The p53 tumor suppressor is a transcription factor functioning in a pathway activated by DNA damaging agents, hypoxia, oncogenes, telomere abnormalities and other conditions that impact on tumor growth and survival. This pathway is inactivated in most human neoplasms, enabling tumor cells to cycle with damaged genomes, or under conditions that induce genomic instability. Cell culture models elicited both elegant mechanisms of p53 regulation and significant controversy over their relevance in vivo. The proposed studies use homologous recombination in embryonic stem cells to generate mice with mutations in putative p53 regulatory domains to study their effects on p53 regulation and function in genetically defined ceils in different tissues under conditions of normal p53 expression. Specifically, experiments are proposed to continue analysis of mice we recently generated with a deletion of an N-terminal putative protein interaction domain reported to affect apoptosis but not cell cycle arrest. We propose to generate mice with mutations in a C-terminal domain that impacts on p53 stability and transcriptional regulation. The impact of these mutations on p53 stability, target gene binding, cell cycle arrest, apoptosis, and aging will be determined in response to activating stresses such as those described above as they are most relevant to tumor initiation, progression and chemotherapy response. We will also study spontaneous tumorigenesis, as well as several models of oncogene induced tumorigencity to assess the impact of these mutations on p53 dependent tumor suppression. The models proposed will enable in rive assessments of the contribution of protein-protein interactions in the N- terminal regulatory domain, and importance of stabilization and post-translational modifications on the transcriptional and biological output of the p53 pathway. These studies are essential for unambiguous conclusions about p53 regulation in different cell types under physiologically relevant conditions. The data obtained and systems developed have relevance for p53-targeted therapies, and they provide a paradigm for how transcription factors convert complex inputs into distinct regulatory decisions. ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA100845-02
Application #
6736855
Study Section
Pathology B Study Section (PTHB)
Program Officer
Blair, Donald G
Project Start
2003-04-15
Project End
2008-03-31
Budget Start
2004-04-01
Budget End
2005-03-31
Support Year
2
Fiscal Year
2004
Total Cost
$465,079
Indirect Cost
Name
Salk Institute for Biological Studies
Department
Type
DUNS #
078731668
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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