGAGTAATTT GATTCAGGTGTTCTAGAAGT CATATTATATGTGCCTATCACCCTGAGGAGTAATTT -GATTCAGGTGTTCTAGAAGT CATATTACATGTGTCTATCAGCCTGAGGAGTAGTT- GATTCAGGTGTTCTAGAAGT

AAAATAATCAGGCATTATTCTACTAAGTATTGGTCTCCATAACTCCTCTATTTTCTTTAG

1622 1622 1892 1902 1600 1623 1622 1622 1622 1622 1622 1622 1622 1622 1625 1626 162S 1679 1679 1949 1959 1657 1680 1679 1679 1679 1679 1679 1679 1679 1679 1679 1683 1683 1735 1735 2005 2015 1713 1736 1735 1735 1735 1735 1735 1735 1735 1735 1735 1739 1743 WO 03/072 724 8.9 8.10 8.3 8.11 4. 2_a 4.3 4.2_b 4.4 4.1 b 8 .1 8-7 8.6 8.8 8 .5 8 .2 4 .1-a 8 -9 8.10 8.3 8.11 4 .2_-a 4 .5 4.3 4 .2_1b 4 .4 4.1_12 8.1 8.7 8.6 8.8 8.2 4 1a 8.9 8.10 8.3 8.11 4 .2_a 4.3 4.2_1b 4.4 4.1_1b 8.1 8.7 8.6 8.8 8.2 4.-1_a PCT11JS03105338 -92- CATGATGTGGACTGTGTCTGTTGAATTCCCAGCGATGCAAGGGGACACACCCTGTGACTC 1795 CATCATGTGGGCTGTGTCTGTTGAATTCCCAGCCATGCAAGGGGACACACCCTGTGACTC 1795 CATCATGTc3GGCTGTSTCTGTTGAATTCCCAGCGATGCAAGGGGACACACCCTGTGACTC 2065 CATGATGTGGGCTGTGTCTGTTGAATTCCCAGCGATGCAAGGGGACACACCCTGTGACTC 2075 CATGCTGTGGGCTGTGTCTGTTGAATTCCCAGCGATGCCAGGGGACACACCCTGTGACTC 1773 CATGCTGTGGGCTGTGTCTGTTGAAPTCCCAGCGATGCAhAGGGGACACACCCTGTGACTC 1796 CATGCTGTGGGCTGTGTCTGTTGAATTCCCAGCCATGCCAGGGGACACACCCTGTGACTC 1795 CATGCTGTGGGCTGTGTCTGTTGAATTCCCAGCGATGCCAGGGGACACACCCTGTGACTC 1795 CATGCTGTGGGCTCTGTCTCTTGAATTCCCAGCGATCCCAGGGGACACACCCTGTGACTC 1795 CATGATGTGGGCTGTGTCTGTTGAATTCCCAGCGATGCAAGGGGACACACCCTGTGACTC 1795 CATGATGTCGGCTGTGTCTGTTGAATTCCCAGCGATCCAAGG3GGACACACCCTGTGACTC 1795 CATGATGTGGGCTGTQTCTGTTGAAVTCCCAGCGATGCAAGGGGACACACCCTGTGACTC 1795 CATCATGTGQGCTCTCTCTGTTGAATTCCCAGCGATGCAAGGGCACACACCCTGTGACTC 1795 CATGATGTGGGCTGTGTCTGTTGAATTCCCAGCGATCCAAGGGGACACACCCTCTGACTC 1795 CATGATGTGGGCTGTGTCTGTTGAAVTCCCAGCGATGCAAGGGGACACACCCTGTGACTC 1795 CATGATGTGGGCTGTGTCTGTTGAATTCCCAGCGATGCAAGGGGACACACCCTGTGACTC 1799 GAAAAGTTACTCTAAGACATTTGSCATAAAGGCTATGCCAAAGCTTTGGTGGGGTCAGCC 1803 *TGTGGGGGGGG185 ATTCCTTI\ATTGAGTGCTGATATTTGATTGGTTTATTGCCCACCTTATGGTCGGGTGGGG 1855 ATTCCTTAATTGAGTGCTGATATTTGATTGGTTTATCGCGCACCTGATGGGTGGGTGGGG 215 ATTCCTTAATTAAATGCTGACATTTGATTCGCTTTATCGCGCACCTGATCAGTGGTCACG 2125 ATTCCTTAATTAATGCTGATATTTGATTGGTTTATCGCGCACCTGATGAGTGGTOAGG 1835 CTTCCTGAATTGAGTGCTGATATTTGATTGGCTTATCGCGCACCTGATGAGTGGTGGGG 1833 CTTCCTGAATTGAGTGCTGATATTTGATTGGCTTATCGCGCACCTGATGAGTGGGTGGGG 1856 CTTCCTGAATTGAGTGCTGTTATTTGATTGGCTTATCGCGCACCTGATGAGTGGGTGGGG 1855 CTTCCTGAATTGACTGCTGATATTTGATTCGCTTATCGCGCACCTCATGAGTGGGTGCGG 1855 CTTCCTGAATTGAGTGCTGATATTTGATTGGCTTATCGCGCACCTGATGAGTGGGTGGGG 1855 CTTCCTGAATTGAGTGCTGATATTTGATTGTATATCGCGCACCTGATGAGTGGGTGGGG 18S5 ATTCCTTAATTGAGTGCTGATATTTGATTGTTTATCGCGCACCTGAGGGTGGCTGGGG 1855 ATTCCTPAATTGAGTGCTGATATTTCATTCGTTTATCGCACACCTGA'GGTGGGTGGGG 1855 ATTCCTTAATTGAGTGCTGATATTTGATTGGTTTATCGCACACCTGATGGGTGGGTGGGG 1855 ATTCCTTAATTGAGTGCTGATATTTGATTGGTTTATCGCACACCTGATGGGTGGGTGGGG 1855 ATTCCTTAATTGAGTGCTGATATTTCATTGGTTTATCGCACACCTGATGGCTGGGTGGGG 1855 AGGAACGATTCGTGGGGTCTCCTTGAAAATACTGCAATA-ATCTAAGAA.ATCTTCAACC 1862 TGTTCGCTCTTGGTGCGGGTGAGTTATGTAAGSGCTGATTTGGCCAGAGAACTCGTTATT 1915 TGTTCGCGGTTGGTGGGGGTGAGTTATATAAGGGCTGATGCCGCCAGAGACCTCGTCATT 1915 TGTTCGCCGTTGGTGGGGGTGAGTTATATAAGGGCTGATGCGGCCAGAGAGCTCGTCATT 2185 TGTTCGCCGTTGGTGCGGGTGAGTTATATAAGGGCTGATGCGGCCAGAGAGCTCGTCATT 2195 TGTTCGCGGTTGGTGGGGGTGACTTACAGAAGGGCTCATGTCGCCACAGAGCTCGTCATT 1893 TGTTCGCGGTTGGTGGGT-TGACTTACAGAAGGGCTGATGCG- CCAGAGAGCTCGTCATT 1915 TGTTCCCGTTGGTGCCGGTGACTTATAGAAGGGCTGATGCCGCCAGAGAGCPCGTCATT 1915 TGTTCGCTGTTGGTGSGGGTGACTTACAGAAGGGCTGATGCGGCCAGAGAGCTCGTCATT 1915 TGTTCGCGGTTCCTGGGGGTGACTTACAGAAGGGCTGATGCGGCCAGACACCTCGTCATT 1915 TGTTCGCGGTTGGTGTGGGTGAGTTATAGAAGGGCTGATGCGGCCAGAGAGCTCGTCATT 1915 TGTTCGCGGTTGGTGGGGGTGAGTTCTATAAGGGATGATGCGGCCAGAGAGCTCGTCATT 1915 TGTTCGCGGTTGGTGGGGGTGAGTTATATAAGGGCTGATGCGGCCAGAGAGCTCGTCATT 1915 TGTTCGCGGTTGGAGGGGGTGAGTTATATAAGGGCTGATGCGGCCAGAGAGCTGGTCATT 1915 TGTTCGCGGTTGGAGGGGGTGACTTATATAACGGCTCATCCGGCCAGAGAGCTGGTCATT 1915 TGTTCGCGGTTGGTGGGGGTGAGTTATATAAGGGCTGATGCGGCCAGAGAGCTCGTCATT 1915 TGTTCGCGQTTGGTCGGOGTCAGTTATATAAGCGCTGATGCCGCCAGAGACCCCGTCATT 1919 TATTGCCCCTCAGTACTGTTG-GTCCCCTGTACTTGACTTTTCCCCTTAAGTTTG--ATT 1919 WO 03/072724 PCT111S03105338 8.9 8.10 8.3 8.11 4 .2_a 4.3 4.2_b 4.4 4.1-b 8.1 8.7 8.6 8.8 8.5 8.2 4 1a 8.9 8.10 8.3 8.11 4.2_a 4.5 4 .3 4 .2_b 4.4 4.1 b 8.1 8.7 8.6 8.8 8.2 4 .1_a 8.9 8 .ic 8.3 8.11 4.2_a 4.3 4 .2_b 4.4 4.1_-b 8.1 8.7 8.6 8.8B 8.2 4 .l1a

TGAAGACTCTCTCGGAAGAGATAGCGTTTTTCTGCAACCTACGGTCCCAGCAGAAAAACC

TGAAGACTCTCTCGGAAGACATAGCATCTTTCTGCAACCTGCGGTCCCAGCCGAAAAACC

TGAAGACTCTCTCGGAAGAGATAGAGTCTTPCTGCAACATAAGCTCCCAGCCGAAAAACC

TGAACACTCTCTCGGAAGAGATAGCOTCTTTCTGCAACATAAGGTCCCAGCCGAAAAACC

TQAAGACTCTCTCGGAAGGGATAGCCTCTTTCTCCAACCTCTGGTCCCAGCAGACAAACC

TCAAGACTCTCTCGGAAGGGATAGCGTCTTTCTGCAACCTGCGGTCCCAGCAGAAAAACC

TGAAGACTCTCTCGGAAGGGATAGCGTCTTTCTGCAACCTGCGCTCCCACCACAAAAACC

TGAAGACTCTCTCGGAA.GGGATAGCGTCTTTCTGCAACCTGCGGTCCCAGCAGAAAAACC

TGAAGACTCTCTCGGAAGGGATAGCGTCTTITCTGCAACCTGCGGTCCCAGCAGACAAACC

TGAAGACTCTCTCGGAAGAGATAGCGTCTTTCTGCAACCTGCGGTCCCAGCAGAAAAACC

TGAACACTCTCTCGGAAGAGATAGCGTCTTGCTGCAACCTGCGGTCCCAGCAGAAAAACC

TGAAGACTCTCTTGGAAGAGATAGCGTCTTGCTGCAACCTOCGCTCCCAGCACAAAAACC

TGAACACTCTCTCGGAAGAGATACCTCTTGCTGCAACCTGCGGTCCCAGCAGAAAAACC

TGAAGACTCTCTCGGAAGAOATAGCCTCTTGCTGCAACCTGCGGTCCCAGCAQAAAAACC

TGAAGACTCTCTTGGAACAGATAGCGTCTTGCTGCAACCTGCGGTCCCAGCAGAAAAACC

TGAAGACTC- GGAAGAGATAGCGTCTTTCTGCAACCTGCGGTCCCAGCCGAAAAACC

CCATTTCCTAATATTATCCTTCCCTCTTCCTCCTCAGCAACTAGTCTTCTAAATTAGAAC

*T T A C T G TG G G G C T

TTGTGATCCTTGTTCCAGTCGACATGGAGGACGACTCACTCTACTTGGGAGGTGAGTGGC

TTGTGATCCTCGTTCCAGTCGACATG TTAAACACAAT 1975 1975 2245 2255 1953 1975 1975 1975 1975 1975 1975 1975 1975 1975 1975 197S 1979 2001 2001 2271 2281 2013 2001 2001 2001 2001 2001 2001 2001 2001 2001 2001 2001 2001 AGTTCAACCACTTTTCAAAACTCACATCTTCTCGGCCAGATGCAGCTTTTGCTGAA-ATCC 2073 WO 03/072724 WO 03/72724PCT/IJSO3/05338 8.9 8.10 8.3 8-11 4 .2_a 4.3 4.2 b 4.4 4.1 b 8.1 8.7 8.6 8.8a 8.-5 8.2 4 1a 8 .9 8.10 8.3 8.11 4. 2-a 4.5 4.3 4.2_b 4.4 4.1_b 8.1 8.7 8.6 8.8 8.2 4 .1la 8.9 8.10 8.3 8.11 4.2_a 4.3 4.2_b 4.4 4. 1_b 8.1 8.7 8.6 8.8 8.2 4 .l1a AGCGGACTTCTCTCCCTGAGAACTCACCACTCTCATGTGAGACCCGTGTCGACCTCTCAG 2133 ATGATTTGGCTCCTGTGGCAAGACAGCTTGCTCCCAGGGAGAAGCTTCCTCTGAGTAGCA 2193 L GGAGACCTGCTGCGGTGGGGGCTGGGCTCCAGAATATG 2231 HDUB4.6 putative promoter sequence upstream of initiation ATG gCatgactgg goacaccyat ctcqqcatct ctccctgtgg ggcacaygaa yggccaaagg ggccctgaag cagacayctt gcccaggtcc gcattgctca agcatctttc gccttctgat tcacagtcct ccagggctgt atcgattggg cggctgcagg tgcttctggg taagcagtgc ggagcacacc ctcatcccat ttctttacac ctcccctcaa aataagaCc gatcattCtC tcttttcttc tggcccatqa catcctcctt ctagagycct aatcggttat tccagggtct ctgaaaatgg ccccaggaca aaagacaagg aaaatcatcc tggcgccggg gagcattcaa tgtgtgaagc tggctccttt ctttacatcc gaaagaaacg taatttcatg cctcaattcc WO 03/072724 WO 03/72724PCT/US03/05338 gccctgttec ctgctaagec tgtccacttt acaatgcgta caggatatgc ggcacgctat c agggc ctea tecaaattag ggaaatatta aacaaacggt taaactgccg ctggcaaaca ccaaaggctt tctaccattt gacttgtett c9tggaaagg ggaagaaaat cactttcgac acttggaagt cacgaacaca gccattgctt ctattatatg tgtgggctgt tgaattgagt gcggttggag aetctctcgg atccttgttc ttaccgtcta agacagccgg cggcagcatt actggaaatg acggcttatt cctctgtttC cttccgtcag aactttttat tcacacatgc tatagctggg tcgcacgtc taaatttggg tcacagtcta catgctttct gttctceact ttatcgetgg acgctgtgct ttcttgtctt tcatcgeaga atcacacaca tacctaaaat tgcctatcat gtctgttgaa gctgatattt ggggtgactt aagggatagc cagtcgacat agacatgttg aaga cac ace acaattttgg gaggcaacat ttggeetttt actccctgct ccgggctttt ttcacctcta tgtgagatae ataccttctg gaaaccgctc gattgtcate ctttgtgcac tatttggcaa ggeaggtaat a agg t ctgt t aaatactata tccgtcgctg aaaaacacae cacacactca aaggcaactg cctgaggagt ttcccagcga gattggctta acagaaggge gtetttctgc g ggaaaatccc eaaattctgt eaccaaatgt etccgatcct eccactgaaa tttaaacgtc ecacggtata ggaaacgttg gttgttttta agttctcaag actatgcagt aattagtetc tgagtatctc: tetagcttce ttcaetcaga tgattccacg CttCattgae agaggatgat acacacacgc eacggt tt ce tgtggc cac t aatttgatte tgcaagggga tcgcgcacct tgatgcggcc aacctgcggt tagagccagg ccctcttact gctaactgca gaaegatcga caagggccag tccgatgttt at tt tcc ttg atecattatc ttttcatcaa ttttttgttt gtcatgaccg tcggggattg ttcaaacttc acaagagcat tagagaatca gate tet cet tattctcagg ggeagetgcc gcccccccca taegtaaaga gtcecaaeccc aggtgttctg cacacectgt gatgagtggg agagagctcg cccageagaa atcttcattc tcagggaaca attccaccat tgcgagaatc tattaaaaat ctccctgaga tttgcttttg aeatacgtat ttctttaata cgtgttttct tetctctttt catgatttcc agtgcatgtt ttcatgcaaa ataggctcaa ttctcattag teagaaagcg aaaagtacat cacacacaca tttcttccct ggttacactc gaagtcatgc gactcettcc tgtggtgttc teatttgaag aaaccttgtg HDUB4.7 putative promoter sequence upstream of initiation ATC tectcagcgt ceatcatett ttttcctcat cctaatggag cattcactta aetttgggaa catggtgaaa tgtaatccca gttgcagtga agaaaacaaa tgatccaatg tgtettgtga gttctgagat tgctggaaag attggttggc tccteecto ggctctgctg agaagagata ttteacgcct tccacaagag ggatagagaa acggatctct gactattctc gatggcagct cacgeceCcc taggtaaaga gtcecaaccc aggtgttctg cacaccctgt gatgagtggg cggtttttag tggeetagtt cccactgate atttaatgee catacttgca geegaggtgg ccccgtctct getacteagg gceaagatta aaacccaaaa cttcctttt tatttacaat gtetgctgtg caggtcttgg cagaagccea ectectc gctgccaaga agaaattcea gtaateccag catttcacgc tcaat agget eettteteat aggtcagaaa gccaaaagta eacacacaca tttettccct ggttacgctc gaagtcatgt gacteettee tggggtgttc gcetggcata aaeacctccc ccaaacccag attaaateag gagteggcca gtggatcacg aetaaaaata agge tgaggc tgeeattgca act tgcagag tetctttctc ctaggagaag tttgeaggta cgctatattt attgtcacte tctceaagat tgggecaeca cagggctgat caettgggag aaagacttgt caacgtggaa tagggaagaa gegeactttc catacttgga cacaeaaaca gccattgctt ctattatatg tgtgggctgt tgaat tgagt gcggttggtg agctgtttga ctccgtgtgt gacaccctac aagaaattcet ggtgtgttgg aggtca agaa caaaaattaa aggegatttg etecagcctg tgaatttagg aaatattttg 9eaggagaga ccttccctca ataccatggt tetctctctg atccagtaae 9caaaaaggg aagaaagaee gceaggatgg cttyttctcc aggttatege aataegetgt gacttcttgt agttcatccc cactcacaca tacctaaaat tgcetatcat gtctgttgaa getgatattt ggggtgactt aaeeeaggaa ggtggt ttgg agctgctgac gattcteagg ctcacacctg ttcgagacca etggtgtage cttgaacctg ggcaaceagag aaaccatgaa agccaggtac gaactaagaa atttccctac acttcccctc tctcetete tgactgatca aaaattggt t atgggettce tcggatttgg actggcaggt tggaaggtct gctaaatact cctteCgtcg agcacaaaea cacacacgea aaggcaactg cctgaggagt ttcccagega gattggctta acagaagggc cgtaccceae agaacctgct caggattaaa gactgacatt taateeeagc tcctggccaa tstgcgtgcc ggaggtggag cgagactctc gtacacagtt tatectagac cagagagcat tcaetggeca cctatactca getcetce gctgggggtg gtgagtgaga aggegeggtg caatctagct aattteacte gt t taat tce atacttcatt ctgagaggat eacacacaca eacggtttcc tgaggccact aatttgatte tgccagggga tegcgcacct tgatgcggcc WO 03/072724 WO 03/72724PCTIUS03/05338 agagayctcg tcatttgaag actctctcgg aagggatagc gtccttctgc aacctgcqgt cccagcagac aaaccttgtg atccttgttc cagtcgacat g HDU24.8 putative promoter sequence upstream of initiation ATG

CAGGGCTCCG

TACGAACAGG

GACAGCTTAT

CCAGGTCCCG

ATTGCTCATG

CATCTTTCTA

CTTCTGATGG

ACAGTCCTCT

AGGGCTGTTT

ACCGTCTAAG

ACAGCCGGAA

GCAGCATTAC

TGGAAATGGA

GGCTTATTTT

TCTGTTTCAC

TCCGTCAGCC

CTTTTTATTT

ACACATGCTG

TAGCTGGGAT

GCACGTCCGA

AATTTGGGGA

ACAGTCTACT

TGCTTTATTA

TCTCCACTGG

ATCOCTGGAA

GCTGTGCTAA

CTTGTCCTTC

ATCCCAGCAC

CACACACACA

TAAAATAAGG

TATCATCCTG

GTTGAATACC

ATATTTGATT

TGACTTACAG

TAGAACCACA

GTCTCCGTGT

CGATTGGGCT

GCTGCAGGAA

CTTCTGGGGA

AGCAGTGCTC

ACCACACCTG

CATCCCATCA

CTTTACACCT

ACATGTTGGG

GACACACCCA

AATTTTGGCA

GGCAACATCT

GGCCTTTTCC

TCCCTGCTTT

GGGCTTTTCT

CACCTCTAGG

TGAGATACGT

ACCTTCTGAG

AACCGCTCAC

TTGTCATCAA

TTGTGCACTG

TTTGGCAATC

CAGGTAATTT

GGTCTGTTTG

ATACTATACT

CGTCGCTGAG

AAACACACAC

CACTCACACG

CAACTGTGTG

AG3GAGTAATT

CAGCGATGCA

GGCTTATCGC

AAGGGCTGAT

GAATCTTGGG

GACGTGTGTG

CCCCTCAAAA

TAAGACCCTC

TCATTCTCCT

TTTTCTTCCC

GCCCATGAAA

TCCTCCTTAA

AGAGGCCTTG

AAAATCCCTA

AATTCTGTCC

CCAAATGTGC

CCGATCCTGA

CACTGAAACA

TAAACGTCTC

ACGGTATAAT

AALACGTTGAT

TGTTTTTATT

TTCTCAAGTT

TATGCAGTGT

TTAGTCTCTC

AGTATCTCTT

TAGCTTCCAC

CACTTGGACA

ATTCCACGGA

TCATTGACTA

AGGATGATGG

ACACACGCGC

GTTTCCTACG

GCCACTGTCC

TGATTCAGGT

AGGGGACACA

GCACCTGATG

CGCAACCCTG

AAAACTACAG

TCCCTTATCA

CAGGGTCTTG

GAAAATGGTG

CCAGGACACT

AGACAAGGGA

AATCATCCTA

GCGCCGGGCC

GAGCCAGGAT

CTCTTACTTC

TAACTGCAAT

ACGATCGATG

AGGGCCAGTA

CGATGTTTCT

TTTCCTTGTT

CCATTATCAC

TTCATCAATT

TTTTGTTTCG

CATGACCGTC

GGGGATTGCA

CAAACTTCAG

AAGAGCATTT

GAGAATCAAT

TCTCTCCTTT

TTCTCAGGTC

CAGCTGCCAA

CCCCCCCACA

TAAAGATTTC

CAACCCGGTT

GTTCTGGAAG

CCCTGTGACT

AGTGGGTGGG

CTCAAGCACC

TGTGATGAGC

CCATTCAAGC

TGTGAAGCCT

GCTCCTTTCT

TTACATCCGG

AAGAAACGGG

ATTTCATGGG

TCAATTCCGC

CTTCATTCCT

AGGGAACATG

TCCACCATAC

CGAGALATCCA

TTAAAAATGG

CCCTGAGACA

TGCTTTTGTC

ATACGTATGG

CTTTAATAAA

TGTTTTCTTA

TCTCTTTTCT

TGATTTCCCC

TGCATGTTTC

CATGCAAAGA

AGGCTCAACG

CTCATTAGGG

AGAAAGCGCA

AAGTACATAC

CACACACACA

TTCCCTGCCA

ACACTCCTAT

TCATGCTGTG

CC TT CCTGAA

GTGTTCGCGG

CAALATGTGCA

ATGACTGGCA

ACACCCATGC

CGGCATCTGC

CCCTGTGGAG

CACAGGAAGC

GCCAAAGGTC

CCCTGAAGCC

CCTGTTCCTT

GCTAAGCCAG

TCCACTTTCG

AATGCGTAAC

GGATATGCAC

CACGCTATCC

GGGCCTCACT

CAAATTAGAA

AAATATTATC

CAAACGGTTA

A.ACTGCCGTC

GGCAAACATA

AAAGGCTTTC

TACCATTTGA

CTTGTCTTCT

TGGAAAGGTT

AAGAAAATAC

CTTTCGACTT

TTGGAGGTTC

CGAACACAAT

TTGCTTTACC

TATATGTGCC

GGCTGTGTCT

TTGAGTGCTG

TTGGTGGGGG

HDUB4.9 putative promoter sequence upstream of initiation ATG gcatctttct ccttctgatg cacagtcctc agggctgttt accgtctaag acagccggaa gcagcattac tggaaatgga ggcttatttt tctgtttcac tccgtcagcc ctttttattt acacatgctg agtcagcgct gagcacacct tcctcccatc ctttacacct acatgttggg gacacaccca aattttggca ggcaacatct ggccttttcc tccctgcttt gggcttttCt catctctagg tgagatacgt c t t t ctt cg ggcccatgaa atcctcctta agaggccttg aaaatcccta aattctgtcc ccaaatytgc ccgatcctga cactgaaaca taaacgtctc acggtataat aaacgttgat tgtttttatt cccaggacac aagccaaggg aaatcatcct gcgccgggec gagccaggat ctcttacttc taactgcaat acgatcgatg agggccagta cgatgttgct tttccttgtt ccattatcac ttcatcaatt tttacatccg aaagaaacgg aatttcctgg tcaattccgc cttcattcct agggaacatg tccaccatac cgagaatcca ttaaaaatgg ccctgagaca tgcttttgtc atacgtatgg ctttaataaa gcacacgaag ggcc aaaggt ccctgaagcc cctgttcctt.

gctaagccag tccactttcg aatgcctaac ggatatgcac cacgctatcc ggacctcact caaattagaa aaatattatc caaaaggtta WO 03/072724 WO 03/72724PCTIUS03/05338 tagctgggat gcacgtccga aatttgggga acagtctact tgctttatta tctccactgg ttcgctggaa actgtgctaa cttgtccttc atoccagcac acacacacaa aataaggcaa catcctgagg gaattcccag atttgattgg acttacagaa tagcgtcttt acatg a oct tctgag aaccgctcac ttgtcatcaa ttgtgcactg tttggcaatc caggtacttt ggtctgtttg atactatact cgtcgctgag aaacacacac tcacacggtt ctgtgtgacc agtaatttga cgatgccagg cttatcgcgc gggctgatgc ctgcaacctg t tot caagt t tatgcagtgt ttagtctcto agtatctctt tagcttccac cactoggaca attccacgga tcattgacta aggatgatgg acacgcgccc tcctaggtaa actgtcccaa ttcaggtgtt ggga caca Co acctgatgag ggccagagag cggtoccagc ttttgtttcg catgaccgtc ggggattgca caaacttoag aagagcattt gagaatcaat tctotcttt ttctcaggtc oagotgccaa ccccacacac agatttottc cccggttaca ctggaagtca ctgtgactco tgggtggggt ctcgtcattt agaaaaacct tgttttctta totcttttct tgatttcccc tgcatgtttc catgcaaaga aggctcaacg ctcattaggg agaaagcgca aagtacatac acaoacaaac octgccatgg ctcctattat tgctgtggga ttootgaatt gttcgcggtt gaagactctc tgtgatcctt aactgccgtc ggcaaacata aaaggctttc tacaatttga ottgtcttgt tggaaaggtt aagaaaatac ctttcgactt ttggaagttc acaatcacac ctttacctaa atgtgootat tgtgtctgtt gagtgotgat ggtgggggtg t cggaaggga gttccagtcg HDtJB4.1O putative promoter sequence upstream of initiation ATO agcaagcttt gtggtgtttg aggtcctcat atgtgoaata otcttgtcta attacttctc tcaocgccgc agaagagtga ttggcgcaga gcctccaggc tagaccactg aagtoaaagg ggatgaag~a cgacacatca gatccaaagg ggaagtaccg aactacaccc aatcctacat agtgatggct agtottocga gtgtgtattt gactcggttt gaaggtgaaa gaaaotggaa tttttacact ccacataacg agtccaaacg aataaaggaa gaaatcaatc ccagctgcga ccgacgtggt ctgattagac gaggaaagO t ccctgctcaa ggaacagttg tctccagagg ccttgtattg tcctgagtgc tgtcotctat ttatgtcaaa tagcatcact atgggaaaga agacacagac cccogagttg gaaattcctt taccotgoct coatcatcct ggagtccatg gaagaacaaa aoccaoacgt agaagcgcgo aaactaatga acatctcagg aootctggag ctgaatatga cgtattttct tgtggctcat tgcatttgga ggttcctgaa ccggaagcgg gaaaattttc agcaaacaca tcactgggtg aagctgcatc gtttccgtgg ttcatggtcc gccoagggoa gcacccaaat gtgaagcocg gcgcoggcct aagagattct cttgacatgc gctgtgctgg gctcaagaag tctgtcctga catagtgaga aggcgagcaa gacgagcact caagagcaaa ccgacgtac gaacagcaaa aacactggca cacagcaaga aggggtgcao aogcaaacac ggagcccaag atgagcocgc ggactgtctg cctaccgacg ottggggtgt gtgggacatc agagaagaac tggacctcag acagaccgac ccacgggcat ggagtgtgtg tgtttaaaaa tctgaagcac aaatgattgt ctttctcgtc o aac tcaggg aagaactcaa ccaagacgtt ccgatgtcac agocatacat tccaogctga gccagtggta gtcaacaggc gtgtgtoaag cgcaaggaga tggtggaaag acaaaacgaa ttgtgattca.

gctcoctgct cactcgcttc gggctctgct acacacacgc acacacacc tttctgtctc atatgggaaa.

agtgtttgtg tgtaggtttg gtttoattog ogtggatoat ggtgctcttc gcgccctggg ttgcctgttt.

gtaagtcatc tattcaaotg tggoatttgg agtcCctgtc gggaaatggc aggtacagtg ctocgtagaa tggagagaat aactttacac aggoaacaag gtotoagoag gtggagttgt taaaatggat St aog toot c aggcagggaa gctoaagaga agccactcag gocctgagt to tcaatcaaaa aaacctctct cctgcgaggg tgtgtgccag acacacacag acacaaacac tacaacaggg catcaagttt ttcatgatag cgtgtgaggt tcagttgttg tctcgocacc tttcttcccc acttgtgcto caoggtgccc tggaagtaag aaataaattc ggaatttctg ccgcagtgag cccttccttt atcaaagttg ccaoagaato gcctatcatt aoctctgcoa attgccaaga aacacaggac cacaacggac gatgccgagg ttttacatcc ccaagagcoo gaccacccot gaaagcacct aacgtcagaa tacaagtgtg togtcgacoc agggccagga tgatctcagt acacacacat gaacaccgtc aoaactggat tggggtcgtg gtgacattoa aat tgoaggg gtcggcatga ttgaatagtg ggtcgccg ttgotggaao gcttcccatg ctgtattgat agaaagccc t ggtcatttgt act tat tgat to totat ttg accagcoca ttgggcgcaa HDtTB4.11 putative promoter sequence upstream of initiation ATG WO 03/072724 WO 03172724PCT/US03/05338 cagcaagctt tgtggtgttt aaggt cc t ca aatgtgcaat cctctcgtct cattactcct gtcaccgcct cagaagagtg cttggcgtag tgcctccagg ttagaccact agagtcgaag cggatgaaga ccgacagatc agatccaaag tggaagtac c taactacacc caatcctaca tagagatggc gagtcttccg agtgtgtatt ggactcggtt agaaggtgaa ggaaactgga gtttttacac cccacataac gagtccaaac t aa taaagga tgaaatcaat tccagctgcg tccgacgtgg gctgact aga agaggaaag c accctgctca tggaacagtt gtctccagag tccttgtatt atcctgagtg atgtcctcta cttatgtcaa ctagcatcac aatgggaaag aagacacaga cccccgagtt ggaaattcct gtacggtgcc accatcatcc aggagtccat ggaagaacaa gacccacacg cagaagcgcg taaactaatg tacatctcag aacctctgga tatgaatatg tcgtattttc atttggctca atgcatttgg tagttcetga gccggaagca ggaaaatttt aagcaaacac ctcactgggt aaagctgcat tgtttccgtg cttcatggtc tgcccagggc agcacccaaa ggtgaagccc ggcgcCggc gaagagattc ccttgacatg tgctgtgctg agctcaagaa ttctgtcctg acacagtgag caggcgagca ggacgagcac tcaagagcaa tcccgacgta tgaacagcaa gaacactggc acacagcaag taggggtgca cacgcaaaca aggagcccaa gatgagcccg gggactgtct acctaccgac tcttggggtg tgtgggacat aagagaagaa atggacctca gacagaccya cccacgqgca aggagtgtgt gtgtttaaaa ctctgaagca gaaatgattg cc t tt ct cgt acaactcagg tg gaagaactca tccaagacgt cccgatgtca cagccataca gtccacgctg ggccagtggt agtcaacagg agtgtgtcaa acgcaaggag ttggtggaaa aacaaaacga cttgtgattc agctccctgc acactcgctt agggctctgc tacacacaea cacacacacc gt tto tgtct catatgggaa gagtgtttgt gtgtaggttt tgtttcattc ccgtggatca cggtgctctt ggcgcc ctgg cttgoctgt tgtaagtcat gtattcaaca atggcatttg cagtccctgt tgggaaatgg caggtacagt gctccataga atggagagaa taactttaca caggcaacaa tgtctcagca ggtggagttg ataaaatgga cctacgtcct gaggcaggga agctcaagag gagccactca agcctgagtt atcaatcaaa taaacctctc ccctacgagg ttgtgtgcca cacacacaca cacacaaaca gtacaacagg acatcaagtt gttcatgata gcgtgtgagg gacagttgtt ttctcgccac ctttcttccc gacttgtgct tcacqgtgcc ctggaagtaa gaaataaatt gggaatttct cccgcagtga ccccttcctt gatcaaagtt accacagaat tgcctatcat caactzctgcc aattgccaag gaa cac agga tcacaacgga tgatgccgag cttttacatc accaagagcc agaccacccc ggaaagcacc caacgtcaga atacaagtgt t tcgacgacc gaggaccagg gtgatctcag cacacacaca cgaacaccgt gacaactgga ttggggtcgt ggtgacattc taattgcagg ggtcggcacg cttgaatagt cgggct cgcc cttgctggaa cgcttcccat gctgtattga cagaaagccc gggtcatttg gacttattta ttctctattt gaccaacccc cttgggagca

Claims (14)

1. An isolated polynucleotide encoding a human deubiquitinating protease, wherein the open reading frame of the polynucleotide has at least 96% identity to the open reading frame of the polynucleotide sequence of hDUB 4.1 b. 0 5 2. An isolated polynucleotide according to claim 1, wherein the polynucleotide r'- m is selected from the group consisting of hDUB 4.1b, hDUB 4.2b, hDUB 4.3, hDUB hDUB 4.6, hDUB 4.7, hDUB 4.9, hDUB 4.1a, hDUB 4.2a, hDUB 4.4, hDUB t' 4.8, hDUB 4.10, and hDUB 4.11.

3. An isolated polynucleotide comprising the human deubiquitinating protease hDUB 4.1b.

4. An isolated polypeptide comprising a human deubiquitinating protease, wherein the polypeptide has at least 88% identity to the polypeptide sequence of hDUB 4.1b. An isolated polypeptide according to claim 4 wherein the polypeptide has at least 94% identity to the polypeptide sequence of hDUB 4.1 b.

6. An isolated polypeptide according to claim 4 or 5 wherein the polypeptide is selected from the group consisting of hDUB 4.1a, hDUB 4.1b, hDUB 4.2a, hDUB 4.2b, hDUB 4.3, hDUB 4.5, hDUB 4.6, hDUB 4.7, hDUB 4.9, hDUB 4.4, hDUB 4.8, hDUB 4.10, and hDUB 4.11.

7. An isolated polypeptide comprising the human deubiquitinating protease hDUB 4.1b.

8. An isolated polypeptide comprising a human deubiquitinating protease domain, wherein the domain sequence has at least 99% homology to amino acid residues 79 to 372 (GAGL.....AYVLFY) of the polypeptide sequence of hDUB 4.1b. 100 00 O 9. An isolated polypeptide comprising a human deubiquitinating protease C domain, wherein the domain comprises amino acid residues 79 to 372 c (GAGL.....AYVLFY) of the polypeptide sequence of hDUB 4.1b. A method of using a polynucleotide according to any one of claims 1 to 3, wherein the polynucleotide is used in an assay to identify an inhibitor of a hDUB Sof any one of claims 1 to 3.

11. A method of using a polypeptide of any one of claims 4 to 9, wherein the m polypeptide is used in an assay to identify an inhibitor of a hDUB of any one of Sclaims 4 to 9.

12. A method of reducing inflammation by regulating proinflammatory cytokine signaling, by administering a compound capable of inhibiting a polypeptide of any one of claims 4 to 9.

13. A method of modulating an autoimmune disease by altering cytokine receptor signaling involved in lymphocytes proliferation, by administering a compound capable of inhibiting a polypeptide of any one of claims 4 to 9.

14. A method of modulating an immune reaction during infection, by administering a compound capable of inhibiting a polypeptide of any one of claims 4 to 9. A method of reducing inflammation by regulating proinflammatory cytokine signaling, by administering a compound capable of altering regulation of transcription of a polynucleotide of any one of claims 1 to 3.

16. A method of modulating an autoimmune disease by altering cytokine receptor signaling involved in lymphocytes proliferation, by administering a compound capable of altering regulation of transcription of a polynucleotide of any one of claims 1 to 3. 00 0 17. A method of modulating an immune reaction during infection, by cl administering a compound capable of altering regulation of transcription of a c polynucleotide of any one of claims 1 to 3.

18. A method of identifying a modulator of a human deubiquitinating protease, wherein a compound is added to the reporter assay comprising a polynucleotide O immediately 5' to a human deubiquitinating protease selected from the group ten consisting of hDUB 4.1a, hDUB 4.1b, hDUB 4.2a, hDUB 4.2b, hDUB 4.3, hDUB 4.4, hDUB 4.5, hDUB 4.6, hDUB 4.7, hDUB 4,8, hDUB 4.9, hDUB 4.10, and hDUB 4.11, operatively linked to a reporter gene, and the effect of the compound C 10 is determined.

19. An isolated polynucleotide according to claim 1, substantially as hereinbefore described with reference to the examples. An isolated polypeptide according to claim 4, substantially as hereinbefore described with reference to the examples.

21. Use of a compound capable of inhibiting a polypeptide of any one of claims 4 to 9, or (ii) modulating the expression of a polynucleotide of any one of claims 1 to 3, for the manufacture of a medicament for the prophylaxis or treatment of inflammation. AVENTIS PHARMACEUTICALS INC WATERMARK PATENT TRADE MARK ATTORNEYS P24432AU00