Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
1999-10-01
2004-06-01
Nickol, Gary B. (Department: 1642)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C536S024100, C536S024200, C514S04400A
Reexamination Certificate
active
06743906
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to the fields of oncology, genetics and molecular biology. More particular the invention relates to the identification, on human chromosome 11, of a tumor suppressor gene. Defects in this gene are associated with the development of cancers, such as lung carcinoma.
2. Description of Related Art
Oncogenesis was described by Foulds (1958) as a multistep biological process, which is presently known to occur by the accumulation of genetic damage. On a molecular level, the multistep process of tumorigenesis involves the disruption of both positive and negative regulatory effectors (Weinberg, 1989). The molecular basis for human colon carcinomas has been postulated, by Vogelstein and coworkers (1990), to involve a number of oncogenes, tumor suppressor genes and repair genes. Similarly, defects leading to the development of retinoblastoma have been linked to another tumor suppressor gene (Lee et al., 1987). Still other oncogenes and tumor suppressors have been identified in a variety of other malignancies. Unfortunately, there remains an inadequate number of treatable cancers, and the effects of cancer are catastrophic—over half a million deaths per year in the United States alone.
Lung cancer is one of the most fatal and frequent human cancers in the United States (Parker et al., 1997). Identification of the multiple tumor-suppressor genes involved in pathogenesis of lung cancer is a critical step in the development of new diagnostic methods and tumor-specific treatments. A large body of evidence suggests that chromosome 11 may harbor at least one tumor-suppressor gene(s) involved in lung cancer (Rasio et al., 1995) and a variety of other cancers including colon (Gustafson et al., 1994), breast (Carter et al., 1994), cervical (Hampton et al., 1994), head and neck (El-Naggar et al., 1996), ovarian cancers (Davis et al., 1996) and melanoma (Tomlinson et al., 1996). That this region of the chromosome has suppressor oncogene activity has been shown by the introduction of a normal chromosome 11, or a derivative t(X,11) chromosome containing 11pter-q23, into tumorigenic cells lines reversing the tumorigenic potential. Tumor suppressing activity has been demonstrated on chromosome 11q23 using lung (Satoh et al., 1993), Wilms tumor (Weissman et al., 1987), breast (Negrini et al., 1994) and cervical carcinoma cell lines (Saxon et al., 1986).
Since allelic loss of chromosome 11q22-24 has been implicated in a variety of cancers, significant effort has been applied to detailed mapping of this region of the genome using polymorphic markers. Using this approach, it has been possible to define a common and restricted region of loss of heterozygosity (LOH) region between markers STMY1 at 11q22 and ApoC3 at 11q23 in these neoplasms (Arai et al., 1996). These studies suggest the presence of functional tumor-suppressor gene(s) on chromosome 11q22-q24 localized centromeric to the t(X;11) translocation breakpoint at 11q23.
Despite all of this information, the identity of the gene (or genes) involved with the 11q23-related tumor suppression remains elusive. Without identification of a specific gene and deduction of the protein for which it codes, it is impossible to begin developing an effective therapy targeting this product. Thus, it is an important goal to isolate the tumor suppressor(s) located in this region and determine its structure and function.
SUMMARY OF THE INVENTION
In specific embodiments, the present invention provides an isolated polynucleotide comprising a region, or the complement thereof, encoding a tumor suppressor designated PPP2R1B or an allelic variant or mutant thereof. More particularly, the tumor suppressor coding region is selected from the group consisting of Xenopus, porcine and human. In yet more preferred embodiments, the tumor suppressor coding region is human. In those embodiments in which the polynucleotide is a mutant tumor suppressor, the mutant may comprise a deletion mutation, an insertion mutation, a frameshift mutation, a nonsense mutation, a missense mutation or splice mutation. In certain embodiments, the mutant is a splice mutant. More specifically, the splice mutation is in intron 8. In more defined embodiments, the splice mutation results from a mutation in intron 8.
Yet another preferred embodiments contemplated is one in which the mutation is a change from A
1540
to G
1540
as compared to the wild-type tumor suppressor. More particularly, the mutation results in a change from ASP to GLY at position 504 of the tumor suppressor. In specific embodiments, the mutation results in a change from a loss of heterozygosity. More specific embodiments contemplate a mutation that results in a change from G
51
to C
51
in the tumor suppressor. In yet another embodiment, the mutation results in a change from GLY to ARG at amino acid residue 8 of the tumor suppressor. In certain other embodiments, the mutation is a germline mutation. In yet another embodiments, the mutation is a change from G
298
to A
298
in the tumor suppressor. More particularly, the mutation results in a change from GLY to ASP at amino acid 90 of the tumor suppressor. In another contemplated embodiment, the mutation is a change from A
1056
to G
1056
in the tumor suppressor. Also contemplated is a mutation that results in a change from LYS to GLU at amino acid 343 of the tumor suppressor. In another example, the mutation is a change from C
222
to T
222
in the tumor suppressor. Yet a further mutation results in a change from PRO to SER at amino acid 65 of the tumor suppressor. In still another embodiments, the mutation is a change from T
1663
to C
1663
in the tumor suppressor. An additional mutation results in a change from VAL to ALA at amino acid 545 of the tumor suppressor. Another mutation is one in which there is a change from T
331
to C
331
in the tumor suppressor. Another specific embodiments is one in which the mutation results in a change from LEU to PRO at amino acid 101 of the tumor suppressor. Yet another mutation is a change from T
1372
to C
1372
in the tumor suppressor. More particularly, the mutation results in a change from VAL to ALA at amino acid 448 of the tumor suppressor. In specific embodiments, the mutation is an in-frame deletion of bases 717 to 1583. More particularly this mutation results in a truncated tumor suppressor expression. Yet more specifically, the truncated tumor suppressor lacks amino acids 230 to 518 of the wild-type tumor suppressor. In specific embodiments, the mutation is a deletion of nucleotides 1584 through to 1726. In other embodiments, the mutation results in a frameshift in tumor suppressor expression. In still another embodiments, the tumor suppressor has a frameshift between amino acids 519 and 601. In certain embodiments, the mutation is a deletion of nucleotides 1057 to 1191. More particularly, the mutation results in a truncated tumor suppressor expression. Specifically, the truncated tumor suppressor may lack amino acids 344 to 388 of the wild-type tumor suppressor. In other particularly preferred embodiments, the mutation is a deletion of nucleotides 1315 through to 1505. More particularly, the mutation results in a frameshift in tumor suppressor expression. Yet more particularly, the tumor suppressor has a frameshift between amino acids 422 and 601.
In specific embodiments, the tumor suppressor has the amino acid sequence of SEQ ID NO:1. In other embodiments, the tumor suppressor has the amino acid sequence of SEQ ID NO:2. In yet a further embodiments, the polynucleotide sequence comprises the coding sequence of SEQ ID NO:4 or the complement thereof. In certain specific embodiments, the polynucleotide sequence comprises a porcine PPP2R1B or the complement thereof. In other exemplary embodiments, the polynucleotide sequence comprises a Xenopus PPP2R1B or the complement thereof. In particularly defined embodiments, the polynucleotide may be selected from the group consisting of genomic DNA, complementary DNA and RNA. More particularly, the polynucleotide ma
Esplin Edward D.
Evans Glen A.
Huang Liying
Li Jia Ling
Wang Steven Siqing
Board of Regents The University of Texas
Fulbright & Jaworski
Nickol Gary B.
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