Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
1999-12-22
2001-12-18
Schwartzman, Robert A. (Department: 1632)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C536S023100, C435S320100, C435S325000
Reexamination Certificate
active
06331614
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates generally to the field of human genetics. Specifically, the present invention relates to human CDC14A gene which has been found to be mutated in certain tumor cell lines. More specifically, the invention relates to a novel sequence for the human CDC14A gene. The present invention further relates to somatic mutations in the CDC14A gene in human cancer and their use in the diagnosis and prognosis of human cancer. The invention also relates to the therapy of human cancers which have a mutation in the CDC14A gene, including gene therapy, protein replacement therapy and protein mimetics. The invention further relates to the screening of drugs for cancer therapy. Finally, the invention relates to the screening of the CDC14A gene for mutations, which are useful for diagnosing the predisposition to cancer.
The publications and other materials used herein to illuminate the background of the invention, and in particular, cases to provide additional details respecting the practice, are incorporated herein by reference, and for convenience, are referenced by author and date in the following text and respectively grouped in the appended List of References.
BACKGROUND OF THE INVENTION
Tumorigenesis is a multistep process that involves loss of function in tumor suppressor genes and gain of function in oncogenes. Genetic and molecular studies in the past several years have contributed significantly to the identification and isolation of numerous tumor suppressor genes from many types of cancer (Brown and Solomon, 1997). Characterization of these genes have revealed that the products they encode participate in a variety of biochemical pathways including cell cycle regulation, cell adhesion, DNA repair, transcription, RNA processing, apoptosis, and signal transduction.
It is well established that some protein kinases acting as oncoproteins in signal transduction pathways perturb normal cell growth and cell proliferation. An excessive increase in phosphorylation activity is one mechanism by which a cell is transformed. Phosphatases are proteins that antagonize the phosphorylation activities of kinases, hence they have been postulated to suppress cancer development (Parsons, 1998). The role of a phosphatase as a tumor suppressor in cancer has not been documented until the recent discovery of MMAC1/PTEN and PPP2R1B (Steck et al, 1997; Li et al, 1997; Wang et al, 1998). The MMAC1/PTEN gene encodes a dual-specificity phosphatase that appears to be involved in signal transduction by dephosphorylating phosphatidylinositol 3,4,5-triphosphate, a lipid component that is involved in cell growth signaling (Maehama and Dixon, 1998). Its loss of function is associated with a wide spectrum of human tumor types including glioma, carcinoma of breast, prostate and endometrium. PPP2R1B gene encodes the beta isoform of the A subunit of serine/threonine protein phosphatase 2A that is mutated in human lung and colon tumors (Wang et al, 1998). Its putative tumor suppressor activity may be exerted through cell cycle regulation or cell growth control. On contrary to the tumor suppression function of MMAC1/PTEN and PPP2R1B, another class of phosphatases, CDC25A and B, have been shown to be oncogenic (Galaktionov et al, 1995). A function of CDC25 is to activate cyclin-dependent kinases which are positive effectors of cell growth. Overexpression of CDC25B have been detected in primary breast cancer (Galaktionov et al, 1995).
It has been amply demonstrated that different members of the same tumor suppressor gene family are targeted for mutation during cancer development. For examples, TP53 and p51 in the p53 family (Osada et al, 1998); RB and p130 in the retinoblastoma family (Helin et al, 1997); Smad 2 and 4 in the Smad family (Eppert et al, 1996; Hahn et al, 1996; Howe et al, 1998); cadE and cadH in the cadherin family (Miki et al, 1997; Hiraguri et al, 1998; Guilford et al, 1998; Sato et al, 1998) are mutated in either primary tumors or tumor cell lines. It is therefore plausible that members in the MMAC1/PTEN phosphatase gene family may be targeted. Recently a human homolog to yeast CDC14 has been cloned and shown to share homology with the phosphatase domain and ser/thr rich C-terminal domain of MMAC1/PTEN (Li et al, 1997). Human CDC14 A is a dual-specificity phosphatase which can functionally complement a yeast strain that carries a cdc14-1
ts
allele (Li et al, 1997). Under certain conditions, human MMAC1/PTEN can also complement the same yeast temperature sensitive strain (Li et al, 1997). A similarity in structural and functional relationship implies that these phosphatases may target common substrates that are involved in the process of tumor suppression.
Loss of tumor suppressor gene activity could occur through a number of mechanisms, such as homozygous deletions, point or frameshift mutations, or loss of expression. We examined a panel of 138 tumor cell lines for homozygous deletions and sequence alterations in the CDC14 A gene. We have identified an acceptor splice site mutation that causes deletion of exon 13 in the breast cell line MDA-MB-436.
SUMMARY OF THE INVENTION
The present invention relates generally to the field of human genetics. Specifically, the present invention relates to human CDC14A gene which has been found to be mutated in certain tumor cell lines. More specifically, the invention relates to a novel sequence for the human CDC14A gene. The present invention further relates to somatic mutations in the CDC14A gene in human cancer and their use in the diagnosis and prognosis of human cancer. The invention also relates to the therapy of human cancers which have a mutation in the CDC14A gene, including gene therapy, protein replacement therapy and protein mimetics. The invention further relates to the screening of drugs for cancer therapy. Finally, the invention relates to the screening of the CDC14A gene for mutations, which are useful for diagnosing the predisposition to cancer.
REFERENCES:
GenBank Accession No. AF064102, L. Hao et al., Aug. 1999, 1153.*
Li et al, 1997, J. Biol. Chem., 272(47): 29403-29406.*
Wong et al, 1999, Genomics, 59(2): 248-251.
Tavtigian Sean V.
Teng David H.-F.
Wong Alexander K. C.
Myriad Genetics Inc.
Paras, Jr. Peter
Rothwell Figg Ernst & Manbeck
Schwartzman Robert A.
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