The long term goal of this proposal is for the principal investigator to develop an independent research career focused on the role of p53 in prostate cancer. The training received by the candidate during the period of the award will bridge the transition from mentored scientist to independent researcher. The candidate will draw from prior research experience in the study of cell cycle regulation and prostate cancer etiology to accomplish his objectives. The co-sponsors, Drs. Nora M. Navone and Guillermina Lozano will provide an excellent training experience for the candidate in the state-of-the-art institutional facilities at U.T.M.D. Anderson, Houston, TX. The impetus for this proposal is the finding that up to 50 percent of metastatic prostate cancers have a mutated p53. Given the high incidence of p53 inactivation in human cancers, it is presumed that cancers that do not demonstrate p53 mutation must have either an upstream or downstream alteration that obviates the need for mutation of the p53 gene. Despite the analysis of cyclin/cdk regulation of p53 by a number of groups, no consensus exists. Our hypothesis is that cyclin/cdk complexes destabilize p53 through phosphorylation in prostate cancer cells. Moreover, we have generated a testable hypothesis whereby growth factor receptor pathways can inactivate p53 via the cyclin/cdks. This proposal seeks to elucidate alternative mechanisms for the regulation of p53 function.
The specific aims of this proposal are as follows: 1) Determine the destabilization of p53 by cyclin/cdks; 2) To elucidate the regulation of p53 by growth factor receptor pathways via cyclin/cdks; 3) Determine whether inhibition of cyclin/cdk activity synergizes with androgen ablation to promote p53 dependent tumor suppression.
The aims of this proposal will be addressed using a variety of approaches including co-transfection experiments, western blot analysis, adenovirus-mediated gene delivery, site-directed mutagenesis, in vivo (mouse) studies, and other methodologies consistent with the proposed Research Career Plans of the candidate. The research outlined in this proposal will provide the basis for the generation of novel therapeutic approaches to eliminate prostate cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01CA092125-02
Application #
6515174
Study Section
Subcommittee G - Education (NCI)
Program Officer
Ojeifo, John O
Project Start
2001-07-01
Project End
2006-06-30
Budget Start
2002-07-08
Budget End
2003-06-30
Support Year
2
Fiscal Year
2002
Total Cost
$93,744
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Internal Medicine/Medicine
Type
Other Domestic Higher Education
DUNS #
001910777
City
Houston
State
TX
Country
United States
Zip Code
77030