The tumor suppressor protein p53 is a transcription factor which functions in the cellular response to DNA damage. Mutation of p53 which results in inactivation of p53 function is the most commonly found genetic alteration in human cancer. This research application is centered on testing the hypothesis that these are mechanisms of carcinogenesis involving functional inactivation of wild-type p53 besides direct genetic alteration. This hypothesis is grounded in three observations. First, a large number of tumor viruses have been shown to express oncoproteins which inactivate the function of wild-type p53. Second, a cellular protein, mdm2, has been identified which binds wild- type p53 and inhibits its ability to act as a transcription factor. Third, there are examples of human tumors in which mechanisms which inactivate the function of wild-type p53 have already been identified. The goal of this proposal is to identify the clone genes which encode proteins which act on wild-type p53 and functionally inactivate it.
Specific aims i nclude: (1) Identification of cell lines to serve as sources for cloning of regulators of wild-type p53 function. Two types of cell lines will be used: rat fibroblasts which are resistant to the growth suppressing activity of p53 and human breast cancer cell lines which overexpress wild-type p53. (2) Cloning of genes that encode regulators of wild-type p53 function. Strategies for cloning p53 binding proteins as well as dominant-acting regulators of p53 will be employed. (3) Determination of the relevance of such regulators in human cancer. The overexpression or mutational activation of such genes will then be examined in human tumors to determine whether the genes encoding such proteins are indeed involved in novel mechanisms of carcinogenesis in human cancer. Because p53 is a tumor suppressor protein, mechanisms for regulating p53 represent mechanisms of carcinogenesis. By inhibiting the ability of the DNA damage signal to be translated into either growth arrest or apoptosis, cells can sustain genetic lesions which can be propagated and result in oncogenic progression. Understanding how wild- type p53 can be functionally inactivated is therefore critical to our understanding of the molecular basis of a variety of human cancers. The research outlined in this proposal can serve as the basis for future clinical studies in both the prognosis and treatment of particular human tumors. Such approaches as outlined here can address two important issues. The first is to determine whether certain types of cancer are linked with specific genetic alterations and can help to determine if overexpression of certain regulators of p53 may be associated with a particular prognosis or a particular success rate for a type of therapy. Second, identification of relevant regulators p53 can allow us to begin to use such protein-protein complexes as targets for therapeutic intervention by designing or screening small molecular weight complexes which can disrupt or inhibit such complexes. Thus, elucidating mechanisms of carcinogenesis involving inactivation of wild-type p53 function represents an important avenue in cancer research.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29CA069161-05
Application #
6172819
Study Section
Chemical Pathology Study Section (CPA)
Program Officer
Pelroy, Richard
Project Start
1996-04-01
Project End
2002-03-31
Budget Start
2000-04-01
Budget End
2002-03-31
Support Year
5
Fiscal Year
2000
Total Cost
$126,991
Indirect Cost
Name
Mount Sinai School of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029