WO2002094870A2 - Proteines et acides nucleiques codant pour ces proteines - Google Patents

Proteines et acides nucleiques codant pour ces proteines Download PDF

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WO2002094870A2
WO2002094870A2 PCT/US2001/051580 US0151580W WO02094870A2 WO 2002094870 A2 WO2002094870 A2 WO 2002094870A2 US 0151580 W US0151580 W US 0151580W WO 02094870 A2 WO02094870 A2 WO 02094870A2
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nucleic acid
amino acid
ofthe
polypeptide
protein
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PCT/US2001/051580
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WO2002094870A8 (fr
Inventor
William M. Grosse
John R. Macdougall
Glennda Smithson
Isabelle Millet
David J. Stone
Erik Gunther
Karen Ellerman
John P. Ii Alsobrook
Denise M. Lepley
Catherine E. Burgess
Kimberly A. Spytek
Shlomit R. Edinger
Esha A. Gangolli
Linda Gorman
Raymond J. Taupier, Jr.
Li Li
Xiaojia Guo
Elma R. Fernandes
Corine A. M. Vernet
Velizar T. Tchernev
Stacie J. Casman
Suresh Shenoy
Vishnu Mishra
Katarzyna Furtak
Jason C. Baumgartner
Steven D. Colman
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Curagen Corporation
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Publication of WO2002094870A8 publication Critical patent/WO2002094870A8/fr

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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • 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 invention generally relates to nucleic acids and polypeptides encoded thereby.
  • the invention generally relates to nucleic acids and polypeptides encoded therefrom. More specifically, the invention relates to nucleic acids encoding cytoplasmic, nuclear, membrane bound, and secreted polypeptides, as well as vectors, host cells, antibodies, and recombinant methods for producing these nucleic acids and polypeptides.
  • the invention is based in part upon the discovery of nucleic acid sequences encoding novel polypeptides.
  • novel nucleic acids and polypeptides are referred to herein as NONX, or ⁇ ON1, ⁇ ON2, ⁇ ON3, ⁇ ON4, ⁇ OV5, NON6, ⁇ OV7, NOV8, NOV9, NOV10, NOV11, NOV12, NOV13, NON 14, and ⁇ ON15 nucleic acids and polypeptides.
  • These nucleic acids and polypeptides, as well as derivatives, homologs, analogs and fragments thereof, will hereinafter be collectively designated as " ⁇ ONX" nucleic acid or polypeptide sequences.
  • the invention provides an isolated ⁇ ONX nucleic acid molecule encoding a ⁇ ONX polypeptide that includes a nucleic acid sequence that has identity to the nucleic acids disclosed in SEQ ID ⁇ OS.l, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41 , 43, 45, and 47.
  • the ⁇ ONX nucleic acid molecule will hybridize under stringent conditions to a nucleic acid sequence complementary to a nucleic acid molecule that includes a protein-coding sequence of a ⁇ ONX nucleic acid sequence.
  • the invention also includes an isolated nucleic acid that encodes a ⁇ ONX polypeptide, or a fragment, homolog, analog or derivative thereof.
  • the nucleic acid can encode a polypeptide at least 80% identical to a polypeptide comprising the amino acid sequences of SEQ ID ⁇ OS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 26, 28, 40, 42, 44, 46, and 48.
  • the nucleic acid can be, for example, a genomic DNA fragment or a cDNA molecule that includes the nucleic acid sequence of any of SEQ ID NOS:l, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, and 47.
  • an oligonucleotide e.g. , an oligonucleotide which includes at least 6 contiguous nucleotides of a NONX nucleic acid (e.g., SEQ ID ⁇ OS.l, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, and 47) or a complement of said oligonucleotide.
  • a NONX nucleic acid e.g., SEQ ID ⁇ OS.l, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, and 47
  • substantially purified NONX polypeptides SEQ ID ⁇ OS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 26, 28, 40, 42, 44, 46, and 48.
  • the NOVX polypeptides include an amino acid sequence that is substantially identical to the amino acid sequence of a human NOVX polypeptide.
  • the invention also features antibodies that immunoselectively bind to NOVX polypeptides, or fragments, homologs, analogs or derivatives thereof.
  • the invention includes pharmaceutical compositions that include therapeutically- or prophylactically-effective amounts of a therapeutic and a pharmaceutically- acceptable carrier.
  • the therapeutic can be, e.g., a NOVX nucleic acid, a NONX polypeptide, or an antibody specific for a ⁇ ONX polypeptide.
  • the invention includes, in one or more containers, a therapeutically- or prophylactically-effective amount of this pharmaceutical composition.
  • the invention includes a method of producing a polypeptide by culturing a cell that includes a ⁇ OVX nucleic acid, under conditions allowing for expression ofthe ⁇ OVX polypeptide encoded by the D ⁇ A. If desired, the ⁇ OVX polypeptide can then be recovered.
  • the invention includes a method of detecting the presence of a ⁇ OVX polypeptide in a sample.
  • a sample is contacted with a compound that selectively binds to the polypeptide under conditions allowing for formation of a complex between the polypeptide and the compound.
  • the complex is detected, if present, thereby identifying the ⁇ OVX polypeptide within the sample.
  • the invention also includes methods to identify specific cell or tissue types based on their expression of a ⁇ OVX.
  • Also included in the invention is a method of detecting the presence of a ⁇ OVX nucleic acid molecule in a sample by contacting the sample with a ⁇ OVX nucleic acid probe or primer, and detecting whether the nucleic acid probe or primer bound to a ⁇ OVX nucleic acid molecule in the sample.
  • the invention provides a method for modulating the activity of a
  • ⁇ OV3 polypeptide by contacting a cell sample that includes the ⁇ OVX polypeptide with a compound that binds to the ⁇ OVX polypeptide in an amount sufficient to modulate the activity of said polypeptide.
  • the compound can be, e.g., a small molecule, such as a nucleic acid, peptide, polypeptide, peptidomimetic, carbohydrate, lipid or other organic (carbon containing) or inorganic molecule, as further described herein.
  • a therapeutic in the manufacture of a medicament for treating or preventing disorders or syndromes including, e.g., Alzheimer's disease, Neurodegenerative disease, Parkinson disease, type 3; Stroke, Parkinson's disease, Huntington's disease, Cerebral palsy, Epilepsy, Ataxia-telangiectasia, Behavioral disorders, Addiction, Anxiety, Pain, Neuroprotection, encephalopathy.
  • disorders or syndromes including, e.g., Alzheimer's disease, Neurodegenerative disease, Parkinson disease, type 3; Stroke, Parkinson's disease, Huntington's disease, Cerebral palsy, Epilepsy, Ataxia-telangiectasia, Behavioral disorders, Addiction, Anxiety, Pain, Neuroprotection, encephalopathy.
  • demyelinating neuropathies including Charcot-Marie-Tooth disease
  • Cardiovascular disease Hemic and Lymphatic Diseases, acute heart failure, hypotension, hypertension, angina pectoris, myocardial infarction, ischemic heart disease, cardiomyopathy, atherosclerosis, congenital heart defects, aortic stenosis , atrial septal defect (ASD), atrioventricular (A-V) canal defect, ductus arteriosus , pulmonary stenosis , subaortic stenosis, ventricular septal defect (VSD), valve diseases, hemophilia, hypercoagulation, idiopathic thrombocytopenic purpura, Erythrokerat
  • the therapeutic can be, e.g., a NOVX nucleic acid, a NOVX polypeptide, or a NOVX-specific antibody, or biologically-active derivatives or fragments thereof.
  • compositions ofthe present invention will have efficacy for treatment of patients suffering from the diseases and disorders disclosed above and/or other pathologies and disorders ofthe like.
  • the polypeptides can be used as immunogens to produce antibodies specific for the invention, and as vaccines. They can also be used to screen for potential agonist and antagonist compounds.
  • a cDNA encoding NOVX may be useful in gene therapy, and NOVX may be useful when administered to a subject in need thereof.
  • the compositions ofthe present invention will have efficacy for treatment of patients suffering from the diseases and disorders disclosed above and/or other pathologies and disorders ofthe like.
  • the invention further includes a method for screening for a modulator of disorders or syndromes including, e.g., the diseases and disorders disclosed above and/or other pathologies and disorders ofthe like.
  • the method includes contacting a test compound with a NOVX polypeptide and determining if the test compound binds to said NOVX polypeptide. Binding ofthe test compound to the NOVX polypeptide indicates the test compound is a modulator of activity, or of latency or predisposition to the aforementioned disorders or syndromes.
  • Also within the scope of the invention is a method for screening for a modulator of activity, or of latency or predisposition to disorders or syndromes including, e.g., the diseases and disorders disclosed above and/or other pathologies and disorders ofthe like by administering a test compound to a test animal at increased risk for the aforementioned disorders or syndromes.
  • the test animal expresses a recombinant polypeptide encoded by a NOVX nucleic acid.
  • Expression or activity of NOVX polypeptide is then measured in the test animal, as is expression or activity ofthe protein in a control animal which recombinantly- expresses NOVX polypeptide and is not at increased risk for the disorder or syndrome.
  • the expression of NOVX polypeptide in both the test animal and the control animal is compared. A change in the activity of NOVX polypeptide in the test animal relative to the control animal indicates the test compound is a modulator of latency ofthe disorder or syndrome.
  • the invention includes a method for determining the presence of or predisposition to a disease associated with altered levels of a NOVX polypeptide, a NOVX nucleic acid, or both, in a subject (e.g., a human subject).
  • the method includes measuring the amount ofthe NOVX polypeptide in a test sample from the subject and comparing the amount of the polypeptide in the test sample to the amount ofthe NOVX polypeptide present in a control sample.
  • An alteration in the level ofthe NOVX polypeptide in the test sample as compared to the control sample indicates the presence of or predisposition to a disease in the subject.
  • the predisposition includes, e.g., the diseases and disorders disclosed above and/or other pathologies and disorders ofthe like.
  • the expression levels ofthe new polypeptides ofthe invention can be used in a method to screen for various cancers as well as to determine the stage of cancers.
  • the invention includes a method of treating or preventing a pathological condition associated with a disorder in a mammal by administering to the subject a NOVX polypeptide, a NOVX nucleic acid, or a NOVX-specific antibody to a subject (e.g., a human subject), in an amount sufficient to alleviate or prevent the pathological condition.
  • the disorder includes, e.g. , the diseases and disorders disclosed above and/or other pathologies and disorders ofthe like.
  • the invention can be used in a method to identity the cellular receptors and downstream effectors of the invention by any one of a number of techniques commonly employed in the art. These include but are not limited to the two-hybrid system, affinity purification, co-precipitation with antibodies or other specific-interacting molecules. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing ofthe present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In the case of conflict, the present specification, including definitions, will control, m addition, the materials, methods, and examples are illustrative only and not intended to be limiting.
  • the present invention provides novel nucleotides and polypeptides encoded thereby. Included in the invention are the novel nucleic acid sequences and their encoded polypeptides. The sequences are collectively referred to herein as “NOVX nucleic acids” or “NOVX polynucleotides” and the corresponding encoded polypeptides are referred to as “NOVX polypeptides” or “NOVX proteins.” Unless indicated otherwise, “NOVX” is meant to refer to any ofthe novel sequences disclosed herein. Table A provides a summary ofthe NOVX nucleic acids and their encoded polypeptides.
  • NOVX nucleic acids and their encoded polypeptides are useful in a variety of applications and contexts.
  • the various NOVX nucleic acids and polypeptides according to the invention are useful as novel members ofthe protein families according to the presence of domains and sequence relatedness to previously described proteins. Additionally, NOVX nucleic acids and polypeptides can also be used to identify proteins that are members ofthe family to which the NOVX polypeptides belong.
  • NOV1 is homologous to a Calgizzarin-like family of proteins.
  • the NOV1 nucleic acids, polypeptides, antibodies and related compounds according to the invention will be useful in therapeutic and diagnostic applications implicated in, for example; Alzheimer's disease, Cardiovascular disease, Neurodegenerative disease, bone disorders, Hemic and Lymphatic Diseases, Muscle Disorders, Myotonia and Cancers including , colon and lung and breast cancer, or other pathologie or conditions.
  • NOV2 is homologous to the Dynactin 1 P150-like family of proteins.
  • NOV2 nucleic acids, polypeptides, antibodies and related compounds according to the invention will be useful in therapeutic and diagnostic applications implicated in, for example; Alstrom syndrome; Glucosidase I deficiency; Orofacial cleft-2; Parkinson disease, type 3; Preeclampsia; Welander distal myopathy; Von Hippel-Lindau (VHL) syndrome, Alzheimer's disease, Stroke, Tuberous sclerosis, hypercalceimia, Parkinson's disease, Huntington's disease, Cerebral palsy, Epilepsy,Lesch-Nyhan syndrome, Multiple sclerosis,Ataxia- telangiectasia,Leukodystrophies,Behavioral disorders, Addiction, Anxiety, Pain, Neuroprotection and/or other pathologies and disorders.
  • VHL Von Hippel-Lindau
  • NOV3 is homologous to a family of Lysosomal acid lipase/gastric lipase-like proteins.
  • the NOV3 nucleic acids and polypeptides, antibodies and related compounds according to the invention will be useful in therapeutic and diagnostic applications implicated in, for example: severe infantile-onset Wolman disease and milder late onset cholesteryl ester storage disease (CESD), Diabetes, Von Hippel-Landau (VHL) syndrome, Pancretaitis, Obesity, and/or other pathologies.
  • NOV4 is homologous to the R o-Interacting Protein-like family of proteins.
  • NOV4 nucleic acids, polypeptides, antibodies and related compounds according to the invention will be useful in therapeutic and diagnostic applications implicated in, for example: Cell adhesion, shape, interaction communication, cytokinesis disorders; myotonic dystrophy; muscular disorders and diseases; immunological disorders and diseases, and/or other pathologies.
  • NOV5 is homologous to the Protein Phosphatase-like family of proteins.
  • NOV5 nucleic acids, polypeptides, antibodies and related compounds according to the invention will be useful in therapeutic and diagnostic applications implicated in, various diseases, disorders and conditions.
  • NOV6 is homologous to the Ubiquitin Ligase-like family of proteins.
  • NOV6 nucleic acids, polypeptides, antibodies and related compounds according to the invention will be useful in therapeutic and diagnostic applications implicated in, for example: autoimmune diseases, Angelman syndrome, inflammatory and immune diseases, Liddle's syndrome, encephalopathy, Prader-Willi syndrome, Neural Dvelopment disease, muscular disease, ataxia, and/or other pathologies/disorders.
  • NOV7 is homologous to members ofthe Salivary Proline-Rich Phosphoprotein Precursor- like family of proteins.
  • the NOV7 nucleic acids, polypeptides, antibodies and related compounds according to the invention will be useful in therapeutic and diagnostic applications implicated in, for example; hypogonadotropic hypogonadism, Kallman syndrome, bacterial/viral infection, immunological and inflammatory diseases and disorders, and/or other pathologies/disorders.
  • NOV8 is homologous to the Kallikrein -like family of proteins.
  • NOV8 nucleic acids and polypeptides, antibodies and related compounds according to the invention will be useful in therapeutic and diagnostic applications implicated in, for example; cancer (especially but not limited to breast, prostate, and skin), neurological disorders, skin disorders, digetive system disorders, reproductive system disorders, protease/protease inhibitor deficiency disorders, and/or other pathologies/disorders.
  • NOV9 is homologous to the Olfactory Receptor-like family of proteins.
  • NOV9 nucleic acids and polypeptides, antibodies and related compounds according to the invention will be useful in therapeutic and diagnostic applications implicated in, for example; bacterial, fungal, protozoal and viral infections (particularly infections caused by HIV-1 or HIV-2), pain, cancer (including but not limited to Neoplasm; adenocarcinoma; lymphoma; prostate cancer; uterus cancer), anorexia, bulimia, asthma, Parkinson's disease, acute heart failure, hypotension, hypertension, urinary retention, osteoporosis, Crohn's disease; multiple sclerosis; and Treatment of Albright Hereditary Ostoeodystrophy, angina pectoris, myocardial infarction, ulcers, asthma, allergies, benign prostatic hypertrophy, and psychotic and neurological disorders, including anxiety, schizophrenia, manic depression, delirium, dementia, severe mental retardation.
  • Diffenatorubro-pallidoluysian atrophy Hypophosphatemic rickets, autosomal dominant (2) Acrocallosal syndrome and dyskinesias, such as Huntington's disease or Gilles de la Tourette syndrome, and/or other pathologies/disorders.
  • NOV10 is homologous to the Serine-Threonine Kinase-like family of proteins.
  • NOV10 nucleic acids and polypeptides, antibodies and related compounds according to the invention will be useful in therapeutic and diagnostic applications implicated in, for example; Koz-Heghers syndrome, pancreatic cancer, gastrointestinal polyps, renal cancer, multiple endocrine neoplasia type II, familial melanoma, ovarian cancer, Ataxia telangeictasia, neurodegenerative disease comprising Alzheimer's, sepsis, ischemic heart disease, arthritis, disease ofthe immune system, human immunodeficiency virus infection, and/or other pathologies/disorders.
  • NOV11 is homologous to the Serine/Threonine-Protein Kinase Pak 5-like family of proteins.
  • NOV11 nucleic acids and polypeptides, antibodies and related compounds according to the invention will be useful in therapeutic and diagnostic applications implicated in, for example; Von Hippel-Lindau (VHL) syndrome, Alzheimer's disease, Stroke, Tuberous sclerosis, hypercalceimia, Parkinson's disease, Huntington's disease, Cerebral palsy, Epilepsy, Lesch-Nyhan syndrome, Multiple sclerosis, Ataxia-telangiectasia, Leukodystrophies, Behavioral disorders, Addiction, Anxiety, Pain, Neuroprotection, cancer, and/or other pathologies/disorders.
  • VHL Von Hippel-Lindau
  • NOV12 is homologous to the Zfpl06-like family of proteins.
  • nucleic acids and polypeptides, antibodies and related compounds according to the invention will be useful in therapeutic and diagnostic applications implicated in, for example; graft versus host disease, diabetes, cardiomyopathy, atherosclerosis, hypertension, congenital heart defects, aortic stenosis , atrial septal defect (ASD), atrioventricular (A-V) canal defect, ductus arteriosus , pulmonary stenosis , subaortic stenosis, ventricular septal defect (VSD), valve diseases, tuberous sclerosis, scleroderma, obesity, transplantation, aneurysm, hypertension, fibromuscular dysplasia, stroke, adrenoleukodystrophy , congenital adrenal hyperplasia, Von Hippel-Lindau (VHL) syndrome , pancreatitis, hyperthyroidism, hypothyroidism, endometri
  • NOV13 is homologous to the Sex-Determination Protein Homolog FEMlA-like family of proteins.
  • nucleic acids and polypeptides, antibodies and related compounds according to the invention will be useful in therapeutic and diagnostic applications implicated in, for example; graft versus host disease, diabetes, cardiomyopathy, atherosclerosis, hypertension, congenital heart defects, aortic stenosis , atrial septal defect (ASD), atrioventricular (A-V) canal defect, ductus arteriosus , pulmonary stenosis , subaortic stenosis, ventricular septal defect (VSD), valve diseases, tuberous sclerosis, scleroderma, obesity, transplantation, aneurysm, hypertension, fibromuscular dysplasia, stroke, adrenoleukodystrophy , congenital adrenal hyperplasia, Von Hippel-Lindau (VHL) syndrome , pancreatitis, hyperthyroidism
  • NOV14 is homologous to the GPCR (Alpha lA/lC Adrenergic Receptor Subfamily)- like family of proteins.
  • GPCR Alpha lA/lC Adrenergic Receptor Subfamily
  • NOV14 nucleic acids and polypeptides, antibodies and related compounds according to the invention will be useful in therapeutic and diagnostic applications implicated in, for example; developmental diseases, MHCII and III diseases (immune diseases), taste and scent detectability disorders, Burkitt's lymphoma, corticoneurogenic disease, signal transduction pathway disorders, retinal diseases including those involving photoreception, cell growth rate disorders, cell shape disorders, feeding disorders, potential obesity due to over-eating, potential disorders due to starvation (lack of appetite), noninsulin- dependent diabetes mellitus (NIDDM1), bacterial, fungal, protozoal and viral infections (particularly infections caused by HIV-1 or HIV-2), pain, cancer (including but not limited to neoplasm; adenocarcinoma; lymphoma;
  • NOV15 is homologous to the GJA3/Connexin 46-like family of proteins.
  • nucleic acids and polypeptides, antibodies and related compounds according to the invention will be useful in therapeutic and diagnostic applications implicated in, for example; deafness, keratinization disorders, gap-junction-related neuropathies and other pathological conditions ofthe nervous system, where dysfunctions of junctional communication are considered to play a casual role, demyelinating neuropathies (including Charcot-Marie-Tooth disease), Erythrokeratodermia variabilis (EKV), atrioventricular (AV) conduction defects such as arrhythmia, and lens cataracts.
  • demyelinating neuropathies including Charcot-Marie-Tooth disease), Erythrokeratodermia variabilis (EKV), atrioventricular (AV) conduction defects such as arrhythmia, and lens cataracts.
  • EKV Erythrokeratodermia variabilis
  • AV atrioventricular
  • nucleic acids and proteins ofthe invention are potentially useful in cancer diagnosis and treatment. Since connexins are also known to participate in oocyte maturation, the nucleic acids and proteins ofthe invention could potentially be used for correcting oocyte maturation defects, and/or other pathologies/disorders.
  • the NOVX nucleic acids and polypeptides can also be used to screen for molecules, which inhibit or enhance NOVX activity or function.
  • the nucleic acids and polypeptides according to the invention may be used as targets for the identification of small molecules that modulate or inhibit, e.g. , neurogenesis, cell differentiation, cell proliferation, hematopoiesis, wound healing and angiogenesis.
  • NOVX nucleic acids and polypeptides according to the invention are disclosed herein.
  • NOV1 includes three novel Calgizzarin-like proteins disclosed below. The disclosed sequences have been named NOVla, NOVlb, and NOVlc.
  • NOVla A disclosed NOVla nucleic acid of 393 nucleotides (also referred to as
  • SC126422078_A encoding a Calgizzarin-like protein is shown in Table 1 A.
  • An open reading frame was identified beginning with an ATG initiation codon at nucleotides 49-51 and ending with a TGA codon at nucleotides 367-369.
  • a putative untranslated region upstream from the initiation codon and downstream from the termination codon is underlined in Table 1 A. The start and stop codons are in bold letters.
  • Table 1A NOVla nucleotide sequence (SEQ ID NO:l).
  • NOVla nucleic acid sequence located on chromsome 11 has 298 of 383 bases (77%) identical to a calgizzarin mRNA from Homo sapiens, (GENBANK-ID: D38583).
  • Public nucleotide databases include all GenBank databases and the GeneSeq patent database.
  • the "E-value” or “Expect” value is a numeric indication ofthe probability that the aligned sequences could have achieved their similarity to the BLAST query sequence by chance alone, within the database that was searched.
  • the probability that the subject (“Sbjct”) retrieved from the NO VI BLAST analysis, e.g., calgizzarin mRNA from Homo sapiens, matched the Query NOV1 sequence purely by chance is 2.2e "41 .
  • the Expect value (E) is a parameter that describes the number of hits one can "expect" to see just by chance when searching a database of a particular size. It decreases exponentially with the Score (S) that is assigned to a match between two sequences. Essentially, the E value describes the random background noise that exists for matches between sequences.
  • the Expect value is used as a convenient way to create a significance threshold for reporting results.
  • the default value used for blasting is typically set to 0.0001.
  • the Expect value is also used instead ofthe P value (probability) to report the significance of matches.
  • an E value of one assigned to a hit can be interpreted as meaning that in a database ofthe current size one might expect to see one match with a similar score simply by chance.
  • An E value of zero means that one would not expect to see any matches with a similar score simply by chance. See, e.g., http://www.ncbi.nlm.nih.gov Education/BLASTinfo/. Occasionally, a string of X's or N's will result from a BLAST search.
  • NOVla polypeptide (SEQ ID NO:2) encoded by SEQ ID NO:l has 106 amino acid residues and is presented in Table IB using the one-letter amino acid code.
  • Signal P, Psort and/or Hydropathy results predict that NOVla has a signal peptide and is likely to be localized in the endoplasmic reticulum (membrane) with a certainty of 0.5500.
  • NOVla may also be localized to the microbody (peroxisome) with acertainty of 0.2066, the lysosome (lumen) with a certainty of 0.1900 or in the endoplasmic reticulum (lumen) with a certainty of 0.1000.
  • the most likely cleavage site for a NOVla peptide is between amino acids 26 and 27, at: RYA-GR.
  • Table IB Encoded NOVla protein sequence (SEQ ID NO:2). AKISGCTEIA CITT CCFPERYAGRDHNSCKLSQRGFLNFMNTV VAFTKNQKGSGALDCMMKK DFNC DGQLDFQDFLSLTDGVAVACPDSFIPAGHAHERI
  • Public amino acid databases include the GenBank databases, SwissProt, PDB and PIR.
  • NOVla is expressed in at least the following tissues: Brain Tissue.
  • sequence is predicted to be expressed in Colorectal Tissue because ofthe expression pattern of (GENBANK-ID: D38583) a closely related Calgizzarin homolog in species Homo sapiens.
  • NOVlb A disclosed NOVlb nucleic acid of 390 nucleotides (also referred to as CG56170-01) encoding a novel Calgizzarin-like protein is shown in Table IC.
  • An open reading frame was identified beginning with an ATG initiation codon at nucleotides 31-33 and ending with a TGA codon at nucleotides 364-366.
  • a putative untranslated regions upstream from the initiation codon and downstream ofthe termination codon are underlined in Table IC. The start and stop codons are in bold letters.
  • Table IC NOVlb nucleotide sequence (SEQ ID NO:3).
  • the NOVlb nucleic acid sequence, located on chromsome 11 has 296 of 380 bases (77%) identical to a gb:GENBANK-
  • NOVlb polypeptide encoded by SEQ ID NO:3 has 105 amino acid residues and is presented in Table ID using the one-letter amino acid code.
  • Signal P, Psort and/or Hydropathy results predict that NOVlb has no signal peptide and is likely to be localized in the endoplasmic reticulum (membrane) with a certainty of 0.5500.
  • NOVlb may also be localized to the lysosome (lumen) with a certainty of 0.1900, the endoplasmic reticulum (lumen) with a certainty of 0.1000 or extracellularly with a certainty of 0.1000.
  • Public amino acid databases include the GenBank databases, SwissProt, PDB and PIR. NOVlb is expressed in at least Brain Tissue. This information was derived by determining the tissue sources ofthe sequences that were included in the invention including but not limited to SeqCalling sources, Public EST sources, Literature sources, and/or RACE sources. NOVlc
  • a disclosed NOVlc nucleic acid of 394 nucleotides (also referred to as CG56170-02) encoding a novel Calgizzarin-like protein is shown in Table IE.
  • An open reading frame was identified beginning with an ATG initiation codon at nucleotides 49-51 and ending with a TGA codon at nucleotides 304-306.
  • a putative untranslated regions upstream from the initiation codon and downstream ofthe termination codon are underlined in Table IE. The start and stop codons are in bold letters.
  • the NOVlc nucleic acid sequence, located on chromsome 11 has 298 of 384 bases (77%) identical to a gb:GENBANK-
  • NOVlc polypeptide (SEQ ID NO:6) encoded by SEQ ID NO:5 has 85 amino acid residues and is presented in Table IF using the one-letter amino acid code.
  • Signal P, Psort and or Hydropathy results predict that NOVlc has a signal peptide and is likely to be localized in the endoplasmic reticulum (membrane) with a certainty of 0.5500.
  • NOVlc may also be localized to the lysosome (lumen) with a certainty of 0.1900, the microbody (peroxisome) with a certainty of 0.1803 or the endoplasmic reticulum (lumen) with a certainty of 0.1000.
  • the most likely cleavage site for NOVlc is between positions 26 and 27, RYA-GR.
  • Public amino acid databases include the GenBank databases, SwissProt, PDB and PIR.
  • NOVlc is expressed in at least in Brain. Expression information was derived from the tissue sources ofthe sequences that were included in the derivation ofthe sequence of CuraGen Ace. No. CG56170-02. The sequence is predicted to be expressed in colorectal tissue because ofthe expression pattern of (GENBANK-ID: gb:GENBANK- ID:HUMCOLO
  • NOVl Homologies to either ofthe above NOVl proteins will be shared by the other NOVl protein insofar as they are homologous to each other as shown below. Any reference to NOVl is assumed to refer to all three ofthe NOVl proteins in general, unless otherwise noted.
  • the disclosed NOVla polypeptide has homology to the amino acid sequences shown in the BLASTP data listed in Table 1G.
  • Novel NOVlc (SEQ ID NO: 6) 4) gi I 1710819 I sp I P50543 I Slll_MOUSE CALGIZZARIN (ENDOTHELIAL MONOCYTE-ACTIVATING POLYPEPTIDE) (EMAP) (SEQ ID N ⁇ :49)
  • NOVl The presence of identifiable domains in NOVl, as well as all other NOVX proteins, was determined by searches using software algorithms such as PROSITE, DOMAIN, Blocks, Pfam, ProDomain, and Prints, and then determining the Interpro number by crossing the domain match (or numbers) using the Interpro website (http:www.ebi.ac.uk/ interpro).
  • the "strong” group of conserved amino acid residues may be any one ofthe following groups of amino acids: STA, NEQK, NHQK, NDEQ, QHRK, MILV, MILF, HY, FYW.
  • Table 1G lists the domain description from DOMAIN analysis results against NOVla. This indicates that the NOVla sequence has properties similar to those of other proteins known to contain this domain.
  • the S-100 domain is a subfamily of the EF-hand calcium binding proteins (SEQ ID NO: 76)
  • CD-Length 44 residues, 93.2% aligned
  • calcium-binding proteins belong to the same evolutionary family and share a type of calcium-binding domain known as the EF-hand.
  • This type of domain consists of a twelve residue loop flanked on both side by a twelve residue alpha-helical domain.
  • the calcium ion is coordinated in a pentagonal bipyramidal configuration.
  • the six residues involved in the binding are in positions 1, 3, 5, 7, 9 and 12; these residues are denoted by X, Y, Z, -Y, -X and -Z.
  • the invariant Glu or Asp at position 12 provides two oxygens for liganding Ca (bidentate ligand).
  • Fibronectin is a multi-domain glycoprotein, found in a soluble form in plasma, and in an insoluble form in loose connective tissue and basement membranes, that binds cell surfaces and various compounds including collagen, fibrin, heparin, DNA, and actin. Fibronectins are involved in a number of important functions e.g., wound healing; cell adhesion; blood coagulation; cell differentiation and migration; maintenance ofthe cellular cytoskeleton; and tumour metastasis . The major part ofthe sequence of fibronectin consists ofthe repetition of three types of domains, which are called type I, II, and III .
  • Type II domain is approximately forty residues long, contains four conserved cysteines involved in disulfide bonds and is part ofthe collagen-binding region of fibronectin. In fibronectin the type II domain is duplicated. Type II domains have also been found in a range of proteins including blood coagulation factor XII; bovine seminal plasma proteins PDC-109 (BSP-A1/A2) and BSP-A3 ; cation- independent mannose-6-phosphate receptor ; mannose receptor of macrophages ; 180 Kd secretory phospholipase A2 receptor . DEC-205 receptor ; 72 Kd and 92 Kd type IV collagenase ( 3.4.24.24 ) ; and hepatocyte growth factor activator .
  • blood coagulation factor XII bovine seminal plasma proteins
  • PDC-109 BSP-A1/A2
  • BSP-A3 bovine seminal plasma proteins
  • cation- independent mannose-6-phosphate receptor mannose receptor of macrophag
  • the S-1U0 domain is a subfamily ofthe EF-hand calcium binding proteins.
  • S-100 are small dimeric acidic calcium and zinc-binding proteins [(Baudier J., (In) Calcium and Calcium Binding proteins, Gerday C, Bollis L., Giller R., Eds., ppl02-l 13, Springer Verlag, Berlin, 1988)] abundant in the brain. They have two different types of calcium-binding sites: a low affinity one with a special structure and a 'normal' EF-hand type high affinity site (see IPR002048 ).
  • the vitamin-D dependent intestinal calcium-binding proteins (ICaBP or calbindin 9 Kd) also belong to this family of proteins, but it does not form dimers.
  • Proteins ofthe SI 00 protein family belong to the large group of EF-hand calcium- binding proteins.
  • Todoroki et al. (1991) purified an SI 00 protein from chicken gizzard that they called calgizzarin.
  • Watanabe et al. (1991) isolated a cDNA encoding rabbit calgizzarin.
  • Tanaka et al. (1995) identified and sequenced a cDNA encoding a human calgizzarin homolog. They found that the expression of human calgizzarin was remarkably elevated in colorectal cancers compared with that in normal colorectal mucosa.
  • neoplastic transformation of cells occurs by a multistep process. For neoplastic transformation of normal human cells, they must be first immortalized and then be converted into neoplastic cells. It is well known that the immortalization is a critical step for the neoplastic transformation of cells and that the immortal phenotype is recessive. Thus, Sakaguchi M et al. investigated proteins downregulated in immortalized cells by two-dimensional gel electrophoresis. As a result, SI OOC, a Ca(2+)-binding protein, was dramatically downregulated in immortalized human fibroblasts compared with their normal counterparts. When the cells reached confluence, SI OOC was phosphorylated on threonine 10.
  • SI OOC (S 100A11 , calgizzarin) inhibits the actin-activated myosin Mg(2+)- ATPase activity of smooth muscle in a dose-dependent manner: its half-maximal effect occurs at a SlOOC/actin molar ratio of 0.05 and its maximal effect occurs at a ratio of 0.20. Furthermore, SI OOC was found to bind to actin with a stoichiometry of 1:6-7 in the presence of Ca(2+), with an affinity of 1 x 10(-6) M determined by cosedimentation assays.
  • Ca(2+)-binding proteins such as SlOOAl, S100A2, S100B, and calmodulin did not inhibit actin-activated myosin Mg(2+)-ATPase activity.
  • Calmodulin, SlOOAl, and S100B reversed the inhibitory effect of calponin in a Ca(2+)-dependent manner, S100A2 had no effect, and SI OOC had additional inhibitory effects.
  • SI OOC might be involved in the regulation of actin-activated myosin Mg(2+)- ATPase activity through its Ca(2+)-dependent interaction with actin filaments. Copyright 2000 Academic Press.
  • a cDNA library (PMID: 7889529, UI: 95196222 ) was constructed from COLO 205 and 1056 clones randomly selected from this library were partially sequenced. Two hundred and two (38.4%) out of 526 independent genes had more than 80% similarity to the genes reported in GenBank. In Northern blot analysis, 96 out of 98 genes were shown to be expressed at the same level in colon and lung carcinoma cell lines and control fibroblasts. Only two clones, including human synovial phospholipase A-2 and a homologue to rabbit calgizzarin, were expressed at different levels among these cell lines. The full sequence of human calgizzarin was determined and its expression was remarkably elevated in colorectal cancers compared with that in normal colorectal mucosa.
  • the disclosed NOVl nucleic acid ofthe invention encoding a Calgizzarin -like protein includes the nucleic acid whose sequence is provided in Table 1A ,1C, or IE or a fragment thereof.
  • the invention also includes a mutant or variant nucleic acid any of whose bases may be changed from the corresponding base shown in Table 1 A, IC, or IE while still encoding a protein that maintains its Calgizzarin-like activities and physiological functions, or a fragment of such a nucleic acid.
  • the invention further includes nucleic acids whose sequences are complementary to those just described, including nucleic acid fragments that are complementary to any ofthe nucleic acids just described.
  • the invention additionally includes nucleic acids or nucleic acid fragments, or complements thereto, whose structures include chemical modifications.
  • modifications include, by way of nonlimiting example, modified bases, and nucleic acids whose sugar phosphate backbones are modified or derivatized. These modifications are carried out at least in part to enhance the chemical stability ofthe modified nucleic acid, such that they may be used, for example, as antisense binding nucleic acids in therapeutic applications in a subject.
  • up to about 23% percent ofthe bases may be so changed.
  • the disclosed NOVl protein ofthe invention includes the Calgizzarin-like protein whose sequence is provided in Table IB, ID, or IF.
  • the invention also includes a mutant or variant protein any of whose residues may be changed from the corresponding residue shown in Table IB, ID, or IF while still encoding a protein that maintains its Calgizzarin-like activities and physiological functions, or a functional fragment thereof. In the mutant or variant protein, up to about 45 % percent ofthe residues may be so changed.
  • the invention further encompasses antibodies and antibody fragments, such as F a or (F ab ) 2 ,that bind immunospecifically to any ofthe proteins ofthe invention.
  • This Calgizzarin-like protein (NOVl) may function as a member of a "Calgizzarin family". Therefore, the NOVl nucleic acids and proteins identified here may be useful in potential therapeutic applications implicated in (but not limited to) various pathologies and disorders as indicated below.
  • the potential therapeutic applications for this invention include, but are not limited to: protein therapeutic, small molecule drug target, antibody target (therapeutic, diagnostic, drug targeting/cytotoxic antibody), diagnostic and/or prognostic marker, gene therapy (gene delivery/gene ablation), research tools, tissue regeneration in vivo and in vitro of all tissues and cell types composing (but not limited to) those defined here.
  • the NOVl nucleic acids and proteins ofthe invention are useful in potential therapeutic applications implicated in cancer including but not limited to various pathologies and disorders as indicated below.
  • a cDNA encoding the Calgizzarin-like protein (NOVl) may be useful in gene therapy, and the Calgizzarin -like protein (NOVl) may be useful when administered to a subject in need thereof.
  • the compositions ofthe present invention will have efficacy for treatment of patients suffering from Alzheimer's disease, Cardiovascular disease, Neurodegenerative disease, bone disorders, Hemic and Lymphatic Diseases, Muscle Disorders, Myotonia and Cancers including , colon and lung and breast cancer, or other pathologies or conditions.
  • the NOVl nucleic acid encoding the Calgizzarin-like protein ofthe invention, or fragments thereof, may further be useful in diagnostic applications, wherein the presence or amount ofthe nucleic acid or the protein are to be assessed.
  • NOVl nucleic acids and polypeptides are further useful in the generation of antibodies that bind immuno-specifically to the novel NOVl substances for use in therapeutic or diagnostic methods. These antibodies may be generated according to methods known in the art, using prediction from hydrophobicity charts, as described in the "Anti-NOVX Antibodies" section below.
  • the disclosed NOVl proteins have multiple hydrophilic regions, each of which can be used as an immunogen.
  • a contemplated NOVl epitope is from about amino acids 20 to 45.
  • a NOVl epitope is from about amino acids 55 to 80.
  • a disclosed NOV2 nucleic acid of 3801 nucleotides (also referred to as sggc_draft_dj534b8_20000725_dal) encoding a novel Dynactin 1 P150-like protein is shown in Table 2A.
  • An open reading frame was identified beginning with an ATG initiation codon at nucleotides 1-3 and ending with a TAA codon at nucleotides 3799-3801.
  • a putative untranslated region upstream from the initiation codon and downstream from the termination codon is underlined in Table 2A, and the start and stop codons are in bold letters.
  • Table 2A NOV2 nucleotide sequence (SEQ ID NO:7).
  • the disclosed NOV2 nucleic acid sequence localized to the pi 3 region of chromsome 2, has 2815 of 3009 bases (93%) identical to a gb:GENBANK-ID:HSDYNACTN
  • acc:X98801 mRNA from Homo sapiens mRNA for dynactin (E 0.0).
  • a NOV2 polypeptide (SEQ ID NO:8) encoded by SEQ ID NO:7 has 1266 amino acid residues and is presented using the one-letter code in Table 2B.
  • Signal P, Psort and/or Hydropathy results predict that NOV2 does not contain a signal peptide and is likely to be localized to the plasma membrane with a certainty of 0.6000.
  • NOV2 may also be localized to the mitochondrial inner membrane with a certainty of 0.4452, the Golgi body with a certainty of 0.4000, or the endoplasmic reticulum (membrane) with a certainty of 0.3000.
  • Table 2B Encoded NOV2 protein sequence (SEQ ID NO:8).
  • NOV2 is expressed in at least Fetal Brain. This information was derived by determining the tissue sources ofthe sequences that were included in the invention. SeqCalling sources: Adrenal Gland/Suprarenal gland, Amygdala, Bone, Bone Marrow, Brain, Colon, Coronary Artery, Dennis, Epidermis, Foreskin,Hair Follicles, Heart, Hippocampus, Hypothalamus, Kidney, Liver, Lung, Lymph node, Lymphoid tissue, Mammarygland/Breast, Oesophagus, Ovary, Pancreas, Parathyroid Gland, Peripheral Blood, Pineal Gland, Pituitary Gland, Placenta,Prostate, Retina, Salivary Glands, Small Intestine, Spleen, Stomach, Testis, Thalamus, Thymus, Tonsils, Trachea, UmbilicalVein, Uterus, Whole Organism.
  • SeqCalling sources Adrenal Gland/
  • sequence is predicted to be expressed in fetal brain because ofthe expression pattern of (GENBANK-ID: gb:GENBANK-ID:HSDYNACTN
  • NOV2 also has homology to the amino acid sequences shown in the BLASTP data listed in Table 2C.
  • Tables 2E-F list the domain description from DOMAIN analysis results against NOV2. This indicates that the NOV2 sequence has properties similar to those of other proteins known to contain this domain.
  • NOV2 also has homology to sequences found in the patp patent database. Results for BLASTX searches in this database are shown below in Table 2G.
  • the human dynactin 1 gene (DCTNl) is positioned on chromosome 2pl3, the candidate region for various diseases including Alstrom syndrome, limb-girdle muscle dystrophy, and Miyoshi myopathy (Collin GB, et.al.; Genomics 1998 Nov l;53(3):359-64).
  • DCTNl human dynactin 1 gene
  • Dynactin is a required activator for the molecular motor cytoplasmic dynein, and is likely to be essential for normal neuronal development (Tokito MK, et.al.; Biochim Biophys Acta 1998 Nov 8;1442(2-3):432-6).
  • LGMB2B limb-girdle muscular dystrophy
  • LGMD2B limb-girdle muscular dystrophy type 2B
  • Miyoshi myopathy The genes for the human neuromuscular diseases limb-girdle muscular dystrophy type 2B (LGMD2B) and Miyoshi myopathy are located on chromosome 2pl3-pl4, and two neuromuscular mutations ofthe mouse have been mapped to regions homologous to human chromosome 2pl3 by conserved synteny, wobbler (wr) on proximal Chr 11 and motor neuron degeneration 2 (mnd2) on Chr 6 (Korthaus D, et.al.; Genomics 1997 Jul 15;43(2):242-4). Neither one is a mouse homologue of LGMD2B.
  • DCTNl coding for the large subunit ofthe cytoskeletal protein dynactin
  • FISH fluorescent in situ hybridization
  • mapping data based on radiation hybrid and physical mapping that more precisely define the location of nine genetic markers in the critical region and the homology relationship of human chromosome 2p with mouse proximal Chr 11 and Chr 6.
  • the human dynactin gene was mapped between markers TGFA and D2S1394, implying that the mouse dynactin gene Dctnl is located on Chr 6, distal to mnd2.
  • DCTNl/Dctnl is a candidate for LGMD2B but not for mnd2 or wr.
  • Alstrom syndrome is a rare autosomal recessive disorder characterized by retinal degeneration, sensorineural hearing loss, early-onset obesity, and non-insulin-dependent diabetes mellitus (Collin GB, et.al. Hum Genet 1999 Nov;105(5):474-9). Cytoplasmic dynein is a microtubule-based biologic motor proteins. Holzbaur and
  • dyneins were initially discovered as enzymes in eukaryotic cilia and flagella that couple ATP hydrolysis to provide a force for cellular motility.
  • a distinct cytoplasmic form of dynein (600112) was subsequently characterized and thought to be responsible for the intracellular retrograde motility of vesicles and rganelles along microtubules (Holzbaur and Vallee, Ann. Rev. Cell Biol. 10: 339-372, 1994).
  • a second large macromolecular complex, dynactin is also required for the cytoplasmic dynein-driven movement of organelles along microtubules.
  • Dynactin is composed of 10 distinct polypeptides of 150, 135, 62, 50, 45, 42, 37, 32, 27, and 24 kD, with a combined mass of 10 million daltons.
  • the largest polypeptide ofthe dynactin complex, pl50(Glued) binds directly to microtubules and to cytoplasmic dynein.
  • a binding of dynactin to dynein is critical for neuronal function, as antibodies that specifically disrupt this binding block vesicle motility along microtubules in extruded squid axoplasm.
  • the disclosed NOV2 nucleic acid ofthe invention encoding a Dynactin 1 P150-like protein includes the nucleic acid whose sequence is provided in Table 2A or a fragment thereof.
  • the invention also includes a mutant or variant nucleic acid any of whose bases may be changed from the corresponding base shown in Table 2A while still encoding a protein that maintains its Dynactin 1 PI 50 -like activities and physiological functions, or a fragment of such a nucleic acid.
  • the invention further includes nucleic acids whose sequences are complementary to those just described, including nucleic acid fragments that are complementary to any ofthe nucleic acids just described.
  • the invention additionally includes nucleic acids or nucleic acid fragments, or complements thereto, whose structures include chemical modifications.
  • modifications include, by way of nonlimiting example, modified bases, and nucleic acids whose sugar phosphate backbones are modified or derivatized. These modifications are carried out at least in part to enhance the chemical stability ofthe modified nucleic acid, such that they may uc uscu, lur example, as aimscuoc binding nucleic acids in therapeutic applications in a subject. In the mutant or variant nucleic acids, and their complements, up to about 10% percent ofthe bases may be so changed.
  • the disclosed NOV2 protein ofthe invention includes the Dynactin 1 PI 50 -like protein whose sequence is provided in Table 2B.
  • the invention also includes a mutant or variant protein any of whose residues may be changed from the corresponding residue shown in Table 2B while still encoding a protein that maintains its Dynactin 1 PI 50 -like activities and physiological functions, or a functional fragment thereof.
  • a mutant or variant protein any of whose residues may be changed from the corresponding residue shown in Table 2B while still encoding a protein that maintains its Dynactin 1 PI 50 -like activities and physiological functions, or a functional fragment thereof.
  • up to about 30% percent ofthe residues may be so changed.
  • the NOV2 nucleic acids and proteins ofthe invention are useful in potential therapeutic applications implicated in Alstrom syndrome; Glucosidase I deficiency; Orofacial cleft-2; Parkinson disease, type 3; Preeclampsia; Welander distal myopathy; Von Hippel- Lindau (VHL) syndrome, Alzheimer's disease, Stroke, Tuberous sclerosis, hypercalceimia, Parkinson's disease, Huntington's disease, Cerebral palsy, Epilepsy,Lesch-Nyhan syndrome, Multiple sclerosis, Ataxia-telangiectasia,Leukodystrophies,Behavioral disorders, Addiction, Anxiety, Pain, Neuroprotection and/or other pathologies and disorders.
  • VHL Von Hippel- Lindau
  • the NOV2 nucleic acid encoding Dynactin 1 P150-like protein, and the Dynactin 1 P150-like protein ofthe invention, or fragments thereof, may further be useful in diagnostic applications, wherein the presence or amount ofthe nucleic acid or the protein are to be assessed.
  • NOV2 nucleic acids and polypeptides are further useful in the generation of antibodies that bind immunospecifically to the novel substances ofthe invention for use in therapeutic or diagnostic methods. These antibodies may be generated according to methods known in the art, using prediction from hydrophobicity charts, as described in the "Anti-NOVX Antibodies" section below.
  • the disclosed NOV2 protein has multiple hydrophilic regions, each of which can be used as an immunogen.
  • a contemplated NOV2 epitope is from about amino acids 50 to 190. In another embodiment, a NOV2 epitope is from about amino acids 200 to 580. In additional embodiments, NOV2 epitopes are from about amino acids 620 to 640, from about 660 to 740, from about amino acids 850 to 1050, and from about amino acids 1100 to 1200. These novel proteins can be used in assay systems for functional analysis of various human disorders, which are useful in understanding of pathology ofthe disease and development of new drug targets for various disorders. NOV3
  • NOV3 includes three novel Lysosomal acid lipase/gastric lipase -like proteins disclosed below. The disclosed sequences have been named NOV3a, NOV3b, and NOV3c.
  • a disclosed NOV3a nucleic acid of 1343 nucleotides (also referred to as 135148488- EXT) encoding a novel Lysosomal acid lipase/gastric lipase-like protein is shown in Table 3a.
  • An open reading frame was identified beginning with a ATG initiation codon at nucleotides 9- 11 and ending with a TAA codon at nucleotides 1203-1205.
  • the start and stop codons are in bold letters, and the 5' and 3' untranslated regions are underlined.
  • a disclosed NOV3a protein (SEQ ED NO: 10) encoded by SEQ ID NO:9 has 398 amino acid residues, and is presented using the one-letter code in Table 3B. Signal P, Psort and/or Hydropathy results predict that NOV3a does have a signal peptide, and is likely to be localized to the lysosome (lumen) with a certainty of 0.5500.
  • NOV3a is also likely to be localized extracellularly with a certainty of 0.3700, to the microbody (peroxiasome) with a certainty of 0.2746, or to the endoplasmic reticulum (membrane) with a certainty of 0.1000.
  • the most likely cleavage site for NOV3a is between positions 17 and 18, (LNA-GG).
  • Table 3B Encoded NOV3a protein sequence (SEQ ID NO:12).
  • the NOV3a sequence is predicted to be expressed in the placenta, uterus, pancreas, and fetal lung.
  • a disclosed NOV3b nucleic acid of 820 nucleotides (also referred to as Curagen Accession No. 135148485_EXT1) encoding a novel Lysosomal acid lipase-/Gastric lipase-like protein is shown in Table 3C.
  • An open reading frame was identified beginning with an ATG initiation codon at nucleotides 1-3 and ending with a TAA codon at nucleotides 809-811.
  • a putative untranslated regions upstream from the initiation codon and downstream from thr termination codon are underlined in Table 3C. The start and stop codons are in bold letters.
  • NOV3b nucleic acid sequence located on chromosome 10
  • acc:A01046.1 mRNA from Homo sapiens (H.sapiens mRNA for human gastric lipase (E 1.Se "46 ).
  • Public nucleotide databases include all GenBank databases and the GeneSeq patent database.
  • NOV3b polypeptide (SEQ ID NO: 12) encoded by SEQ ID NO: 11 has 267 amino acid residues and is presented in Table 3B using the one-letter amino acid code.
  • Signal P, Psort and or Hydropathy results predict that NOV3b has a signal peptide and is likely to be localized in the lysosome (lumen) with a certainty of 0.5500.
  • NOV3b may also be localized extracellularly with acertainty of 0.3700, in the microbody (peroxisome) with a certainty of 0.2530, or in the endoplasmic reticulum (membrane) with a certainty of 0.1000.
  • the most likely cleavage site for NOV3b is between positions 17 and 18, LNA-GG.
  • Table 3D Encoded NOV3b protein sequence (SEQ ID NO: 12).
  • Public amino acid databases include the GenBank databases, SwissProt, PDB and PIR.
  • NOV3b is predicted to be expressed in the following tissues and cell lines because of the expression pattern of the closely related human gastric and lysosomal acid lipases: Esophagus, Stomach, lung, testis, NbHL19W, testis NHT, and B-cell NCI CGAP GCB1.
  • a disclosed NOV3c nucleic acid of 1316 nucleotides (also referred to as Curagen Accession No. 135148485_EXT2) encoding a novel Gastric and Lysosomal acid lipase-like protein is shown in Table 3E.
  • An open reading frame was identified beginning with an ATG initiation codon at nucleotides 48-50 and ending with a TAA codon at nucleotides 1242-1244.
  • the start and stop codons are in bold letters.
  • the NOV3c nucleic acid sequence located on chromosome 10
  • acc:A01046 mRNA from Homo sapiens (H. sapiens mRNA for human gastric lipase (E 5.9e "84 ).
  • Public nucleotide databases include all GenBank databases and the GeneSeq patent database.
  • NOV3c polypeptide (SEQ ID NO:14) encoded by SEQ ID NO:13 has 397 amino acid residues and is presented in Table 3F using the one-letter amino acid code.
  • Signal P, Psort and/or Hydropathy results predict that NOV3c has a signal peptide and is likely to be localized in the lysosome (lumen) with a certainty of 0.5500.
  • NOV3c may also be localized extracellularly with acertainty of 0.4419, in the microbody (peroxisome) with a certainty of 0.2757, or in the endoplasmic reticulum (membrane) with a certainty of 0.1000.
  • the most likely cleavage site for NOV3c is between positions 23 and 24, LNA-GG.
  • Table 3F Encoded NOV3c protein sequence (SEQ ID NO:14).
  • Public amino acid databases include the GenBank databases, SwissProt, PDB and PIR.
  • NOV3c is predicted to be expressed in the following tissues and cell lines because of the expression pattern ofthe closely related human gastric and lysosomal acid lipases: Esophagus, Stomach, lung, testis, NbHL19W, testis NHT, and B-cell NCI CGAP GCB1. NOV3a also has homology to the amino acid sequences shown in the BLASTP data listed in Table 3G.
  • N0V3a SEQ ID NO: 10
  • Table 31 lists the domain description from DOMAIN analysis results against NOV3a. This indicates that the NOV3a sequence has properties similar to those of other proteins known to contain this domain.
  • CD-Length 226 residues, 96.0% aligned
  • Lysosomal acid lipase (LEPA, or LAL), otherwise known as acid cholesteryl ester hydrolase, is coded for by a gene (LIPA) on chromosome 10.
  • LIPA Lysosomal acid lipase
  • Gastric lipase (EC 3.1.1.3) plays an important role in the digestion of dietary triglycerides in the gastrointestinal tract, especially in patients suffering from pancreatic lipase deficiencies (see 246600).
  • the enzyme is secreted by the fundic mucosa ofthe stomach and hydrolyzes the ester bonds of triglycerides under acidic pH conditions, while cholesteryl esters are not attacked.
  • REFERENCES 1. Anderson, R. A.; Byrum, R. S.; Coates, P. M.; Sando, G. N. : Mutations at the lysosomal acid cholesteryl ester hydrolase gene locus in Wolman disease. Proc. Nat. Acad. Sci. 91: 2718-2722, 1994. PubMed ID : 8146180 2. Anderson, R. A.; Rao, N.; Byrum, R. S.; Rothschild, C. B.; Bowden, D.
  • the disclosed NOV3 nucleic acid ofthe invention encoding a Lysosomal acid lipase/gastric lipase-like protein includes the nucleic acid whose sequence is provided in Table 3 A, 3C, or 3E or a fragment thereof.
  • the invention also includes a mutant or variant nucleic acid any of whose bases may be changed from the corresponding base shown in Table 3A, 3C, or 3E while still encoding a protein that maintains its Lysosomal acid lipase/gastric lipase-like activities and physiological functions, or a fragment of such a nucleic acid.
  • the invention further includes nucleic acids whose sequences are complementary to those just described, including nucleic acid fragments that are complementary to any ofthe nucleic acids just described.
  • the invention additionally includes nucleic acids or nucleic acid fragments, or complements thereto, whose structures include chemical modifications.
  • modifications include, by way of nonlimiting example, modified bases, and nucleic acids whose sugar phosphate backbones are modified or derivatized. These modifications are carried out at least in part to enhance the chemical stability ofthe modified nucleic acid, such that they may be used, for example, as antisense binding nucleic acids in therapeutic applications in a subject.
  • up to about 34% percent ofthe bases may be so changed.
  • the disclosed NOV3 protein ofthe invention includes the Lysosomal acid lipase/gastric lipase-like protein whose sequence is provided in Table 3B, 3D, or 3F.
  • the invention also includes a mutant or variant protein any of whose residues may be changed from the corresponding residue shown in Table 3B, 3D or 3F while still encoding a protein that maintains its Lysosomal acid lipase/gastric lipase-like activities and physiological functions, or a functional fragment thereof. In the mutant or variant protein, up to about 47 percent ofthe residues may be so changed.
  • NOV3 Lysosomal acid lipase/gastric lipase-like protein and nucleic acid
  • the NOV3 nucleic acids and proteins ofthe invention are useful in potential diagnostic and therapeutic i ⁇ ese mciu ⁇ e serving as a specific or selective nucleic acid or protein diagnostic and/or prognostic marker, wherein the presence or amount ofthe nucleic acid or the protein are to be assessed, as well as potential therapeutic applications such as the following: (i) a protein therapeutic, (ii) a small molecule drug target, (iii) an antibody target (therapeutic, diagnostic, drug targeting/cytotoxic antibody), (iv) a nucleic acid useful in gene therapy (gene delivery/gene ablation), and (v) a composition promoting tissue regeneration in vitro and in vivo.
  • the NOV3 nucleic acids and proteins ofthe invention are useful in potential diagnostic and therapeutic applications implicated in various diseases and disorders described below.
  • the compositions ofthe present invention will have efficacy for treatment of patients suffering from severe infantile-onset Wolman disease and milder late onset cholesteryl ester storage disease (CESD), Diabetes, Von Hippel-Landau (VHL) syndrome, Pancretaitis, Obesity and/or other pathologies.
  • the NOV3 nucleic acid, or fragments thereof may further be useful in diagnostic applications, wherein the presence or amount ofthe nucleic acid or the protein are to be assessed.
  • NOV3 nucleic acids and polypeptides are further useful in the generation of antibodies that bind immunospecifically to the novel substances ofthe invention for use in therapeutic or diagnostic methods. These antibodies may be generated according to methods known in the art, using prediction from hydrophobicity charts, as described in the "Anti-NOVX Antibodies" section below.
  • the disclosed NOV3 protein have multiple hydrophilic regions, each of which can be used as an immunogen.
  • contemplated NOV3 epitope is from about amino acids 20 to 100.
  • a NOV3 epitope is from about amino acids 120 to 160.
  • NOV3 epitopes are from about amino acids 220 to 240, from about amino acids 255 to 285, from about amino acids 290 to 325, and from about amino acids 370 to 385.
  • This novel protein also has value in development of powerful assay system for functional analysis of various human disorders, which will help in understanding of pathology ofthe disease and development of new drug targets for various disorders.
  • NOV4 includes three novel Rho Interacting Protein-like proteins disclosed below.
  • the disclosed sequences have been named NOV4a, and NOV4b.
  • NOV4a A disclosed NOV4a nucleic acid of 2152 nucleotides (designated CuraGen Ace. No. wugc_draft_h_nh0350nl5_20000809_dal) encoding a novel Rho Interacting Protein-like protein is shown in Table 4a.
  • An open reading frame was identified beginning with an ATG initiation codon at nucleotides 6-8 and ending with a TAG codon at nucleotides 1780-1782.
  • a putative untranslated region downstream from the termination codon is underlined in Table 4 A, and the start and stop codons are in bold letters.
  • a NOV4a polypeptide (SEQ ID NO: 16) encoded by SEQ ID NO: 15 is 593 amino acid residues and is presented using the one letter code in Table 4B. Signal P, Psort and/or Hydropathy results predict that NOV4a has no signal peptide and is likely to be localized at the nucleus with a certainty of 0.7600. In other embodiments, NOV4a may also be localized to the mitochondrial membrane space with a certainty of 0.1000, or the lysosome (lumen) with a certainty of 0.1000. Table 4B. NOV4a protein sequence (SEQ ID NO:16)
  • the target sequence NOV4a (also known as CG55863-01) was subjected to the exon linking process to confirm the sequence.
  • PCR primers were designed by starting at the most upstream sequence available, for the forward primer, and at the most downstream sequence available for the reverse primer. In each case, the sequence was examined, walking inward from the respective termini toward the coding sequence, until a suitable sequence that is either unique or highly selective was encountered, or, in the case of the reverse primer, until the stop codon was reached.
  • Such primers were designed based on in silico predictions for the full length cDNA, part (one or more exons) ofthe DNA or protein sequence ofthe target sequence, or by translated homology ofthe predicted exons to closely related human sequences sequences from other species.
  • primers were then employed in PCR amplification based on the following pool of human cDNAs: adrenal gland, bone marrow, brain - amygdala, brain - cerebellum, brain - hippocampus, brain - substantia nigra, brain - thalamus, brain -whole, fetal brain, fetal kidney, fetal liver, fetal lung, heart, kidney, lymphoma - Raji, mammary gland, pancreas, pituitary gland, placenta, prostate, salivary gland, skeletal muscle, small intestine, spinal cord, spleen, stomach, testis, thyroid, trachea, uterus.
  • sequence traces were evaluated manually and edited for corrections if appropriate. These procedures provide the sequence reported below, which is designated NOV4b (Accession Number CG55863-02). This differs from the previously identified sequence, NOV4a in missing 13 aminoacid from position 22, amino acid changes at positions 75 T->I, 179 H->R, 289 R->C.
  • a disclosed NOV4b nucleic acid of 1817 nucleotides (designated CuraGen Ace. No. CG55863-02) encoding a novel TARA-like protein is shown in Table 4C.
  • An open reading frame was identified beginning with an ATG initiation codon at nucleotides 1-3 and ending with a TAG codon at nucleotides 1741-1743.
  • a putative untranslated region downstream from the termination codon is underlined in Table 4C, and the start and stop codons are in bold letters.
  • nucleic acid sequence of NOV4b located on the pi 5.1 -pi 4 region of chromosome 5, had 804 of 829 bases (96%) identical to a gb:GENBANK-ID:AB015343
  • acc:AB015343.1 mRNA from Homo sapiens (Homo sapiens HRIHFB2122 mRNA, partial eds) (E 2.5e "169 ).
  • a NOV4b polypeptide (SEQ ID NO: 18) encoded by SEQ ID NO: 17 is 580 amino acid residues and is presented using the one letter code in Table 4D. Signal P, Psort and/or Hydropathy results predict that NOV4b has no signal peptide and is likely to be localized at the nucleus with a certainty of 0.7600. In other embodiments, NOV4b may also be localized to the mitochondrial membrane space with a certainty of 0.1000, or the lysosome (lumen) with a certainty of 0.1000. Table 4D. NOV4b protein sequence (SEQ ID NO:18)
  • NOV4b is expressed in at least the following tissues: Bone Marrow, Brain, Cervix, Epidermis, Foreskin, Hair Follicles, Kidney, Liver, Lung, Lymph node, Ovary, Pancreas, Placenta, Prostate, Retina, Small Intestine, Spinal Chord, Substantia Nigra, Synovium/Synovial membrane, Thyroid, Umbilical Vein, Urinary Bladder, Uterus, Adrenal Gland/Suprarenal gland, Amygdala, Brain, Cartilage, Epidermis, Heart, Kidney, Liver, Lung, Mammary gland/Breast, Spleen, Testis, Trachea. This information was derived by determining the tissue sources ofthe sequences that were included in the invention including but not limited to SeqCalling sources, Public EST sources, Literature sources, and/or RACE sources.
  • NOV4a also has homology to the amino acid sequences shown in the BLASTP data listed in Table 4E.
  • N0V4a SEQ ID NO: 16
  • Tables 4G-H list the domain description from DOMAIN analysis results against NOV4a. This indicates that the NOV4a sequence has properties similar to those of other proteins known to contain this domain.
  • Table 4H Domain Analysis of NOV4a gnl I Pfam
  • PH stands for pleckstrin homology (SEQ ID NO: 74 ⁇
  • NOV4a also has homology to sequence found in the patp patent database. Data from BLASTX alignments are found below in Table 41
  • Actin stress fibers are one ofthe major cytoskeletal structures in fibroblasts and are linked to the plasma membrane at focal adhesions (Ridley AJ, Hall A; Cell 1992 Aug 7;70(3):389-99).
  • rho a ras-related GTP-binding protein, rapidly stimulated stress fiber and focal adhesion formation when microinjected into serum-starved Swiss 3T3 cells. Readdition of serum produced a similar response, detectable within 2 min. This activity was due to a lysophospholipid, most likely lysophosphatidic acid, bound to serum albumin.
  • Other growth factors including PDGF induced actin reorganization initially to form membrane ruffles, and later, after 5 to 10 min, stress fibers.
  • Rho guanosine 5'-triphosphatase cycles between the active guanosine triphosphate (GTP)-bound form and the inactive guanosine diphosphate-bound form and regulates cell adhesion and cytokinesis, but how it exerts these actions is unknown(Watanabe G, etal.; Science 1996 Feb 2;271(5249):645-8).
  • Rho-binding domain of this protein has 40 percent identity with a putative regulatory domain of a protein kinase, PKN.
  • PKN itself bound to GTP-Rho and was activated by this binding both in vitro and in vivo.
  • This study indicates that a serine-threonine protein kinase is a Rho effector and presents an amino acid sequence motif for binding to GTP-Rho that may be shared by a family of Rho target proteins.
  • the rho GTPase (see Ridley and Hall, 1992) is involved in a signaling pathway that regulates cell adhesion and cytokinesis, among other activities. Watanabe et al.(1996).
  • the Dbl oncogene is a putative exchange factor for the small GTPases RhoA and Cdc42, which are involved in actin polymerization into stress fibers and filopodia, respectively(Olivo C, etal.; Oncogene 2000 Mar 9;19(11):1428-36).
  • RhoA and Cdc42 RhoA and Cdc42
  • untransformed NIH3T3 cells acquire the characteristic fibroblast morphology and organize a regular mesh of long stress fibers.
  • Dbl-transformed and in untransformed NIH3T3 cells the different shape and actin cytoskeleton organization observed in the early steps of adhesion involves activation of distinct GTPases.
  • cell morphology of Dbl-transformed NIH3T3 cells depends on activation of RhoA and not of Cdc42. In contrast Cdc42 activation is necessary to untransfected NIH3T3 cells to acquire their fibroblast shape.
  • RhoA activation In both Dbl- transformed and in untransformed NIH3T3 cells a basal Rac activation is necessary to support stress fiber organization, while constitutive Rac activation promotes ruffles and lamellipodia formation.
  • Dbl-transtormed cells show high activity of ROCK-alpha and CRIK kinases, two known RhoA effectors.
  • Dbl-transformed and NTH3T3 cells expressing the constitutive active form of RhoA are less motile on fibronectin than cells expressing constitutive active Cdc42.
  • Rho The small GTP binding protein Rho is implicated in cytoskeletal responses to extracellular signals such as lysophosphatidic acid to form stress fibers and focal contacts (Matsui T, et.al.; EMBO J 1996 May 1;15(9):2208-16).
  • Rho- interacting protein with a molecular mass of approximately 164 kDa (pi 64) from bovine brain.
  • Rho-kinase Rho-associated kinase
  • Rho-kinase is a putative target serine/threonine kinase for Rho and serves as a mediator ofthe Rho-dependent signaling pathway.
  • the disclosed NOV4 nucleic acid ofthe invention encoding a Rho-interacting Protein - like protein includes the nucleic acid whose sequence is provided in Table 4A, or 4C or a fragment thereof.
  • the invention also includes a mutant or variant nucleic acid any of whose bases may be changed from the corresponding base shown in Table 4A or 4C while still encoding a protein that maintains its Rho-interacting Protein -like activities and physiological functions, or a fragment of such a nucleic acid.
  • the invention further includes nucleic acids whose sequences are complementary to those just described, including nucleic acid fragments that are complementary to any ofthe nucleic acids just described.
  • the invention additionally includes nucleic acids or nucleic acid fragments, or complements thereto, whose structures include chemical modifications. Such modifications include, by way of nonlimiting example, modified bases, and nucleic acids whose sugar phosphate backbones are modified or derivatized. These modifications are carried out at least in part to enhance the chemical
  • the modified nucleic acid such that they may be used, for exam le, as antisense binding nucleic acids in therapeutic applications in a subject.
  • up to about 10% percent ofthe bases may be so changed.
  • the disclosed NOV4 protein ofthe invention includes the Rho-Inter acting Protein -like protein whose sequence is provided in Table 4B or 4D.
  • the invention also includes a mutant or variant protein any of whose residues may be changed from the corresponding residue shown in Table 4B or 4D while still encoding a protein that maintains its Rlio-Interacting Protein -like activities and physiological functions, or a functional fragment thereof. In the mutant or variant protein, up to about 62% percent ofthe residues may be so changed.
  • Interacting Protein-like protein and nucleic acid disclosed herein suggest that this NOV4 protein may have important structural and/or physiological functions characteristic of the Rho-interacting Protein family. Therefore, the NOV4 nucleic acids and proteins ofthe invention are useful in potential diagnostic and therapeutic applications.
  • nucleic acid or protein diagnostic and/or prognostic marker serving as a specific or selective nucleic acid or protein diagnostic and/or prognostic marker, wherein the presence or amount of the nucleic acid or the protein are to be assessed, as well as potential therapeutic applications such as the following: (i) a protein therapeutic, (ii) a small molecule drug target, (iii) an antibody target (therapeutic, diagnostic, drug targeting/cytotoxic antibody), (iv) a nucleic acid useful in gene therapy (gene delivery/gene ablation), and (v) a composition promoting tissue regeneration in vitro and in vivo.
  • the NOV4 nucleic acids and proteins ofthe invention are useful in potential diagnostic and therapeutic applications implicated in various diseases and disorders described below.
  • the compositions ofthe present invention will have efficacy for treatment of patients suffering from Cell adhesion, shape, interaction communication, cytokinesis disorders; myotonic dystrophy; muscular disorders and diseases; immunological disorders and diseases; and/or other pathologies.
  • the NOV4 nucleic acids, or fragments thereof may further be useful in diagnostic applications, wherein the presence or amount ofthe nucleic acid or the protein are to be assessed.
  • NOV4 nucleic acids and polypeptides are further useful in the generation of antibodies that bind immunospecifically to the novel substances ofthe invention for use in therapeutic or diagnostic methods. These antibodies may be generated according to methods known in the art, using prediction from hydrophobicity charts, as described in the "Anti-NOVX Antibodies" section below.
  • the disclosed NOV4 protein has multiple hydrophilic regions, each of which can be used as an immunogen.
  • a contemplated NOV4 epitope is from about amino acids 5 to 90.
  • a NOV4 epitope is from about amino acids 110 to 380.
  • NOV4 epitopes are from about amino acids 390 to 440, and from about amino acids 450 to 570.
  • a disclosed NOV5 nucleic acid of 1295 nucleotides (also referred to as Sggc_draft_bal43h20_20000730_dal2) encoding a novel protein phosphatase-like protein is shown in Table 5 A.
  • An open reading frame was identified beginning with an ATG initiation codon at nucleotides 12-14 and ending with a TAG codon at nucleotides 930-932. Putative untranslated regions upstream from the initiation codon and downstream from the termination codon are underlined in Table 5 A, and the start and stop codons are in bold letters.
  • a disclosed NOV5 polypeptide (SEQ ID NO:20) encoded by SEQ ID NO: 19 is 306 amino acid residues and is presented using the one-letter code in Table 5B.
  • Signal P, Psort and/or Hydropathy results predict that NOV5 has no signal peptide and is likely to be localized in the cytoplasm with a certainty of 0.6500.
  • NOV5 may also be localized to the mitochondrial matrix space with acertainty of 0.1000, or the lysosome (lumen) with a certainty of 0.1000.
  • NOV5 is expressed in at least HepG2 (liver)
  • the sequence is predicted to be expressed in adrenal gland supraarenal gland, ascending colon, bone, bone marrow, brain, amygdala, cerebellum, hippocampus, substantia nigra, thalamus, colon, coronary artery, dermis, fetal brain, fetal kidney, fetal liver, fetal lung, foreskin, heart, kidney, liver, lung, lymph node, lymphoid tissue, lymphoma, mammary gland/breast, ovary, pancreas, parathyroid gland, peripheral blood, pineal gland, pituitary gland, placenta, prostate, salivary gland, skeletal muscle, skin, small intestine, spinal cord, spleen, stomach, testis, thalamus, thyroid, trachea, tonsils, and uterus.
  • NOV5 also has homology to the amino acid sequences shown in the BLASTP data listed in Table 5C.
  • NOV5 sequence has properties similar to those of other proteins known to contain this domain.
  • CD-Length 287 residues, 95.5% aligned
  • CD-Length 271 residues, 99.6% aligned
  • NOV5 also has homology to sequence found in the patp patent database. Data from BLASTX alignments are found below in Table 5G
  • Type 1 protein phosphatases comprise a group of widely distributed enzymes that specifically dephosphorylate serine and threonine residues of certain phosphoproteins. They all contain an isoform ofthe same catalytic subunit, which has an extremely conserved primary structure.
  • One ofthe properties of PP-1 that allows one to distinguish them from other serine/threonine protein phosphatases is their sensitivity to inhibition by two proteins, termed inhibitor 1 and inhibitor 2, or modulator.
  • the latter protein can also form a 1 :1 complex with the catalytic subunit that slowly inactivates upon incubation. This complex is reactivated in vitro by incubation with MgATP and protein kinase FA/GSK-3.
  • PP-1 plays an essential role in glycogen metabolism, calcium transport, muscle contraction, intracellular transport, protein synthesis, and cell division.
  • the activity of PP-1 is regulated by hormones like insulin, glucagon, alpha- and beta-adrenergic agonists, glucocorticoids, and thyroid hormones.
  • the invention also includes a mutant or variant nucleic acid any of whose bases may be changed from the corresponding base shown in Table 5 A while still encoding a protein that maintains its Protein Phosphatase -like activities and physiological functions, or a fragment of such a nucleic acid.
  • the invention further includes nucleic acids whose sequences are complementary to those just described, including nucleic acid fragments that are complementary to any ofthe nucleic acids just described.
  • the invention additionally includes nucleic acids or nucleic acid fragments, or complements thereto, whose structures include chemical modifications. Such modifications include, by way of nonlimiting example, modified bases, and nucleic acids whose sugar phosphate backbones are modified or derivatized.
  • modifications are carried out at least in part to enhance the chemical stability ofthe modified nucleic acid, such that they maybe used, for example, as antisense binding nucleic acids in therapeutic applications in a subject.
  • the mutant or variant nucleic acids, and their complements up to about 1 % percent of the bases may be so changed.
  • the disclosed NOV5 protein ofthe invention includes the Protein Phosphatase -like protein whose sequence is provided in Table 5B.
  • the invention also includes a mutant or variant protein any of whose residues may be changed from the corresponding residue shown in Table 5B while still encoding a protein that maintains its Protein Phosphatase-like activities and physiological functions, or a functional fragment thereof. In the mutant or variant protein, up to about 15% percent ofthe residues may be so changed.
  • the NOV5 nucleic acids and proteins ofthe invention are useful in potential therapeutic applications implicated in various diseases, disorders and conditions.
  • the NOV5 nucleic acid, or fragments thereof, may further be useful in diagnostic applications, wherein the presence or amount ofthe nucleic acid or the protein are to be assessed.
  • NOV5 nucleic acids and polypeptides are further useful in the generation of antibodies that bind immunospecifically to the novel substances ofthe invention for use in therapeutic or diagnostic methods. These antibodies may be generated according to methods known in the art, using prediction from hydrophobicity charts, as described in the "Anti-NOVX Antibodies" section below.
  • the disclosed NOV5 protein have multiple hydrophilic regions, each of which can be used as an immunogen.
  • contemplated NOV5 epitope is from about amino acids 20 to 60.
  • NOV5 epitope is from about amino acids 75 to 110, from about amino acids 130 to 210, from about amino acids 220 to 240, and from about amino acids 260 to 300.
  • This novel protein also has value in development of powerful assay system for functional analysis of various human disorders, which will help in understanding of pathology ofthe disease and development of new drug targets for various disorders.
  • a disclosed NOV6 nucleic acid of 4690 nucleotides (also referred to as AC074370_da2) encoding a novel Ubiquitin Ligase-like protein is shown in Table 6A.
  • An open reading frame was identified beginning with an ATG initiation codon at nucleotides 585- 587 and ending with a TAG codon at nucleotides 2709-2711.
  • a putative untranslated region upstream from the initiation codon and downstream from the termination codon is underlined in Table 6 A, and the start and stop codons are in bold letters.
  • AACCAAACAG C T GCCC T CA TTAGCGGATTCCGTTCCATTATCAAA CCCGAGTGGATCCGAA ' ⁇ GTTCTCAA CT CC T G AA C T GCAG C G T CTC ATCTCTGGCGACAATGCTGAGATTGA T C TGG A AGA T TTAA A GAAGCACAC A GTC T AC T ACGGTGGT T TCC ATG G AAGTCA C AGAGTC A TCAT C TG GCTCT GG GAT AT TCT G ⁇ CCTCCGAC TTCACACC G GAT G AGA GAGC TATGTTTCTGAAGTTCGTGACCAGCT GCTCC A GACC C CCG C ⁇ ICCTGGGAT TCGCCTAC C T C A AGC CT CCA TTCTCCATCCGCTGCGTGGAGGTGT CGGAC GA TCA GG ACA C GGGGACAC TCTGGGCA G C G T CC TC CGGGG CTTCTTCACCATCCGCAAGCGG G A G C CAG G CGGC
  • a disclosed NOV6 polypeptide (SEQ ID NO:22) encoded by SEQ ID NO:21 is 708 amino acid residues and is presented using the one-letter amino acid code in Table 6B.
  • Signal P, Psort and/or Hydropathy results predict that NOV6 contains no signal peptide and is likely to be localized in the mitochondrial membrane space with a certainty of 0.8876.
  • NOV6 is also likely to be localized to the mitochondrial matrix membrane with a certainty of 0.5807, the mitochondrial intermembrane space with a certainty of 0.5807, or to the mitochondrial outer membrane with a certainty of 0.5807.
  • Table 6B Encoded NOV6 protein sequence (SEQ ID NO:22).
  • FTLSQTSRA FIDRARQAREERLVQKERERAAWIQAHVRSFLCRSRLQRDIRREIDDFFKADDPESTKRSALC IFKIARKLLFLFRIKEDNERFEKLCRSILSSMDAENEPKVWYVSLACSKDLTLLWIQQIKNILWYCCDFLK Q LKP EILQDSRLITLYLTMLVTFTDTST KILRGKGESLRPAMNHICANIMGHLNQHGFYSVLQILLTRGLARPRPCLS KGTLTAAFSLALRPVIAAQFSDNLIRPFLIHIMSVPALVTHLSTVTPERLTVLESHDMLRKFIIFLRDQDRCRDV CESLEGCHTLCLMGNLLHLGSLSPRVLEEETDGFVSLLTQTLCYCRKYVSQKKSNLTH HPVLG FSQSVDYGLN ESMHLITKQLQFLWGVPLIRIFFCDILSKKLLESQ
  • NOV6 is expressed in adrenal gland, bone marrow, brain, amydala, cerebellum, hippocampus, substantia nigra, thalamus, fetal brain, fetal kidney, fetal liver, fetal lung, heart kidney, lymphoma, mammary gland, pancreas, pituitary gland, placenta, prostate, salivary gland, skeletal muscle, small intestine, spinal cord, spleen, stomach, testis, thyroid, trachea, and uterus.
  • sequence is predicted to be expressed in the following tissues because ofthe expression pattern of (GENBANK-ID: ACC:AL096740) a closely related DKFZp586K2123 homolog in species Homo sapiens) : developing tissues, developing epidermis, kidney, colon, lung, liver, fibroblasts, heart, and brain.
  • NOV6 also has homology to the amino acid sequences shown in the BLASTP data listed in Table 6C.
  • NOV6 also has homology to sequence found in the patp patent database. Data from
  • UBE3A E6-AP ubiquitin- protein ligase gene
  • AS Angelman syndrome
  • proximal chromosome 15q defined by the breakpoint of an interstitial deletion on the centromeric side and the breakpoint in a familial t(14;15) on the telomeric side.
  • the region is telomeric to the Prader-Willi syndrome region which contains the SNRPN gene.
  • IGF2 insulin-like growth factor-2
  • Albrecht et al. (Imprinted expression ofthe murine Angelman syndrome gene, Ube3a, in hippocampal and Purkinje neurons. Nature Genet. 17: 75-78, 1997) used mice with partial paternal uniparental disomy (UPD) encompassing Ube3a to differentiate maternal and paternal expression. They found by in situ hybridization that expression of UBE3A in Purkinje cells, hippocampal neurons, and mitral cells ofthe olfactory bulb in UPD mice was markedly reduced compared to non-UPD littermates. In contrast, expression of UBE3A in other regions ofthe brain was reduced only moderately or not at all in UPD mice. The major phenotypic features of AS correlate with the loss of maternal-specific expression of Ube3a in hippocampus and cerebellum as revealed in this mouse model.
  • UPD partial paternal uniparental disomy
  • her ataxia was less severe than is typically seen in Angelman syndrome, she did not exhibit inappropriate laughter, and she had normal occiput formation as well as a normal EEG at age 2 years and 6 months.
  • the 14-bp deletion was found in the patient, her normal sib, and her unaffected mother.
  • E2-E3 enzyme cascade Science 286: 1321-1326, 1999) determined that the crystal structure ofthe catalytic hect domain of E6AP revealed a bilobal structure with a broad catalytic cleft at the junction ofthe 2 lobes.
  • the cleft consists of conserved residues whose mutation interferes with ubiquitin-thioester bond formation and is the site of Angelman syndrome mutations.
  • the crystal structure of E6AP hect domain bound to the UBCH7 ubiquitin-conjugating (E2) enzyme revealed the determinants ofthe E2-E3 specificity and provided insights into the transfer of ubiquitin from the E2 to the E3.
  • the disclosed NOV6 nucleic acid ofthe invention encoding a Ubiquitin Ligase-like protein includes the nucleic acid whose sequence is provided in Table 6A or a fragment thereof.
  • the invention also includes a mutant or variant nucleic acid any of whose bases may be changed from the corresponding base shown in Table 6A while still encoding a protein that maintains its Ubiquitin Ligase-like activities and physiological functions, or a fragment of such a nucleic acid.
  • the invention further includes nucleic acids whose sequences are complementary to those just described, including nucleic acid fragments that are complementary to any ofthe nucleic acids just described.
  • the invention additionally includes nucleic acids or nucleic acid fragments, or complements thereto, whose structures include chemical modifications. Such modifications include, by way of nonlimiting example, modified bases, and nucleic acids whose sugar phosphate backbones are modified or derivatized. These modifications are carried out at least in part to enhance the chemical stability ofthe modified nucleic acid, such that they may be used, for example, as antisense binding nucleic acids in therapeutic applications in a subject. In the mutant or variant nucleic acids, and their complements, up to about 10% percent ofthe bases may be so changed.
  • the disclosed NOV6 protein ofthe invention includes the Ubiquitin Ligase-like protein whose sequence is provided in Table 6B.
  • the invention also includes a mutant or variant protein any of whose residues may be changed from the corresponding residue shown in Table 6B while still encoding a protein that maintains its Ubiquitin Ligase-like activities and physiological functions, or a functional fragment thereof. In the mutant or variant protein, up to about 68% percent ofthe residues may be so changed.
  • NOV6 Ubiquitin Ligase- like proteins
  • the above defined information for this invention suggests that these Ubiquitin Ligase- like proteins (NOV6) may function as a member of a "Ubiquitin Ligase family". Therefore, the NOV6 nucleic acids and proteins identified here may be useful in potential therapeutic applications implicated in (but not limited to) various pathologies and disorders as indicated below.
  • the potential therapeutic applications for this invention include, but are not limited to: protein therapeutic, small molecule drug target, antibody target (therapeutic, diagnostic, drug targeting/cytotoxic antibody), diagnostic and/or prognostic marker, gene therapy (gene delivery/gene ablation), research tools, tissue regeneration in vivo and in vitro of all tissues and cell types composing (but not limited to) those defined here.
  • the nucleic acids and proteins of NOV6 are useful in autoimmune diseases, Angelman syndrome, inflammatory and immune diseases, Liddle's syndrome, encephalopathy, Prader- Willi syndrome, Neural Dvelopment disease, muscular disease, ataxia, and/or other pathologies and disorders.
  • the novel NOV6 nucleic acid encoding NOV6 protein, or fragments thereof, may further be useful in diagnostic applications, wherein the presence or amount ofthe nucleic acid or the protein are to be assessed. These materials are further useful in the generation of antibodies that bind immunospecifically to the novel substances ofthe invention for use in therapeutic or diagnostic methods.
  • NOV6 nucleic acids and polypeptides are further useful in the generation of antibodies that bind immunospecifically to the novel substances ofthe invention for use in therapeutic or diagnostic methods. These antibodies may be generated according to methods known in the art, using prediction from hydrophobicity charts, as described in the "Anti-NOVX Antibodies" section below.
  • the disclosed NOV6 protein have multiple hydrophilic regions, each of which can be used as an immunogen.
  • contemplated NOV6 epitope is from about amino acids 5 to 40.
  • NOV6 epitope is from about amino acids 50 to 70, from about amino acids 90 to 140, from about amino acids 160 to 190, from about amino acids 280 to 300, from about amino acids 330 to 380, from about amino acids 400 to 460, from about amino acids 480 to 500, from about amino acids 580 to 640, or from about amino acids 650 to 700.
  • This novel protein also has value in development of powerful assay system for functional analysis of various human disorders, which will help in understanding of pathology ofthe disease and development of new drug targets for various disorders.
  • a disclosed NOV7 nucleic acid of 608 nucleotides (also referred to K03203_dal) encoding a novel Salivary Proline-Rich Phosphoprotein-like protein is shown in Table 7A.
  • An open reading frame was identified beginning with an ATG initiation codon at nucleotides 45- 47 and ending with a TAA codon at nucleotides 492-494.
  • Table 7 A the 5' and 3' untranslated regions are underlined and the start and stop codons are in bold letters.
  • a disclosed NOV7 polypeptide (SEQ ID NO:24) encoded by SEQ ID NO:23 is 149 amino acid residues and is presented using the one-letter amino acid code in Table 7B.
  • Signal P, Psort and or Hydropathy results predict that NOV7 has a signal peptide and is likely to be localized extracellularly with a certainty of 0.05326.
  • NOV7 is also likely to be localized to the enoplasmic reticulum (membrane) with a certainty of 0.1000, to the endoplasmic reticulum (lumen) with a certainty of 0.1000, or the lysosome (lumen) with a certainty of 0.1000.
  • the most likely cleavage site for a NO V7 peptide is between amino acids 16 and l7, at: SSA-QD.
  • Table 7B Encoded NOV7 protein sequence (SEQ ID NO:24).
  • NOV7 amino acid sequence has 131 of 143 amino acid residues (91%) identical to, and 123 of 143 amino acid residues (93%) similar to, the 166 amino acid residue ptnr:PIR-ACC:B25372 protein from Homo sapiens (Human) Salivary proline rich phosphoprotein precursor (PRH1) (1.2e "69 ).
  • NOV7 also has homology to the amino acid sequence shown in the BLASTP data listed in Table 7C.
  • NOV7 also has homology to sequence found in the patp patent database. Data from
  • Clones cPl and cP2 contain repetitive regions in which sites for the restriction enzyme Haelll occur repeatedly; they code for the precursors of acidic.
  • Clones cP3 to cP7 contain repetitive regions in which BstNI sites occur repeatedly; they code for precursors of basic and glycosylated PRPs.
  • the clones cP3, cP4, and cP5 are identical except that cP4 and cP5 are missing 399 and 459 base pairs, respectively, from the repetitive region of cP3.
  • the sequences at these deletion end points are homologous to the consensus sequences of RNA splicing donor and acceptor sites. This strongly suggests that all three cDNAs are derived from the transcript of a single gene via differential RNA splicing. All ofthe precursor proteins share a feature ⁇ the N-terminal region, following the signal peptide, is acidic, while the remainder of the molecule, made of proline-rich repeats of about 21 amino acids, is basic.
  • Each precursor can generate multiple PRPs by various post-translational cleavages on the carboxylic side of specific arginine residues.
  • the data show how differential RNA splicing and post-translational cleavages could generate a large number of proteins, such as those found in saliva, from a much smaller number of genes.
  • Two members ofthe human salivary proline-rich protein (PRP) multigene family have been isolated and completely sequenced (Kim HS, et.al.; J Biol Chem 1986 May 25;261(15):6712-8). These PRP genes, PRH1 and PRH2, are ofthe Haelll-type subfamily and code for acidic PRP proteins.
  • Both genes are approximately 3.5 kilobase pairs (kb) in length and contain four exons.
  • Exon 3 encodes the proline-rich part ofthe protein and includes five 63-base pair (bp) repeats.
  • CAT and ATA boxes and several possible enhancer sequences occur in a 1-kb region 5' to exon 1.
  • Two sets of repeats occur in the sequenced region in addition to the 63-bp repeats: one pair of about 140 bp flanks 500 bp of DNA in the first intervening sequence, and the other pair of 72 bp is tandemly repeated 1.4 kb 5 1 to the PRH1 gene.
  • the 4- kb region of sequenced DNA from PRH1 differs by an average of 8.7% from the same region in PRH2, but the nucleotide sequences ofthe exon 3 ofthe two genes differ by only 0.2%.
  • PRPs proline-rich phosphoproteins
  • Human submandibular/sublingual saliva contains one non-glycosylated basic proline- rich protein whereas parotid saliva contains multiple such components (Robinson R, et.al.; Biochem J 1989 Oct 15;263(2):497-503).
  • the submandibular protein has a primary structure identical with the C-terminal segment [TZ] ofthe human parotid acidic proline-rich proteins that contain 150 amino acid residues (Mr 16,000).
  • Azen and Denniston found that PIF shows a high order of heterozygosity in whites, blacks, and Chinese. Studies in 41 families supported the genetic control of PEF by a single autosomal locus. A lod score of 3.56 at theta of 0.00 was found for PEF versus GI (168840). (PIF has also been used as the symbol for prolactin release- inhibiting factor, 152760.) Azen et al. (Am. J. Hum. Genet. 41: 1035-1047,1987) cloned and sequenced the entire exon and intron structures of Db and Pa genetic determinants at the PRH1 locus.
  • the Db and PIF proteins are proteolytically cut at argl06 and show a double-banded phenotype.
  • the Db protein has an extra 21 -amino acid repeat that accounts for its larger size compared with the other 2 proteins.
  • Luteinizing hormone-releasing hormone (LHRH), a decapeptide, is a key molecule in the hypothalamic-pituitary-gonadal axis that controls human reproduction. It is produced by hypothalamic neurons, secreted in a pulsatile manner into the capillary plexus ofthe median eminence, and effects the release of luteinizing hormone and follicle-stimulating hormone from gonadotrophic cells ofthe anterior pituitary. Seeburg and Adelman (Nature 311: 666- 668, 1984) isolated cloned genomic and cDNA encoding the precursor of LHRH.
  • LHRH also referred to as 'gonadotropin-releasing hormone' (GNRH), and prolactin release-inhibiting factor (PIF) are derived from the same 92-amino acid precursor protein, which is encoded by a single gene. (PIF has also been used as the symbol for a parotid salivary protein; see 168730.) .
  • Phosphoprotein Precursor-like protein includes the nucleic acid whose sequence is provided in Table 7A or a fragment thereof.
  • the invention also includes a mutant or variant nucleic acid any of whose bases may be changed from the corresponding base shown in Table 7A while still encoding a protein that maintains its Salivary Proline-Rich Phosphoprotein Precursor-like activities and physiological functions, or a fragment of such a nucleic acid.
  • the invention further includes nucleic acids whose sequences are complementary to those just described, including nucleic acid fragments that are complementary to any ofthe nucleic acids just described.
  • the invention additionally includes nucleic acids or nucleic acid fragments, or complements thereto, whose structures include chemical modifications.
  • modifications include, by way of nonlimiting example, modified bases, and nucleic acids whose sugar phosphate backbones are modified or derivatized. These modifications are carried out at least in part to enhance the chemical stability ofthe modified nucleic acid, such that they may be used, for example, as antisense binding nucleic acids in therapeutic applications in a subject. In the mutant or variant nucleic acids, and their complements, up to about 10% percent ofthe bases may be so changed.
  • the disclosed NOV7 protein ofthe invention includes the Salivary Proline-Rich Phosphoprotein Precursor-like protein whose sequence is provided in Table 7B.
  • the invention also includes a mutant or variant protein any of whose residues may be changed from the corresponding residue shown in Table 7B while still encoding a protein that maintains its Salivary Proline-Rich Phosphoprotein Precursor-like activities and physiological functions, or a functional fragment thereof. In the mutant or variant protein, up to about 34% percent ofthe residues may be so changed.
  • Salivary Proline-Rich Phosphoprotein Precursor-like protein and nucleic acid disclosed herein suggest that NOV7 may have important structural and or physiological functions characteristic ofthe Salivary Proline-Rich Phosphoprotein Precursor-like family. Therefore, the NOV7 nucleic acids and proteins ofthe invention are useful in potential diagnostic and therapeutic applications.
  • nucleic acid or protein diagnostic and/or prognostic marker serving as a specific or selective nucleic acid or protein diagnostic and/or prognostic marker, wherein the presence or amount ofthe nucleic acid or the protein are to be assessed, as well as potential therapeutic applications such as the following: (i) a protein therapeutic, (ii) a small molecule drug target, (iii) an antibody target (therapeutic, diagnostic, drug targeting/cytotoxic antibody), (iv) a nucleic acid useful in gene therapy (gene delivery/gene ablation), and (v) a composition promoting tissue regeneration in vitro and in vivo.
  • the NOV7 nucleic acids and proteins ofthe invention are useful in potential diagnostic and therapeutic applications implicated in various diseases and disorders described below and/or other pathologies.
  • the compositions ofthe present invention will have efficacy for treatment of patients suffering from hypogonadotropic hypogonadism, Kallman syndrome, bacterial viral infection, immunological and inflammatory diseases and disorders, and/or other pathologies/disorders.
  • the NOV7 nucleic acid, or fragments thereof may further be useful in diagnostic applications, wherein the presence or amount ofthe nucleic acid or the protein are to be assessed.
  • NOV7 nucleic acids and polypeptides are further useful in the generation of antibodies that bind immunospecifically to the novel substances of the invention for use in therapeutic or diagnostic methods.
  • NOV7 protein have multiple hydrophilic regions, each of which can be used as an immunogen.
  • contemplated NOV7 epitope is from about amino acids 15 to 140.
  • This novel protein also has value in development of powerful assay system for functional analysis of various human disorders, which will help in understanding of pathology ofthe disease and development of new drug targets for various disorders.
  • a disclosed NOV8 nucleic acid of 392 nucleotides (also referred to as AC011483_da2) encoding a novel Kallikrein-like protein is shown in Table 8 A.
  • An open reading frame was identified beginning with an ATG initiation codon at nucleotides 54-56 and ending with a TGA codon at nucleotides 390-392.
  • a putative untranslated region upstream from the initiation codon is underlined in Table 8A. The start and stop codons are in bold letters.
  • Table 8A NOV8 nucleotide sequence (SEQ ID NO:25).
  • the NOV8 nucleic acid sequence is located on chromsome 19, has 277 of 278 bases
  • NOV8 polypeptide (SEQ ID NO:26) encoded by SEQ ID NO:25 has 111 amino acid residues and is presented in Table 8B using the one-letter amino acid code.
  • Signal P, Psort and/or Hydropathy results predict that NOV8 has a signal peptide and is likely to be localized extracellularly with a certainty of 0.8191.
  • NOV8 may also be localized to the endoplasmic reticulum (membrane) with a certainty of 0.1000, the endoplasmic reticulum (lumen) with a certainty of 0.1000, or the lysosome (lumen) with a certainty of 0.1000.
  • the most likely cleavage site for NOV8 is between positions 29 and 30, VLA-NN.
  • Table 8B Encoded NOV8 protein sequence (SEQ ID NO:26).
  • NOV8 is found in at least coronary artery, larynx, lung, mammary gland breast, ovary, prostate, skin, testis, and tongue.
  • sequence is predicted to be expressed in the stratum corneum because ofthe expression pattern of GENBANK-ID:AF168768, a closely related homolog.
  • NOV8 also has homology to the amino acid sequence shown in the BLASTP data listed in Table 8C.
  • Proteolytic enzymes that exploit serine in their catalytic activity are ubiquitous, being found in viruses, bacteria and eukaryotes . They include a wide range of peptidase activity, including exopeptidase, endopeptidase, oligopeptidase and omega-peptidase activity. Over 20 families (denoted SI - S27) of serine protease have been identified, these being grouped into 6 clans (SA, SB, SC, SE, SF and SG) on the basis of structural similarity and other functional evidence. Structures are known for four ofthe clans (SA, SB, SC and SE): these appear to be totally unrelated, suggesting at least four evolutionary origins of serine peptidases and possibly many more.
  • Chymotrypsin, subtilisin and carboxypeptidase C clans have a catalytic triad of serine, aspartate and histidine in common: serine acts as a nudeophile, aspartate as an electrophile, and histidine as a base.
  • serine acts as a nudeophile
  • aspartate acts as a nudeophile
  • histidine acts as a base.
  • the geometric orientations of the catalytic residues are similar between families, despite different protein folds.
  • the linear arrangements ofthe catalytic residues commonly reflect clan relationships. For example the catalytic triad in the chymotrypsin clan (SA) is ordered HDS, but is ordered DHS in the subtilisin clan (SB) and SDH in the carboxypeptidase clan (SC).
  • trypsin family is almost totally confined to animals, although trypsin-like enzymes are found in actinomycetes ofthe genera Streptomyces and Saccharopolyspora, and in the fungus Fusarium oxysporum .
  • the enzymes are inherently secreted, being synthesised with a signal peptide that targets them to the secretory pathway.
  • Animal enzymes are either secreted directly, packaged into vesicles for regulated secretion, or are retained in leukocyte granules.
  • Proteases play a pivotal role in several biologic processes, including tissue remodeling and cell migration.
  • the deduced 260-amino acid protein contains a signal peptide, 3 key amino acids essential for serine protease activity, an asp residue in a position that suggests a trypsin-type substrate specificity for basic amino acids at the PI position, conserved amino acids that can form an oxyanion hole, and a potential N- glycosylation site.
  • KLKl 1 shares 48% amino acid sequence identity with mouse neuropsin, 43%) identity with both human trypsin- 1 and human kallikrein, and 38% identity with the mouse nerve growth factor gamma subunit.
  • Western blot analysis of recombinant KLKl 1 suggested that the protein is secreted and posttranslationally processed.
  • Northern blot analysis of RNA from keratinocyte primary cultures detected a 1.1 -kb KLKl 1 transcript
  • KLKl encode human kallikrein 1 (hKl) or pancreatic/renal kallikrein
  • KLK2 encoding hK2
  • KLK3 encoding hK3 or prostate-specific antigen (PSA)
  • PSA prostate-specific antigen
  • PRSSL1 gene encoding normal epithelial cell-specific 1 gene (NES1)]
  • NES1 normal epithelial cell-specific 1 gene
  • zyme/protease M/neurosin the gene encoding zyme/protease M/neurosin
  • prostase/KLK-Ll the gene encoding prostase/KLK-Ll
  • Another five putative kallikrein genes provisionally named KLK-L2, KLK-L3, KLK-L4, KLK-L5 and KLK-L6, have also been identified.
  • kallikrein-like genes are regulated by steroid hormones, and a few kallikreins (NES1, protease M, PSA) are known to be downregulated in breast and possibly other cancers.
  • NES1 appears to be a novel breast cancer tumor suppressor protein and PSA a potent inhibitor of angiogenesis.
  • the disclosed NOV8 nucleic acid ofthe invention encoding a Kallikrein-like protein includes the nucleic acid whose sequence is provided in Table 8A, or a fragment thereof.
  • the invention also includes a mutant or variant nucleic acid any of whose bases may be changed from the corresponding base shown in Table 8A while still encoding a protein that maintains its Kallikrein-like activities and physiological functions, or a fragment of such a nucleic acid.
  • the invention further includes nucleic acids whose sequences are complementary to those just described, including nucleic acid fragments that are complementary to any ofthe nucleic acids just described.
  • the invention additionally includes nucleic acids or nucleic acid fragments, or complements thereto, whose structures include chemical modifications.
  • modifications include, by way of nonlimiting example, modified bases, and nucleic acids whose sugar phosphate backbones are modified or derivatized. These modifications are carried out at least in part to enhance the chemical stability ofthe modified nucleic acid, such that they may be used, for example, as antisense binding nucleic acids in therapeutic applications in a subject. In the mutant or variant nucleic acids, and their complements, up to about 10% percent ofthe bases may be so changed.
  • the disclosed NOV8 protein ofthe invention includes the Kallikrein-like protein whose sequence is provided in Table 8B.
  • the invention also includes a mutant or variant protein any of whose residues may be changed from the corresponding residue shown in Table 2 while still encoding a protein that maintains its Kallikrein-like activities and physiological functions, or a functional fragment thereof. In the mutant or variant protein, up to about 54% percent ofthe residues may be so changed.
  • the invention further encompasses antibodies and antibody fragments, such as F ab or (F ab ) 2, that bind immunospecifically to any of the proteins of the invention.
  • NOV8 Kallikrein-like protein
  • the above defined information for this invention suggests that this Kallikrein-like protein (NOV8) may function as a member of a "Kallikrein family". Therefore, the NOV8 nucleic acids and proteins identified here may be useful in potential therapeutic applications implicated in (but not limited to) various pathologies and disorders as indicated below.
  • the potential therapeutic applications for this invention include, but are not limited to: protein therapeutic, small molecule drug target, antibody target (therapeutic, diagnostic, drug targeting/cytotoxic antibody), diagnostic and/or prognostic marker, gene therapy (gene delivery/gene ablation), research tools, tissue regeneration in vivo and in vitro of all tissues and cell types composing (but not limited to) those defined here.
  • the NOV8 nucleic acids and proteins ofthe invention are useful in potential therapeutic applications implicated in cancer including but not limited to Liflamation, Autoimmune disorders, Aging and Cancer.
  • a cDNA encoding the Kallikrein- like protein (NOV8) may be useful in gene therapy, and the Kallikrein-like protein (NOV8) may be useful when administered to a subject in need thereof.
  • the compositions ofthe present invention will have efficacy for treatment of patients suffering from cancer (especially but not limited to breast, prostate, and skin), neurological disorders, skin disorders, digetive system disorders, reproductive system disorders, protease/protease inhibitor deficiency disorders, and other such conditions..
  • the NOV8 nucleic acid encoding Kallikrein-like protein, and the Kallikrein-like protein ofthe invention, or fragments thereof, may further be useful in diagnostic applications, wherein the presence or amount ofthe nucleic acid or the protein are to be assessed.
  • NOV8 nucleic acids and polypeptides are further useful in the generation of antibodies that bind immuno-specifically to the novel NOV8 substances for use in therapeutic or diagnostic methods. These antibodies may be generated according to methods known in the art, using prediction from hydrophobicity charts, as described in the "Anti-NOVX Antibodies" section below.
  • the disclosed NOV8 protein has multiple hydrophilic regions, each of which can be used as an immunogen.
  • a contemplated NOV8 epitope is from about amino acids 30 to 90.
  • a NOV8 epitope is from about amino acids 95 to 105.
  • NOV9 A disclosed NOV9 nucleic acid of 1002 nucleotides (also referred to as
  • AC021809_dal encoding a novel Olfactory Receptor-like protein is shown in Table 9A.
  • An open reading frame was identified beginning with an ATG initiation codon at nucleotides 11- 13 and ending with a TAG codon at nucleotides 938-940.
  • a putative untranslated region upstream from the initiation codon and downstream from the termination codon is underlined in Table 9 A. The start and stop codons are in bold letters.
  • Table 9A NOV9 nucleotide sequence (SEQ ID NO:27).
  • the disclosed NOV9 nucleic acid sequence, localized to chromosome 11, has 590 of
  • NOV9 polypeptide (SEQ ID NO:28) encoded by SEQ ID NO:27 has 309 amino acid residues and is presented in Table 9B using the one-letter amino acid code.
  • Signal P, Psort and/or Hydropathy results predict that NOV9 has a signal peptide and is likely to be localized in the plasma membrane with a certainty of 0.6000.
  • NOV9 may also be localized to the Golgi body with a certainty of 0.4000, the endoplasmic reticulum (membrane) with a certainty of 0.3000, or the mitochondrial inner membrane with a certainty of 0.0300.
  • the most likely ceavage site for NOV9 is between positions 40 and 41, SLG-GN.
  • Table 9B Encoded NOV9 protein sequence (SEQ ID NO:28).
  • NOV9 is expressed in brain, neuroepithelium, nervous tissue, olfactory cilia, male reproductive system, and testis.
  • the sequence is predicted to be expressed inmouse epithelium because ofthe expression pattern of GENBANK-ID:AF247657, a closely related homolog.
  • the disclosed NOV9 polypeptide has homology to the amino acid sequences shown in the BLASTP data listed in Table 9C.
  • Table 9E lists the domain description from DOMAIN analysis results against NOV9. This indicates that the NOV9 sequence has properties similar to those of other proteins known to contain this domain.
  • NOV9 also has homology to sequence found in the patp patent database. Data from BLASTX alignments are found below in Table 9F
  • GPCRs G-Protein Coupled Receptor
  • ORs olfactory epithelium Olfactory receptors
  • OR genes cloned in different species were from random locations in the respective genomes.
  • the human OR genes are intron less and belong to four different gene subfamilies, displaying great sequence variability. These genes are dominantly expressed in olfactory epithelium.
  • the disclosed NOV9 nucleic acid ofthe invention encoding a Olfactory Receptor-like protein includes the nucleic acid whose sequence is provided in Table 9A, or a fragment thereof.
  • the invention also includes a mutant or variant nucleic acid any of whose bases may be changed from the corresponding base shown in Table 9A while still encoding a protein that maintains its Olfactory Receptor-like activities and physiological functions, or a fragment of such a nucleic acid.
  • the invention further includes nucleic acids whose sequences are complementary to those just described, including nucleic acid fragments that are complementary to any ofthe nucleic acids just described.
  • the invention additionally includes nucleic acids or nucleic acid fragments, or complements thereto, whose structures include chemical modifications.
  • modifications include, by way of nonlimiting example, modified bases, and nucleic acids whose sugar phosphate backbones are modified or derivatized. These modifications are carried out at least in part to enhance the chemical stability ofthe modified nucleic acid, such that they may be used, for example, as antisense binding nucleic acids in therapeutic applications in a subject. In the mutant or variant nucleic acids, and their complements, up to about 10% percent ofthe bases may be so changed.
  • the disclosed NOV9 protein ofthe invention includes the Olfactory Receptor-like protein whose sequence is provided in Table 9B.
  • the invention also includes a mutant or variant protein any of whose residues may be changed from the corresponding residue shown in Table 2 while still encoding a protein that maintains its Olfactory Receptor-like activities and physiological functions, or a functional fragment thereof. In the mutant or variant protein, up to about 63% percent ofthe residues may be so changed.
  • the invention further encompasses antibodies and antibody fragments, such as F ab or
  • NOV9 Olfactory Receptorlike protein
  • the above defined information for this invention suggests that this Olfactory Receptorlike protein (NOV9) may function as a member of a "Olfactory Receptor family". Therefore, the NOV9 nucleic acids and proteins identified here may be useful in potential therapeutic applications implicated in (but not limited to) various pathologies and disorders as indicated below.
  • the potential therapeutic applications for this invention include, but are not limited to: protein therapeutic, small molecule drug target, antibody target (therapeutic, diagnostic, drug targeting/cytotoxic antibody), diagnostic and/or prognostic marker, gene therapy (gene delivery/gene ablation), research tools, tissue regeneration in vivo and in vitrcTo ⁇ all tissues and cell types composing (but not limited to) those defined here.
  • NOV9 nucleic acids and proteins ofthe invention are useful in potential therapeutic applications implicated in cancer including but not limited to Inflamation, Autoimmune disorders, Aging and Cancer.
  • a cDNA encoding the Olfactory Receptor-like protein (NOV9) may be useful in gene therapy, and the Olfactory Receptor-like protein (NOV9) may be useful when administered to a subject in need thereof.
  • compositions ofthe present invention will have efficacy for treatment of patients suffering from bacterial, fungal, protozoal and viral infections (particularly infections caused by HIV-1 or HIV-2), pain, cancer (including but not limited to Neoplasm; adenocarcinoma; lymphoma; prostate cancer; uterus cancer), anorexia, bulimia, asthma, Parkinson's disease, acute heart failure, hypotension, hypertension, urinary retention, osteoporosis, Crohn's disease; multiple sclerosis; and Treatment of Albright Hereditary Ostoeodystrophy, angina pectoris, myocardial infarction, ulcers, asthma, allergies, benign prostatic hypertrophy, and psychotic and neurological disorders, including anxiety, schizophrenia, manic depression, delirium, dementia, severe mental retardation.
  • cancer including but not limited to Neoplasm; adenocarcinoma; lymphoma; prostate cancer; uterus cancer
  • anorexia, bulimia asthma, Parkinson's disease, acute heart failure, hypotension, hypertension,
  • Dentatorubro-pallidoluysian atrophy(DRPLA) Hypophosphatemic rickets, autosomal dominant (2) Acrocallosal syndrome and dyskinesias, such as Huntington's disease or Gilles de la Tourette syndrome, and/or other pathologies or conditions.
  • the NOV9 nucleic acid encoding Olfactory Receptor-like protein, and the Olfactory Receptor-like protein ofthe invention, or fragments thereof, may further be useful in diagnostic applications, wherein the presence or amount ofthe nucleic acid or the protein are to be assessed.
  • NOV9 nucleic acids and polypeptides are further useful in the generation of antibodies that bind immuno-specifically to the novel NOV9 substances for use in therapeutic or diagnostic methods. These antibodies may be generated according to methods known in the art, using prediction from hydrophobicity charts, as described in the "Anti-NOVX Antibodies" section below.
  • the disclosed NOV9 protein has multiple hydrophilic regions, each of which can be used as an immunogen.
  • a contemplated NOV9 epitope is from about amino acids 5 to 20.
  • a NOV9 epitope is from about amino acids 170 to 180.
  • a NOV9 epitope is from about amino acids 230 to 240, from about amino acids 250 to 260, and from about amino acids 280 to 300.
  • a disclosed NOV10 nucleic acid of 4796 nucleotides (also referred to as 11073674_dal) encoding a novel Serine-Threonine Kinase-like protein is shown in Table 10A.
  • An open reading frame was identified beginning with an ATG initiation codon at nucleotides 549-551 and ending with a TGA codon at nucleotides 1833-1835.
  • a putative untranslated region upstream from the initiation codon and downstream from the termination codon is underlined in Table 10A. The start and stop codons are in bold letters.
  • Table 10A NOV10 nucleotide sequence (SEQ ID NO:29).
  • Public nucleotide databases include all GenBank databases and the GeneSeq patent database.
  • NOV10 polypeptide (SEQ ID NO.30) encoded by SEQ ID NO:29 has 428 amino acid residues and is presented in Table 10B using the one-letter amino acid code.
  • Signal P, Psort and or Hydropathy results predict that NOV10 has no signal peptide and is likely to be localized in the nucleus with a certainty of 0.7000.
  • NOV10 may also be localized to the microbody (peroxisome) with acertainty of 0.3883, the mitochondrial matrix space with a certainty of 0.1000, or in the lysosome (lumen) with a certainty of 0.1000.
  • Table 10B Encoded NOV10 protein sequence (SEQ ID NO:30).
  • NOV10 is expressed in at least the heart, brain, lung, liver, skeletal muscle, kidney, pancreas, spleen, testis, ovary, tumors, nervous tissue, lymphoid tissue, adipose, gastrointestinal tissue, dermis, mesenchyme below the epidermis, lung mesenchyme, developing limbs, developing teeth, developing brain, colon, and embryonic tissues.
  • the disclosed NOV10 polypeptide has homology to the amino acid sequences shown in the BLASTP data listed in Table IOC.
  • PAK-5 protein kinase PAK5 [Homo sapiens] (SEQ ID NO: 101)
  • Tables 10E-10F lists the domain description from DOMAIN analysis results against NOVIO. This indicates that the NOVIO sequence has properties similar to those of other proteins known to contain this domain.
  • FAS death receptor plays a critical role in the homeostasis ofthe immune systems. Following ligand-induced oligomerization, the FAS receptor recruits caspase-8 to the receptor signaling complex through FADD, which leads to processing and release into the cytosol of caspase-8. Active cas ⁇ ase-8 induces a cascade of caspases and the rapid demise ofthe cell.
  • RIP is a death domain-containing protein kinase that interacts with the death domain of FAS, but does not appear to mediate FAS-initiated apoptosis. To identify a kinase that might be involved in the regulation of FAS-induced apoptosis, Inohara et al.
  • RICK a novel protein kinase containing a caspase recruitment domain, interacts with CLARP and regulates CD95-mediated apoptosis.
  • Note: Erratum: J. Biol. Chem 273: 18675 only, 1998) searched an EST database for clones with homology to the catalytic domain of RIP. They identified cDNAs encoding a protein that they designated RICK (RIP-like interacting CLARP kinase).
  • the predicted 540-amino acid protein contains an N-terminal serine/threonine kinase catalytic domain and a C-terminal caspase activation and recruitment domain (CARD).
  • CARDs mediate homophilic interactions allowing for the recruitment of caspases to receptor complexes, and have been identified in a number of molecules involved in apoptotic signaling, including RAEDD, caspase-2, and cLAP2 (API2)(McCarthy et al., RDP2 is a novel NF-kappa-B-activating and cell death-inducing kinase. J. Biol. Chem. 273: 16968-16975, 1998). Inohara et al. (RICK, a novel protein kinase containing a caspase recruitment domain, interacts with CLARP and regulates CD95-mediated apoptosis. J. Biol. Chem.
  • the disclosed NOVIO nucleic acid ofthe invention encoding a Serine Threonine Kinase -like protein includes the nucleic acid whose sequence is provided in Table 10A or a fragment thereof.
  • the invention also includes a mutant or variant nucleic acid any of whose bases may be changed from the corresponding base shown in Table 10A while still encoding a protein that maintains its Serine Threonine Kinase-like activities and physiological functions, or a fragment of such a nucleic acid.
  • the invention further includes nucleic acids whose sequences are complementary to those just described, including nucleic acid fragments that are complementary to any of the nucleic acids just described.
  • the invention additionally includes nucleic acids or nucleic acid fragments, or complements thereto, whose structures include chemical modifications.
  • modifications include, by way of nonlimiting example, modified bases, and nucleic acids whose sugar phosphate backbones are modified or derivatized. These modifications are carried out at least in part to enhance the chemical stability ofthe modified nucleic acid, such that they may be used, for example, as antisense binding nucleic acids in therapeutic applications in a subject.
  • up to about 10% percent ofthe bases may be so changed.
  • the disclosed NOV10 protein ofthe invention includes the Serine Threonine Kinase- like protein whose sequence is provided in Table 10B.
  • the invention also includes a mutant or variant protein any of whose residues may be changed from the corresponding residue shown in Table 10B while still encoding a protein that maintains its Serine Threonine Kinase - like activities and physiological functions, or a functional fragment thereof. In the mutant or variant protein, up to about 38% percent ofthe residues may be so changed.
  • the invention further encompasses antibodies and antibody fragments, such as F ab or (F ab ) 2, that bind immunospecifically to any ofthe proteins ofthe invention.
  • NOV10 Serine Threonine Kinase-like protein
  • the above defined information for this invention suggests that this Serine Threonine Kinase-like protein (NOV10) may function as a member of a "Serine Threonine Kinase family". Therefore, the NOV10 nucleic acids and proteins identified here may be useful in potential therapeutic applications implicated in (but not limited to) various pathologies and disorders as indicated below.
  • the potential therapeutic applications for this invention include, but are not limited to: protein therapeutic, small molecule drug target, antibody target (therapeutic, diagnostic, drug targeting/cytotoxic antibody), diagnostic and/or prognostic marker, gene therapy (gene delivery/gene ablation), research tools, tissue regeneration in vivo and in vitro of all tissues and cell types composing (but not limited to) those defined here.
  • NOVIO nucleic acids and proteins ofthe invention are useful in potential therapeutic applications implicated in cancer including but not limited to various pathologies and disorders as indicated below.
  • a cDNA encoding the Serine Threonine Kinase-like protein (NOVIO) may be useful in gene therapy, and the Serine Threonine Kinase -like protein (NOVIO) may be useful when administered to a subject in need thereof.
  • compositions ofthe present invention will have efficacy for treatment of patients suffering from Koz-Heghers syndrome, pancreatic cancer, gastrointestinal polyps, renal cancer, multiple endocrine neoplasia type II, familial melanoma, ovarian cancer, Ataxia telangeictasia, neurodegenerative disease comprising Alzheimer's, sepsis, ischemic heart disease, arthritis, disease ofthe immune system, human immunodeficiency virus infection, and other pathologies and conditions.
  • the NOVIO nucleic acid encoding the Serine Threonine Kinase-like protein ofthe invention, or fragments thereof, may further be useful in diagnostic applications, wherein the presence or amount ofthe nucleic acid or the protein are to be assessed.
  • NOVIO nucleic acids and polypeptides are further useful in the generation of antibodies that bind immuno-specifically to the novel NOVIO substances for use in therapeutic or diagnostic methods. These antibodies may be generated according to methods known in the art, using prediction from hydrophobicity charts, as described in the "Anti- NOVX Antibodies" section below.
  • the disclosed NOV10 protein has multiple hydrophilic regions, each of which can be used as an immunogen.
  • a contemplated NOV10 epitope is from about amino acids 5 to 60.
  • a NOV10 epitope is from about amino acids 70 to 370.
  • NOV11 A disclosed NOVl 1 nucleic acid of 1439 nucleotides (also referred to as 191011974) encoding a novel Serine/Threonine-Protein Kinase Pak 5-like protein is shown in Table 1 IC.
  • An open reading frame was identified beginning with an ATG initiation codon at nucleotides 35-37 and ending with a TGA codon at nucleotides 1406-1408.
  • a putative untranslated region upstream from the initiation codon is underlined in Table 1 IC. The start and stop codons are in bold letters.
  • Table 11C NOV11 nucleotide sequence (SEQ ID NO:31).
  • the NOVl 1 nucleic acid sequence, located on chromosome 20 has 1202 of 1204 bases (99%) identical to a gb:GENBANK- ID:AB040812
  • acc:AB040812.1 mRNA from Homo sapiens (Homo sapiens mRNA for protein kinase PAK5, complete eds) (E 8.1e "317 ).
  • Public nucleotide databases include all GenBank databases and the GeneSeq patent database.
  • the disclosed NOVl 1 polypeptide (SEQ ID NO:32) encoded by SEQ ID NO:31 has
  • NOVl 1 418 amino acid residues and is presented in Table 1 ID using the one-letter amino acid code.
  • Signal P, Psort and/or Hydropathy results predict that NOVl 1 has no signal peptide and is likely to be localized in the nucleus with a certainty of 0.7000.
  • NOVl 1 may also be localized to the microbody (peroxisome) with acertainty of 0.3347, the mitochondrial matrix space with a certainty of 0.1000, or in the lysosome (lumen) with a certainty of 0.1000.
  • Table 11D Encoded NOV11 protein sequence (SEQ ID NO:32).
  • NOVl 1 is expressed in at least in the brain. Expression information was derived from the tissue sources ofthe sequences that were included in the derivation ofthe sequence of NOVl 1. The sequence is predicted to be expressed in the brain because ofthe expression pattern of (GENBANK-ID: gb:GENBANK-ID:AB040812
  • the disclosed NOVl 1 polypeptide has homology to the amino acid sequences shown in the BLASTP data listed in Table 1 IC.
  • Tables IE- IF lists the domain description from DOMAIN analysis results against NOVl 1. This indicates that the NOVl 1 sequence has properties similar to those of other proteins known to contain this domain.
  • PAK5 is a member ofthe larger family of p21 -activating kinase (PAK) genes that also includes human PAK1, PAK2, PAK 3 and PAK65, as well as yeast Ste20.
  • PAK proteins are highly conserved in their amino acid sequence, and have been implicated as critical downstream effectors that link Rho GTPases to the actin cytoskeleton and to MAP kinase cascades, including the JUN N-terminal kinase (JNK) and p38.
  • JNK JUN N-terminal kinase
  • Protein Kinase PAK5 -like protein includes the nucleic acid whose sequence is provided in Table 11 A or a fragment thereof.
  • the invention also includes a mutant or variant nucleic acid any of whose bases may be changed from the corresponding base shown in Table 11A while still encoding a protein that maintains its Serine/Threonine-Protein Kinase PAK5-like activities and physiological functions, or a fragment of such a nucleic acid.
  • the invention further includes nucleic acids whose sequences are complementary to those just described, including nucleic acid fragments that are complementary to any ofthe nucleic acids just described.
  • the invention additionally includes nucleic acids or nucleic acid fragments, or complements thereto, whose structures include chemical modifications.
  • modifications include, by way of nonlimiting example, modified bases, and nucleic acids whose sugar phosphate backbones are modified or derivatized. These modifications are carried out at least in part to enhance the chemical stability ofthe modified nucleic acid, such that they may be used, for example, as antisense binding nucleic acids in therapeutic applications in a subject. In the mutant or variant nucleic acids, and their complements, up to about 10% percent ofthe bases may be so changed.
  • the disclosed NOVl 1 protein ofthe invention includes the Serine/Threonine-Protein Kinase PAK5-like protein whose sequence is provided in Table 1 IB.
  • the invention also includes a mutant or variant protein any of whose residues may be changed from the corresponding residue shown in Table 1 IB while still encoding a protein that maintains its Serine/Threonine-Protein Kinase PAK5 -like activities and physiological functions, or a functional fragment thereof. In the mutant or variant protein, up to about 38% percent ofthe residues may be so changed.
  • the invention further encompasses antibodies and antibody fragments, such as F at , or (F ab ) 2 , that bind immunospecifically to any ofthe proteins ofthe invention.
  • NOVl 1 Serine/Threonine- Protein Kinase PAK5-like protein
  • the potential therapeutic applications for this invention include, but are not limited to: protein therapeutic, small molecule drug target, antibody target (therapeutic, diagnostic, drug targeting/cytotoxic antibody), diagnostic and/or prognostic marker, gene therapy (gene delivery/gene ablation), research tools, tissue regeneration in vivo and in vitro of all tissues and cell types composing (but not limited to) those defined here.
  • NOVl 1 nucleic acids and proteins ofthe invention are useful in potential therapeutic applications implicated in cancer including but not limited to various pathologies and disorders as indicated below.
  • a cDNA encoding the Serine/Threonine- Protein Kinase PAK5-like protein (NOVl 1) may be useful in gene therapy, and the Serine/Threonine-Protein Kinase PAK5 -like protein (NOVl 1) may be useful when administered to a subject in need thereof.
  • compositions ofthe present invention will have efficacy for treatment of patients suffering from Von Hippel- Lindau (VHL) syndrome, Alzheimer's disease, Stroke, Tuberous sclerosis, hypercalceimia, Parkinson's disease, Huntington's disease, Cerebral palsy, Epilepsy, Lesch-Nyhan syndrome, Multiple sclerosis, Ataxia-telangiectasia, Leukodystrophies, Behavioral disorders, Addiction, Anxiety, Pain, Neuroprotection, cancer, and other pathologies and conditions.
  • VHL Von Hippel- Lindau
  • NOVl 1 nucleic acid encoding the Serine/Threonine-Protein Kinase PAK5-like protein ofthe invention, or fragments thereof, may further be useful in diagnostic applications, wherein the presence or amount ofthe nucleic acid or the protein are to be assessed.
  • NOVl 1 nucleic acids and polypeptides are further useful in the generation of antibodies that bind immuno-specifically to the novel NOVl 1 substances for use in therapeutic or diagnostic methods. These antibodies may be generated according to methods known in the art, using prediction from hydrophobicity charts, as described in the "Anti- NOVX Antibodies" section below.
  • the disclosed NOVl 1 protein has multiple hydrophilic regions, each of which can be used as an immunogen.
  • a contemplated NOVl 1 epitope is from about amino acids 5 to 70.
  • a NOVl 1 epitope is from about amino acids 80 to 130.
  • a NOVl 1 epitope is from about amino acids 140 to 170, from about amino acids 190 to 260, from about amino acids 290 to 350, from about amino acids 370 to 420, and from about amino acids 430 to 440.
  • a disclosed NOV12 nucleic acid of 5723 nucleotides (also referred to as Curagen Accession No. 56692324_EXT2) encoding a novel Zfpl06-like protein is shown in Table 12 A.
  • An open reading frame was identified beginning with an ATG initiation codon at nucleotides 35-37 and ending with a TGA codon at nucleotides 5714-5716. Putative untranslated regions upstream from the initiation codon and downstream of the termination codon are underlined in Table 12 A. The start and stop codons are in bold letters.
  • Table 12A NOV12 nucleotide sequence (SEQ ID NO:33).
  • the NOVl 2 nucleic acid sequence, located on chromosome 15, has 2057 of 2552 bases (80%) identical to a gb:GENBANK- ID:AF060246
  • acc:AF060246 mRNA from Mus musculus (Mus musculus strain C57BL/6 zinc finger protein 106 (Zfpl06) mRNA, H3a-a allele, complete eds (E 0.0).
  • Public nucleotide databases include all GenBank databases and the GeneSeq patent database.
  • the disclosed NOV12 polypeptide (SEQ ID NO:34) encoded by SEQ ID NO:33 has 1904 amino acid residues and is presented in Table 12B using the one-letter amino acid code.
  • Signal P, Psort and/or Hydropathy results predict that NOVl 2 has no signal peptide and is likely to be localized in the plasma membrane with a certainty of 0.4400.
  • NOVl 2 may also be localized to the mitochondrial inner membrane with acertainty of 0.3558, or in the microbody (peroxisome) with a certainty of 0.3000.
  • Table 12B Encoded NOVl 2 protein sequence (SEQ ID NO:34).
  • Public amino acid databases include the GenBank databases, SwissProt, PDB and PIR.
  • NOVl 2 is expressed in at least the following tissues: Adrenal Gland/Suprarenal gland, Bone, Bone Marrow, Lymph node, Lymphoid tissue, Spleen, Peripheral Blood, Brain (Hypothalamus, Amygdala, Substantia Nigra, Hippocampus), Spinal Cord, Skin (Dennis, Epidermis, Hair Follicles), Heart, Coronary Artery, Umbilical Vein, Liver, Placenta, Small Intestine, Thyroid, Dermis, Epidermis, Foreskin, Kidney, Mammary gland/Breast, Ovary, Pituitary Gland, Testis, Prostate, Thyroid, Tonsils, Urinary Bladder, Adipose, Uterus, Cervix, Chorionic Villus, Duodenum, , Larynx, Muscle, Pancreas (Islets of Langerhans) and Salivary Glands.
  • SeqCalling sources Adrenal Gland/Suprarenal gland, Bone, Bone Marrow, Brain, Dermis, Epidermis, Hair Follicles, Heart, Liver, Placenta, Small Intestine, Spinal Cord, Spleen, Thyroid, Bone Marrow, Foreskin, Hippocampus, Kidney, Liver, Lymph node, Lymphoid tissue, Mammary gland/Breast, Ovary, Peripheral Blood, Pituitary Gland, Testis, Thyroid, Tonsils, Umbilical Vein, Urinary Bladder, Adipose, Amygdala, Cervix, Chorionic Villus, Coronary Artery, Duodenum, Hypothalamus, Islets of Langerhans, Larynx, Muscle, Ovary, Pancreas, Prostate, Salivary Glands, Spleen, Substantia Nigra,
  • sequence is predicted to be expressed in the following tissues because ofthe expression pattern of (GENBANK-ID: gb:GENBANK-ID:AF060246
  • GfplO ⁇ ⁇ Mus musculus strain C57BL/6 zinc finger protein 106
  • the disclosed NOVl 2 polypeptide has homology to the amino acid sequences shown in the BLASTP data listed in Table 12C.
  • ll protein 106 [Homo (93%) (93%) sapiens] gi I 3372651
  • ll (AF060244) protein 106 [Mus (94%) (97%) musculus]
  • ref APDSSVQIKQEPMSP -7.02 gi 111968023 jref APDSSVQIKQEPMSP giJ337265l
  • Tables 12E-12H lists the domain description from DOMAIN analysis results against NOVl 2. This indicates that the NOVl 2 sequence has properties similar to those of other proteins known to contain this domain.
  • Zfp-106 is a mouse gene that has been determined to be the immunodominant cytotoxic determinant ofthe mouse H3 minor histocompatibility complex. Minor histocompatibility antigens contribute to graft versus host disease in solid tissue and bone marrow transplantations when donor and recepient are matched for the major histocompatibility complex.
  • Zfp-106 is a protein containing zinc finger motifs, that are a characteristic of DNA-binding ability, as well as WD repeats, that enable protein-protein interactions. In addition, it also contains a region nearly identical to a protein called SIRM (Son of Insulin Receptor Mutant), a protein isolated from insulin receptor null mice.
  • SIRM Seson of Insulin Receptor Mutant
  • SIRM has been demonstrated to be involved in the insulin receptor signaling pathway by binding to FYN and Grb-2 and to be phosphorylated by FYN kinase. It is likely that SIRM represents an alternatively spliced form of Zfpl06.
  • the protein of invention may therefore be useful in the treatment of graft versus host disease and diabetes.
  • the disclosed NOV 12 nucleic acid ofthe invention encoding a ZFP-106 -like protein includes the nucleic acid whose sequence is provided in Table 12A or a fragment thereof.
  • the invention also includes a mutant or variant nucleic acid any of whose bases may be changed from the corresponding base shown in Table 12 A while still encoding a protein that maintains its ZFP-106-like activities and physiological functions, or a fragment of such a nucleic acid.
  • the invention further includes nucleic acids whose sequences are complementary to those just described, including nucleic acid fragments that are complementary to any ofthe nucleic acids just described.
  • the invention additionally includes nucleic acids or nucleic acid fragments, or complements thereto, whose structures include chemical modifications. Such modifications include, by way of nonlimiting example, modified bases, and nucleic acids whose sugar phosphate backbones are modified or derivatized.
  • modifications are carried out at least in part to enhance the chemical stability ofthe modified nucleic acid, such that they may be used, for example, as antisense binding nucleic acids in therapeutic applications in a subject.
  • the mutant or variant nucleic acids, and their complements up to about 10% percent ofthe bases may be so changed.
  • the disclosed NOV 12 protein ofthe invention includes the ZFP-106-like protein whose sequence is provided in Table 12B.
  • the invention also includes a mutant or variant protein any of whose residues may be changed from the corresponding residue shown in Table 12B while still encoding a protein that maintains its ZFP-106 -like activities and physiological functions, or a functional fragment thereof. In the mutant or variant protein, up to about 38% percent ofthe residues may be so changed.
  • the invention further encompasses antibodies and antibody fragments, such as F ab or (F ab ) 2 , that bind immunospecifically to any ofthe proteins ofthe invention.
  • NOV 12 ZFP-106-like protein
  • ZFP-106 family ZFP-106-like protein
  • the NOV 12 nucleic acids and proteins identified here may be useful in potential therapeutic applications implicated in (but not limited to) various pathologies and disorders as indicated below.
  • the potential therapeutic applications for this invention include, but are not limited to: protein therapeutic, small molecule drug target, antibody target (therapeutic, diagnostic, drug targeting/cytotoxic antibody), diagnostic and/or prognostic marker, gene therapy (gene delivery/gene ablation), research tools, tissue regeneration in vivo and in vitro of all tissues and cell types composing (but not limited to) those defined here.
  • NOVl 2 nucleic acids and proteins ofthe invention are useful in potential therapeutic applications implicated in cancer including but not limited to various pathologies and disorders as indicated below.
  • a cDNA encoding the ZFP-106-like protein (NOV 12) may be useful in gene therapy, and the ZFP-106 -like protein (NOV 12) may be useful when administered to a subject in need thereof.
  • compositions ofthe present invention will have efficacy for treatment of patients suffering from graft versus host disease, diabetes, cardiomyopathy, atherosclerosis, hypertension, congenital heart defects, aortic stenosis , atrial septal defect (ASD), atrioventricular (A-V) canal defect, ductus arteriosus , pulmonary stenosis , subaortic stenosis, ventricular septal defect (VSD), valve diseases, tuberous sclerosis, scleroderma, obesity, transplantation, aneurysm, hypertension, fibromuscular dysplasia, stroke, adrenoleukodystrophy , congenital adrenal hyperplasia, Von Hippel-Lindau (VHL) syndrome , pancreatitis, hyperthyroidism, hypothyroidism, endometriosis, infertility, cirrhosis, hemophilia, hypercoagulation, idiopathic thrombocyto
  • NOV 12 nucleic acids and polypeptides are further useful in the generation of antibodies that bind immuno-specifically to the novel NOV 12 substances for use in therapeutic or diagnostic methods. These antibodies may be generated according to methods known in the art, using prediction from hydrophobicity charts, as described in the "Anti- NOVX Antibodies" section below.
  • the disclosed NOV 12 protein has multiple hydrophilic regions, each of which can be used as an immunogen.
  • a contemplated NOV12 epitope is from about amino acids 50 to 850.
  • a NOV12 epitope is from about amino acids 900 to 1000.
  • a NOV12 epitope is from about amino acids 1050 to 1150, from about amino acids 1200 to 1550, and from about amino acids 1800 to 1900.
  • NOVl 3 includes three novel Sex -Determination Protein Homolog FEMlA-like proteins disclosed below. The disclosed sequences have been named NOV13a, NOV13b, and NOV 13c.
  • a disclosed NOV 13a nucleic acid of 2010 nucleotides also referred to as Curagen Accession No. sggc_draft_bal86ml2_20000824_dal
  • Table 13 A An open reading frame was identified beginning with an ATG initiation codon at nucleotides 1-3 and ending with a TGA codon at nucleotides 2008-2010. The start and stop codons are in bold letters in Table 13 A.
  • Table 13A NOV13a nucleotide sequence (SEQ ID NO:35).
  • the NOV13a nucleic acid sequence, located on chromosome 17, has 1449 of 2007 bases (72%) identical to a gb :GENBANK- ID:AF064447
  • acc:AF064447.1 mRNA from Mus musculus (Mus musculus sex-determination protein homolog Femla gene, complete eds (E 1.2e "183 ).
  • Public nucleotide databases include all GenBank databases and the GeneSeq patent database.
  • NOV13a polypeptide (SEQ ID NO 36) encoded by SEQ ID NO:35 has 669 amino acid residues and is presented in Table 13B using the one-letter amino acid code.
  • Signal P, Psort and/or Hydropathy results predict that NOV 13a has no signal peptide and is likely to be localized in the cytoplasm with a certainty of 0.6500.
  • NOVl 3 A may also be localized to the lysosome (lumen) with acertainty of 0.1689, or in the mitochondrial membrane space with a certainty of 0.1000.
  • Table 13B Encoded NOV13a protein sequence (SEQ ID NO:36).
  • Public amino acid databases include the GenBank databases, SwissProt, PDB and P1R.
  • a disclosed NOV 13b nucleic acid of 2010 nucleotides also referred to as Curagen Accession No. sggc_draft_bal86ml2_20000824_da2 encoding a novel Sex -Determination Protein Homolog FEMlA-like protein is shown in Table 13C.
  • An open reading frame was identified beginning with an ATG initiation codon at nucleotides 1-3 and ending with a TGA codon at nucleotides 2008-2010.
  • a putative untranslated region upstream from the initiation codon is underlined in Table 13C. The start and stop codons are in bold letters.
  • Table 13C NOV13b nucleotide sequence (SEQ ID NO:37).
  • the NOV 13b nucleic acid sequence, located on chromosome 17, has 1447 of 2007 bases (72%) identical to a gb:GENBANK- ID:AF064447
  • acc:AF064447.1 mRNA from Mus musculus (Mus musculus sex-determination protein homolog Femla gene, complete eds (E 7.5e " ).
  • Public nucleotide databases include all GenBank databases and the GeneSeq patent database.
  • NOVl 3b polypeptide (SEQ ID NO:38) encoded by SEQ ID NO:37 has 669 amino acid residues and is presented in Table 13D using the one-letter amino acid code.
  • Signal P, Psort and/or Hydropathy results predict that NOV 13b has no signal peptide and is likely to be localized in the cytoplasm with a certainty of 0.6500.
  • NOV13B may also be localized to the lysosome (lumen) with acertainty of 0.1715, or in the mitochondrial membrane space with a certainty of 0..1000.
  • Table 13D Encoded NOVl 3b protein sequence (SEQ ID NO:38).
  • NOV 13 is expressed in at least the following tissues: Brain, Colon, Eye, Germ Cell, Heart, Kidney, Lung, Marrow, Muscle, Ovary, Pancreas, Parathyroid, Prostate, Spleen, Testis, Tonsil, Uterus, Breast, Cervix, Colon, Head_neck, Kidney, muscle, Prostate_tumor, Skin, Melanotic Melanoma, skeletal muscle
  • a disclosed NOV13c nucleic acid of 2010 nucleotides also referred to as Curagen Accession No. CGI 18840-02 encoding a novel Sex-Determination Protein Homolog FEMlA-like protein is shown in Table 13E.
  • An open reading frame was identified beginning with an ATG initiation codon at nucleotides 1-3 and ending with a TGA codon at nucleotides 2008-2010.
  • a putative untranslated region upstream from the initiation codon is underlined in Table 13E. The start and stop codons are in bold letters.
  • the disclosed NOV 13c polypeptide (SEQ ID NO:40) encoded by SEQ ID NO:39 has 669 amino acid residues and is presented in Table 13F using the one-letter amino acid code.
  • Signal P, Psort and or Hydropathy results predict that NOV13c has no signal peptide and is likely to be localized in the cytoplasm with a certainty of 0.6500.
  • SEQ ID NO:40 The disclosed NOV 13c polypeptide encoded by SEQ ID NO:39 has 669 amino acid residues and is presented in Table 13F using the one-letter amino acid code.
  • Signal P, Psort and or Hydropathy results predict that NOV13c has no signal peptide and is likely to be localized in the cytoplasm with a certainty of 0.6500.
  • NOV13C may also be localized to the lysosome (lumen) with acertainty of 0.1703, or in the mitochondrial membrane space with a certainty of 0.1000.
  • Table 13F Encoded NOV13c protein sequence (SEQ ID NO:40).
  • Public amino acid databases include the GenBank databases, SwissProt, PDB and PIR. NOVl 3c is expressed in at least the following tissues: Heart, Umbilical Vein, Adrenal
  • Gland Suprarenal gland Pancreas, Parathyroid Gland, Thyroid, Liver, Colon, Bone Marrow, Peripheral Blood, Spleen, Tonsils, Thymus, Bone, Cartilage, Synovium Synovial membrane, Muscle, Skeletal Muscle, Brain, Temporal Lobe, Amygdala, Cerebral Medulla/Cerebral white matter, Spinal Chord, Mammary gland/Breast, Ovary, Placenta, Uterus, Vulva, Prostate, Testis, Lung, Kidney, Retina, Skin, Dermis. Expression information was derived from the tissue sources ofthe sequences that were included in the derivation ofthe sequence of CuraGen Ace. No.
  • CGI 18840-02. The sequence is predicted to be expressed in Kidney and renal cell adenocarcinoma because ofthe expression pattern of (GENBANK-ID: gb:GENBANK-ID:BC004988
  • the disclosed NOVl 3a polypeptide has homology to the amino acid sequences shown in the BLASTP data listed in Table 13G.
  • Tables 13I-13L lists the domain description from DOMAIN analysis results against NOVl 3. This indicates that the NOV 13 sequence has properties similar to those of other proteins known to contain this domain.

Abstract

Cette invention concerne des séquences d'acides nucléiques codant pour des nouveaux polypeptides. L'invention concerne également des polypeptides codés par ces séquences d'acides nucléiques, et des anticorps se liant immunospécifiquement au polypeptides, ainsi que des dérivés, variants, mutants ou fragments du polypeptide, polynucléotide ou anticorps susmentionnés. Par ailleurs, l'invention concerne des méthodes thérapeutiques, diagnostiques et de recherche pour le diagnostic, le traitement et la prévention de troubles en rapport avec l'un quelconque de ces nouveaux acides nucléiques humains ou l'une quelconque de ces nouvelles protéines humaines.
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US9822171B2 (en) 2010-04-15 2017-11-21 AbbVie Deutschland GmbH & Co. KG Amyloid-beta binding proteins
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US10208109B2 (en) 2005-11-30 2019-02-19 Abbvie Inc. Monoclonal antibodies against amyloid beta protein and uses thereof
US10464976B2 (en) 2003-01-31 2019-11-05 AbbVie Deutschland GmbH & Co. KG Amyloid β(1-42) oligomers, derivatives thereof and antibodies thereto, methods of preparation thereof and use thereof
US10538581B2 (en) 2005-11-30 2020-01-21 Abbvie Inc. Anti-Aβ globulomer 4D10 antibodies
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US10464976B2 (en) 2003-01-31 2019-11-05 AbbVie Deutschland GmbH & Co. KG Amyloid β(1-42) oligomers, derivatives thereof and antibodies thereto, methods of preparation thereof and use thereof
US10208109B2 (en) 2005-11-30 2019-02-19 Abbvie Inc. Monoclonal antibodies against amyloid beta protein and uses thereof
US10323084B2 (en) 2005-11-30 2019-06-18 Abbvie Inc. Monoclonal antibodies against amyloid beta protein and uses thereof
US10538581B2 (en) 2005-11-30 2020-01-21 Abbvie Inc. Anti-Aβ globulomer 4D10 antibodies
US9951125B2 (en) 2006-11-30 2018-04-24 Abbvie Inc. Aβ conformer selective anti-Aβ globulomer monoclonal antibodies
US9822171B2 (en) 2010-04-15 2017-11-21 AbbVie Deutschland GmbH & Co. KG Amyloid-beta binding proteins
US9062101B2 (en) 2010-08-14 2015-06-23 AbbVie Deutschland GmbH & Co. KG Amyloid-beta binding proteins
US10047121B2 (en) 2010-08-14 2018-08-14 AbbVie Deutschland GmbH & Co. KG Amyloid-beta binding proteins
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CN111465857A (zh) * 2017-08-08 2020-07-28 昆士兰科技大学 诊断早期心力衰竭的方法

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