Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
1999-01-20
2001-10-23
Ungar, Susan (Department: 1642)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C435S320100, C435S252300, C435S069100
Reexamination Certificate
active
06307035
ABSTRACT:
FIELD OF THE INVENTION
This invention relates generally to the field of genes associated with cancers, and particularly, to BRCA1.
BACKGROUND OF THE INVENTION
The breast and ovarian cancer susceptibility gene, BRCA1, is linked to the hereditary form of breast cancer. The BRCA1 gene is located on chromosome 17 at the locus 17q21 and encodes a protein of 1863 amino acids. The BRCA 1 locus spans >100 kb comprising 24 exons [Miki et al,
Science
, 266:66-71 (1994)]. Expression of wild-type BRCA 1 inhibits colony function and tumor growth in vivo, whereas tumor derived mutations of BRCA 1 abolish this growth suppression [Holt et al,
Nature Genetics
, 12:298-302 (1996)]. Germline mutations in BRCA 1 appear to account for 50% of familial breast cancers and essentially all families with 17q21-linked inherited susceptibility to ovarian and breast cancer [Szabo et al,
Hum. Mol. Genet
., 4:1811-1817 (1995); Hall et al,
Science
, 250:1684-1689 (1990); Easton et al,
Am. J. Hu. Genet
., 56:265-271 (1995); Narod et al,
Am. J. Hu. Genet
., 56:254-264 (1995)]. Kindreds segregating constitutive BRCA1 mutations show a lifetime risk of 40-50% for ovarian cancer and >80% for breast cancer [Easton et al,
Am. J. Hum. Genet
., 52:678-701 (1993); Easton et al,
Am. J. Hum. Genet
., 56:265-271 (1995)].
The classification of BRCA 1 as a highly penetrant, autosomal dominant tumor suppressor gene has been genetically confirmed by the finding of frequent loss or mutation (LOH) of the wild-type allele in breast tumors from mutation carriers [Hall et al,
Science
, 250:1684-1689 (1990); Miki et al, cited above; Smith et al,
Nature Genetics
, 2:128-131 (1992)]. Surprisingly, BRCA 1 mutations in sporadic breast cancer including those which show LOH have yet to be found and are extremely rare in sporadic ovarian cancer [Futreal et al,
Science
, 266:120-122 (1994); Merajver et al,
Nature Genetics
, 9:439-443 (1995)].
Although the BRCA1 protein resembles no known protein, it does contain a RING domain at its amino terminus [Miki, cited above; Bienstock et al,
Cancer Res
., 56:2539-2545 (1996)]. The RING finger domain is a complicated structure which chelates two zinc atoms using 7 Cys residues and 1 His residue [C
3
HC
4
; Lovering et al,
Proc. Natl. Acad. Sci. USA
, 90:2112-2116 (1993); Freemont et al,
Ann. NY Acad. Sci
., 684:174-192 (1993)]. This domain is present in a wide variety of proteins with various functions, but the function of the RING finger domain within these proteins is unknown [for a review see Saurin,
Trends in Biochem. Sci
., 21:208-214 (1996)]. The RING finger of BRCA1 is important to its function since missense mutations in the RING domain (Cys61Gly and Cys64Gly) are found in breast/ovarian kindreds [Friedman et al,
Nat. Genet
., 8:399-404 (1994); Merajver, cited above; Castilla et al,
Nature Genet
., 8:387-391 (1994)]. In addition, the RING finger domain is the most conserved region of BRCA1, when comparing the human, mouse and rat proteins. The BRCA1 RING finger is anticipated to be a binding site for protein(s) which either mediate BRCA1 tumor suppressor function or serve to regulate these functions. Genetic evidence supports this in that single amino-acid substitutions at metal chelating cysteines, C61G and C64G, occur in kindreds; these mutations segregate with the disease susceptibility phenotype and are predicted to abolish RING finger structure.
Other functions of BRCA1 are discussed in the following references which are incorporated herein by reference: Borden et al,
EMBO J
., 14:1532-1541 (1995); Lovering et al,
Proc. Natl. Acad. Sci. USA
, 90:2112-2116 (1993); Koonin et al,
Nature Genet
., 13:266-268 (1996); Chen et al,
Science
, 270:789-791 (1995); Chen et al,
Cancer Research
, 56:3168-3172 (1996); Scully et al,
Science
, 272:123-126 (1996); Thakur et al,
Molecular
&
Cellular Biology
, 17:444-452 (1997); Scully et al,
Cell
, 88:265-275 (1997); Chapman et al,
Nature
, 382:678-679 (1996); Scully et al,
Proc. Natl. Acad. Sci. USA
, 94:5605-5610 (1997); Marquis et al,
Nature Genetics
, 11:17-26 (1995); Gudas et al,
Cancer Res
., 55:4561-4565 (1995); Gudas et al,
Cell Growth and Differentiation
, 7:717-723 (1996); Vaughn et al,
Cell Growth and Differentiation
, 7:711-715 (1996); Marks et al,
Oncogene
, 14:115-121 (1997); Zabludoff et al,
Oncogene
, 13:649-653 (1996); Hakem et al,
Cell
, 85:1009-1023 (1996); Liu et al,
Genes
&
Development
, 10:1835-1843 (1996); Rao et al,
Oncogene
, 12:523-528 (1996); Thompson et al,
Nature Genetics
, 9:444-450 (1995); Chen et al,
J. Biol. Chem
., 271:32863-32868 (1996); Wu et al,
Nature Genetics
, 14:430-440 (1996); Klug et al,
FASEB Journal
, 9:597-604 (1995); Saurin et al,
Trends in Biochem. Sci
., 21:208-214 (1996); Friedman et al,
Genes
&
Development
, 10:2067-2078 (1996); Neuhausen & Marshall,
Cancer Res
., 54:6069-6072 (1994); Schildkraut et al,
Am. J. Obstet. Gynecol
., 172:908-913 (1995); FitzGerald et al,
N. Engl. J. Med
., 334:143-149 (1996); Ford et al,
Lancet
, 343:692-695 (1994); Muto et al,
Cancer Research
, 56:1250-1252 (1996); Rao et al,
Nature Genetics
, 14:185-187 (1996), Struewing et al,
Nature Genetics
, 11:198-200 (1995); Couch et al,
Human Mutation
, 8:8-18 (1996); Holt et al,
Nature Genetics,
12:298-302 (1996); Jensen et al,
Nature Genetics
, 12:303-308 (1996); Bradley & Sharan,
Nature Genetics
, 13:268-271 (1996).
There is a need in the art for compositions and methods useful in the treatment and/or prophylaxis of cancers caused by loss of, and mutations in, BRCA1.
SUMMARY OF THE INVENTION
The present invention meets the needs in the art by identifying a novel mammalian BRCA1 Associated Protein (BAP-1) and nucleic acid sequences encoding same. BAP1 is the first nuclear-localized ubiquitin carboxy-terminal hydrolase to be identified and is a new tumor suppressor gene which functions in the BRCA1 growth control pathway. Compositions, both diagnostic and therapeutic, based on this newly identified protein are provided herein.
Thus, in one aspect, the present invention provides a nucleic acid sequence, which is isolated from cellular materials with which it is naturally associated. The nucleic acid sequence is preferably selected from SEQ ID NO:1, or a fragment thereof. Such a fragment may have a specified biological function as discussed below, or may encode a peptide having a similar biological function as the intact BAP-1. Homologous nucleotide sequences, and modified nucleotide sequences which encode peptides or proteins which have a similar biological function as the intact BAP-1, are also included in this aspect of the invention.
In another aspect, the present invention provides a mammalian BRCA1 associated protein (BAP-1). In one preferred embodiment, the protein is human and has the amino acid sequence of SEQ ID NO:2. In another embodiment a fragment of the SEQ ID NO:2 encodes a peptide having a similar biological function as the intact BAP-1 protein. Amino acid sequences homologous to SEQ ID NO: 2, and modified amino acid sequences of SEQ ID NO: 2, which encode peptides or proteins which have a similar biological function as the intact BAP-1 or a specified biological function as discussed below, are also included in this aspect of the invention.
In yet another aspect, the present invention provides a polynucleotide molecule, for example, a vector or plasmid, that comprises a mammalian BAP-1 nucleic acid sequence as defined herein under the control of suitable sequences which direct and regulate expression of the BAP-1 nucleic acid sequence.
In a further aspect, the present invention provides a host cell transformed with a polynucleotide molecule or vector of the invention.
In yet a further aspect, the present invention provides a method of recombinantly expressing BAP-1 or a peptide fragment thereof, by culturing a recombinant host cell according to the invention under conditions which permit expression of BAP-1 or a fragment thereof.
In still a further aspect,
Jensen David E.
Rauscher, III Frank J.
Howson and Howson
The Wistar Institute of Anatomy and Biology
Ungar Susan
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