WO2000015787A1 - Genes encoding for the human and murine death inducer-obliterator-1 - Google Patents
Genes encoding for the human and murine death inducer-obliterator-1 Download PDFInfo
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- WO2000015787A1 WO2000015787A1 PCT/GB1999/003019 GB9903019W WO0015787A1 WO 2000015787 A1 WO2000015787 A1 WO 2000015787A1 GB 9903019 W GB9903019 W GB 9903019W WO 0015787 A1 WO0015787 A1 WO 0015787A1
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- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
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- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
- C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
- C07K14/4747—Apoptosis related proteins
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
Definitions
- the present invention relates to a novel DNA sequence that codes for expression of a human Death Inducer-Obliterator 1 (DIO-1 )gene and the polypeptide derived from the DNA sequence.
- DIO-1 human Death Inducer-Obliterator 1
- Expression vectors containing such sequences and host cells transformed with such expression vectors are also disclosed, as are methods for the expression of the novel DIO-1 polypeptide of the invention, and uses thereof.
- FasL or TNF The binding of FasL or TNF to their specific receptors triggers oligomerization and activation of a series of events that results in apoptosis (Nagata. 1997).
- Dissection of the signal-transducing machinery for Fas-mediated apoptosis has revealed the presence of a set of molecules, FADD/Mortl . which is recruited by and associates with Fas following its activation.
- FADD/Mortl which is recruited by and associates with Fas following its activation.
- TRADD which associates to TNFRl and triggers cell death.
- TRADD binds to FADD through its death domain such that both stimuli. Fas and TNF- ⁇ activate the same downstream caspase pathway.
- TNF- ⁇ activates still another apoptosis pathway through the recruitment of RIP, a serine/threonine kinase that activates the apoptotic pathway by yet unknown mechanisms. More recently, it has been clearly established that STAT1 is required for TNF- ⁇ -triggered cell death (Kumar et al.. 1997; Hoey. 1997).
- the binding of these factors to their specific receptors triggers a cascade of specific cysteil proteases, the caspases, which cleave various cellular components and lead to the morphological changes characteristic of apoptosis in cells and nuclei.
- the known signaling pathway initiates at the cell surface and operates in the cytoplasm, the main location of the caspases as well as their inhibitors (Vucic et al. 1997; Irmler et al., 1997; Ghayur et al.. 1997: Vaux. 1997; Chinnaiyan et al . 1997). Very little is known as to how these signals are transmitted to the nucleus.
- a caspase-activated deoxyribonuclease (CAD) and its inhibitor (ICAD) have recently been identified in the cytoplasmic fraction of a mouse lymphoma cell line. Caspase pathway activation by different stimuli cleaves ICAD. allowing CAD to enter the nucleus and degrade chromosomal DNA (Enari et al.. 1998; Sakahira et al.. 1998).
- the invention relates to the DNA sequence, amino acid sequences and compounds and methods as defined in the claims. It also relates to the use of the new gene as defined in the claims.
- the new gene has been called DIO-1 gene by the inventors.
- gene means both gcnomic DNA. cDNA. and synthetic DNA.
- the claimed nucleotide and amino acid sequences are new. They have been found to be useful for control of apoptosis and thereby useful not only for the treatment of diseases which are characterized in the alteration in cell death or by hypcrproliferation, but also for the treatment of metabolic, proliferative or inflammatory conditions.
- Figure legends Figures 1 A, B. C and D and E Nucleotide and predicted amino acid sequences of
- Figure 1 E Schematic representation of the predicted murine DIO- 1 ORF. The starting and ending positions of the amino acids defining the motifs are numbered on top.
- Figures 2. a - 2e Northern blots and Western blot analysis, cell death and DIO-1 expression analysis.
- FIG. 5A - 5D Expression pattern of several transcription factors in DK )- ! -infected chick limb bud. Detailed description of the invention Methods
- the resulting 2.6 Kbp band was excised from the gel and cloned in the TA-type vector pGEM-T (Promega, Madison, Wl).
- the resulting clones were sequence-analyzed for orientation, and the oriented sense with respect to the T7 promoter was called DIO- lpGEM-T.
- DIO- lpGEM-T was screened by probing with the RACE clone: the same probe was used to screen a human fetal kidney cDNA library (Clontech) from which the human DIO-1 homologue was cloned.
- WOL-1 cells were derived from the bone marrow of adult BALB/c mice. They are an untransformed, IL-7-dependent, stroma cell- independent pre-BI cell line, capable of reconstituting irradiated SCID mice. WOL-1 cells grow in Iscove ' s modified Dulbecco's medium (IMDM) supplemented with penicillin ( 100 U/ml), streptomycin (100 ⁇ g/ml), 1 mM sodium pyruvate, non-essential amino acids, 50 ⁇ M 2- mercaptoethanol, 2 mM L-glutamine, 10% fetal calf serum (FCS) and IL-7 (3% supernatant from a murine IL-7-producing cell line).
- IMDM Iscove ' s modified Dulbecco's medium
- FCS fetal calf serum
- IL-7 3% supernatant from a murine IL-7-producing cell line.
- A20, BAF/3. and FL5.12 cell lines were maintained in RPMI 1640 with 10% FCS as described, and the FL5.12hBcl- 2 stable cell line was grown in the presence of 1 mg/ml G418.
- MEF( 10.1 )Val5MycER cells were cultured in phenol red-free Dulbecco * s modified Eagle medium (DMEM) containing 10% FCS at 39°C. Where indicated. 1 ⁇ M E2 (17b-estradiol) was added to the medium to activate the MycER fusion protein after 24 h FCS starvation (Wagneer et al. 1994).
- WOL-1 , A20. BAF/3. and FL5.12 cell lines were cultured at 37°C, ancf- all cell lines were kept in a humidified atmosphere with 5% C0 2 -
- Transient DNA transfection was performed by electroporation. For each transfection, 2 x 10 log phase cells were collected by centrifugation. resuspended in 200 ⁇ l of complete RPMI 1640 medium without FCS. After addition of 10 ⁇ g of plasmid DNA (1 mg/ml). samples were gently shaken and electroporated in a 0.4 cm electrode gap gene pulser cuvette at 960 ⁇ F and 320 V with a GenePulser apparatus (Bio-Rad, Hercules. CA). Samples were then diluted with 6 ml of the same medium supplemented with 10% FCS and incubated at 37°C in a humidified atmosphere with 5% CO 2 . Cells were analyzed for cell cycle staining by FACS at 48 h post- electroporation.
- cytoplasmic RNA was prepared as described (Sambrook). R A ( 10 ⁇ g) was Northern blotted using a 32 P-labeled DIO-1 riboprobe made by DIO-1 pGEM-T digestion with Bgl II and in vitro transcribed from SP6 using the Riboprobe in vitro Transcription System (Promega). Hybridization was performed in 50% formamide at
- a peptide was synthesized corresponding to amino acids 58-72 of murine DIO-1 with an additional N terminal cysteine (CSLRRSGRQPKRTERV); it was then coupled to maleimide-activated keyhole limpet hemocyanin and the purified conjugate injected into New Zealand White rabbits. Polvclonal antibody was affinity purified against the peptide coupled to a column. WOL-1 were IL-7 starved by washing four times in complete IMDM without FCS. then resuspended in the same volume of medium plus 10% FCS. In situ hybridization and histology
- Chicken embryos (either from Maclntyre Poultry, San Diego. CA, or SPAFAS, Norwich, CT) were infected with a virus containing the full length cDNA of DIO-1. Virus preparation and injections were as previously described (Morgan et al, 1992). After injection, the embryos were returned to the incubator at 37°C and fixed at different time points either for in situ hybridization or for phenotypic analysis.
- mRNA obtained from the WOL-1 pre-BI cell line was derived from BALB/c adult bone marrow; it grows exponentially in the presence of IL-7 and undergoes apoptosis upon IL-7 withdrawal.
- WOL-1 was derived from BALB/c adult bone marrow; it grows exponentially in the presence of IL-7 and undergoes apoptosis upon IL-7 withdrawal.
- oligonucleotide primers one specific for the polyadenylated tail and the other arbitrary in sequence
- mRNA was amplified from cells in exponential growth or 2 h after IL-7 deprivation; this was followed by RNA reverse transcription and resolution on a denaturing sequencing gel.
- the DIO-1 protein does not belong to any typical family presently identified, and comprises an N-terminal domain, a central non-canonical Zn finger domain, and a C- terminus domain containing a K-rich region. See Figure IF which is a schematic representation of the predicted DIO-1 ORF. The starting and ending positions of the amino acids defining the motifs are numbered on top.
- Example 2 To further characterize DIO-1. its expression pattern was examined Northern blot analysis using a DIO-1 probe of RNA samples isolated from several eel! lines in exponential growth or undergoing apoptosis following triggering in different conditions. Northern blots containing 10 mg per lane of total cytoplasmic RNA from the indicated cell lines, treated with several apoptotic stimuli at different time points, were hybridized to the DIO- 1 riboprobe. The blots were reprobed with an actin probe for normalization of the amounts loaded.
- Figure 2a shows that WOL- 1 in exponential growth phase expresses low levels of DIO-1 , which increase upon induction of apoptosis .
- DIO-1 is upregulated in cells deprived of IL-7. or treated with IFN- ⁇ or with dexamethasone. but not in cells treated with etoposide. V irradiation or in those undergoing Fas-mediated cell death
- FIG. 2b shows Western blot analysis of WOL-1 cells driven to apoptosis by IL-7 starvation.
- the cells were collected at different time points after removal of IL-7 from the culture medium; 5 x 10 "'' cells were lysed with RIPA buffer and the total extract electrophoresed on an 8% PAGE-SDS gel, blotted and incubated with a affinity- purified polyclonal antibody against amino acids 58-72 that specificalh recognizes DIO-1 (1 : 100 dilution in TBS-1 % dry milk). Equivalence of protein loading was confirmed by Ponceau S staining. The position of the DIO-1 gene product is indicated in Figure 2b.
- the DIO-1 ORF was cloned into the pcDNA3 mammalian expression vector (Invitrogen, Inc., San Diego, CA). Both empty vector and the DIO-1 construct were transiently transfected by electroporation into A20 and BAF/3 cell lines. After 48 h expression, the cells were permeabilized and stained with propidium iodide, and cell cycle analyzed by FACS. Under the same conditions, both FL5.12 wild type and stably transfected hBcl-2 cells were transiently transfected.
- DIO-1 is thus differentially expressed under several apoptotic conditions and induces apoptosis when overexpressed.
- Example 4 DIO-1 expression was analyzed in murine tissues by hybridization with the DIO-1 riboprobe of a mouse MTN Blot (Clontech). To determine DIO-1 transcript distribution, various tissues were analyzed in Northern blot. Two mRNA transcript bands corresponding to 9.5 and 5.4 kb were detected in most tissues tested, including thymus, spleen, heart, brain, lung, liver, skeletal muscle, kidney and testis. This expression pattern was confirmed with the anti-DIO-1 antibody in Western blot. DIO- 1 expression was also upregulated in vitro in various cell lines, derived from different tissues, when undergoing apoptosis
- DIO-1 is highly expressed at gestation day 12.5 in the interdigitating membranes, where programmed cell death is known to occur.
- the AER is a pseudostratified epithelium located at the distal part of the developing limb bud shown to be required for limb outgrowth (Summerbell et al , 1973; Todt and Fallon, 1984). Subsequent to the alteration in AER formation, limb outgrowth is arrested. To better understand the role of DIO-1 , retroviral technology was used to misexpress it in the chick limb.
- Example 7 Since misexpression of DIO-1 can perturb AER formation, it could be expected that it is preceded by changes in gene expression, both in the ectoderm and in the underlying limb bud mesoderm.
- In situ hybridization of embryos were infected with the RCAS- Dio-1 construct using riboprobes for mesodermal genes involved in limb outgrowth such as Msx-1. Lhx-2 . and NF- ⁇ B (Kanegae et al, 1998). Msx-1 hx-2 . and NF- ⁇ B (show downregulation in their transcript levels, see Figure 5A. 5C and 5D, respectively.
- transcripts for ectodermal genes involved in limb outgrowth such as Fgf-8 . are also absent or downregulated, see Figure 5B). Note the reduced size of the infected limb buds (left limb buds in all cases).
- Msx-1 (A), Fgf-8 (B), Lhx-2 (C) and NF- ⁇ B D) are strongly downregulated (arrows) in the injected limb buds (compare with the normal expression pattern in the uninjected limb bud, right limb bud in all cases).
- Misexpression of the RCAS-Dio-1 construct thus leads to arrest in limb outgrowth that is preceded by changes in the expression of genes involved in outgrowth of the limb. It is not known whether the misexpression of DIO- 1 is directly responsible for the downregulation of ectodermal gene markers (i.e., Fgf 8) or if this is a consequence of the previously altered mesodermal gene expression. The combination of these results indicates that DIO-1 may regulate cell death and proliferation during limb development.
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Abstract
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Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA002341155A CA2341155A1 (en) | 1998-09-10 | 1999-09-10 | Genes encoding for the human and murine death inducer-obliterator-1 |
JP2000570314A JP2002526040A (en) | 1998-09-10 | 1999-09-10 | Gene encoding human and murine cell death-inducing factor obliterator 1 |
AU58731/99A AU765359B2 (en) | 1998-09-10 | 1999-09-10 | Genes encoding for the human and murine death inducer-obliterator-1 |
NZ510365A NZ510365A (en) | 1998-09-10 | 1999-09-10 | DNA sequences and corresponding amino acid sequences for the human and murine DIO-1 and their use in treating diseases characterised by an alteration in cell death |
EP99946314A EP1109905A1 (en) | 1998-09-10 | 1999-09-10 | Genes encoding for the human and murine death inducer-obliterator-1 |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
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SE9803069A SE9803069D0 (en) | 1998-09-10 | 1998-09-10 | New gene |
SE9803069-5 | 1998-09-10 | ||
US10087398P | 1998-09-17 | 1998-09-17 | |
US60/100,873 | 1998-09-17 |
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WO2000015787A1 true WO2000015787A1 (en) | 2000-03-23 |
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PCT/GB1999/003019 WO2000015787A1 (en) | 1998-09-10 | 1999-09-10 | Genes encoding for the human and murine death inducer-obliterator-1 |
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EP (1) | EP1109905A1 (en) |
JP (1) | JP2002526040A (en) |
AU (1) | AU765359B2 (en) |
CA (1) | CA2341155A1 (en) |
NZ (1) | NZ510365A (en) |
WO (1) | WO2000015787A1 (en) |
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1999
- 1999-09-10 EP EP99946314A patent/EP1109905A1/en not_active Withdrawn
- 1999-09-10 NZ NZ510365A patent/NZ510365A/en unknown
- 1999-09-10 CA CA002341155A patent/CA2341155A1/en not_active Abandoned
- 1999-09-10 WO PCT/GB1999/003019 patent/WO2000015787A1/en active IP Right Grant
- 1999-09-10 AU AU58731/99A patent/AU765359B2/en not_active Ceased
- 1999-09-10 JP JP2000570314A patent/JP2002526040A/en not_active Withdrawn
Non-Patent Citations (4)
Title |
---|
DATABASE GENEMBL 1 July 1997 (1997-07-01), NAGASE ET AL.: "Human mRNA for KIAA0333 gene, partial cds.", XP002130127 * |
DATABASE GENEMBL 9 July 1999 (1999-07-09), GARCIA-DOMINGO ET AL.: "Mus musculus mRNA for death inducer-obliterator-1 (Dio-1)", XP002130128 * |
GARCIA-DOMINGO ET AL.: "DIO-1 is a novel gene involved in onset of apoptosis in vitro, whose misexpression disrupts limb development.", PROC. NATL. ACAD. SCI. USA, vol. 96, no. 14, July 1999 (1999-07-01), pages 7992 - 7997, XP002130126 * |
NAGASE ET AL: "Prediction of the coding sequences of unidentified human genes. VII. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro.", DNA RESEARCH, vol. 4, no. 2, 28 April 1997 (1997-04-28), pages 141 - 150, XP002102085 * |
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Publication number | Publication date |
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AU5873199A (en) | 2000-04-03 |
AU765359B2 (en) | 2003-09-18 |
EP1109905A1 (en) | 2001-06-27 |
CA2341155A1 (en) | 2000-03-23 |
JP2002526040A (en) | 2002-08-20 |
NZ510365A (en) | 2003-10-31 |
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