This proposal seeks to investigate the role of p53 abnormalities in the carcinogenesis and progression of CaP. The applicants found p53 alterations in 31% of 110 localized prostate cancers. Two key functions of the p53 gene are the control of the cell cycle and apoptosis. What now must be determined are the biological effects of different p53 mutations, such as those found by the applicants. The applicants will characterize the biological properties of the mutations they discovered. A yeast assay (FASAY) will be used to determine which p53 mutations are loss-of-function mutations. These will be tranfected into the p53-null SAOS-2 and murine 10(1) cell lines to identify gain of function activities as demonstrated by increased numbers of colonies in soft agar, transactivation of the MDR-1 promoter, and alteration of cell cycle progression as measured by flow cytometry. A subset of gain of function mutation will be analyzed in the p53-null prostate cancer cell line PC3. Whether dominant negative activity is present in these loss of function mutations will be tested in a modified yeast assay. If Class I mutations are found by this method, they will be transfected into the LNCaP cell line, and the response of the transfected cells to radiation will be determined by measuring alterations in cell survival, apoptosis and induction of p21. The applicants hypothesize that the gain of function and dominant negative mutations defined by these studies will play a role in the progression of CaP. The frequency of the different functional types of p53 mutations will be correlated with the stage and grade of CaP. Finally, the p53 functional data will be analyzed with respect to patient and tumor characteristics. The proposed studies are necessary to understand the role of p53 mutations in CaP carcinogenesis and progression. They also form the basis of future studies to investigate p53-based therapies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA077662-01
Application #
2601244
Study Section
Special Emphasis Panel (ZRG4-UROL (01))
Program Officer
Shen, Grace L
Project Start
1998-04-15
Project End
2001-03-31
Budget Start
1998-04-15
Budget End
1999-03-31
Support Year
1
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of California Davis
Department
Urology
Type
Schools of Medicine
DUNS #
094878337
City
Davis
State
CA
Country
United States
Zip Code
95618
Shi, Xu-Bao; Xue, Lingru; Shi, Donghua et al. (2011) Influence of short polyglutamine tracts and p160 coactivators on the transactivation of the androgen receptor. Cancer Biother Radiopharm 26:191-201
Shi, Xu-Bao; Xue, Lingru; Zou, June X et al. (2008) Prolonged androgen receptor loading onto chromatin and the efficient recruitment of p160 coactivators contribute to androgen-independent growth of prostate cancer cells. Prostate 68:1816-26
Shi, Xu-Bao; Xue, Lingru; Tepper, Clifford G et al. (2007) The oncogenic potential of a prostate cancer-derived androgen receptor mutant. Prostate 67:591-602
Tepper, Clifford G; Gregg, Jeffrey P; Shi, Xu-Bao et al. (2005) Profiling of gene expression changes caused by p53 gain-of-function mutant alleles in prostate cancer cells. Prostate 65:375-89
Shi, Xu-Bao; Ma, Ai-Hong; Tepper, Clifford G et al. (2004) Molecular alterations associated with LNCaP cell progression to androgen independence. Prostate 60:257-71
Shi, Xu-Bao; Gandour-Edwards, Regina; Beckett, Laurel A et al. (2004) A modified yeast assay used on archival samples of localized prostate cancer tissue improves the detection of p53 abnormalities and increases their predictive value. BJU Int 94:996-1002
Martel, Cynthia L; Gumerlock, Paul H; Meyers, Frederick J et al. (2003) Current strategies in the management of hormone refractory prostate cancer. Cancer Treat Rev 29:171-87
Nesslinger, Nancy J; Shi, Xu-Bao; deVere White, Ralph W (2003) Androgen-independent growth of LNCaP prostate cancer cells is mediated by gain-of-function mutant p53. Cancer Res 63:2228-33
Shi, Xu-Bao; Ma, Ai-Hong; Xia, Liang et al. (2002) Functional analysis of 44 mutant androgen receptors from human prostate cancer. Cancer Res 62:1496-502
Shi, Xu-Bao; Nesslinger, Nancy J; Deitch, Arline D et al. (2002) Complex functions of mutant p53 alleles from human prostate cancer. Prostate 51:59-72

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