The p53 tumor suppressor protein is a sequence-specific transcription factor that modulates the response of cells to genotoxic stress, including DMA damage. The loss of p53 is associated with development of more than one-half of all human tumors. Upon activation, p53 undergoes massive post-translational modifications that ultimately regulate its biological function. Most of the post-translational modifications are commonly found both in p53 and histones. We have demonstrated previously that acetylation of p53 stimulates recruitment of CBP to the target promoters resulting in acetylation of histones and activation of transcription. We are proposing that methylation, another known posttranslational modification found in histones, is also important for regulation of the p53 function. The overall hypothesis of this proposal is that methylation regulates transcription of p53-dependent genes at multiple levels. The specific questions (aims) that we will address in this proposal are: 1) Does Set9 function as a histone- and/or p53-specific methyltransferase for transcriptional coactivation of the p53-dependent genes in vivo? 2) Is p53 methylated in vivo and what is the functional significance of this modification? Our research design will probe the methylation state of nucleosomes and p53 in vivo and utilize in vivo assays of p53 function to elucidate the role of this modification. The long term goal of our studies are to elucidate the role of post-translational modifications of p53 and chromatin in respect to the transcriptional and tumor suppressor function of p53.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA107549-04
Application #
7350942
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Blair, Donald G
Project Start
2005-04-01
Project End
2008-05-31
Budget Start
2008-03-01
Budget End
2008-05-31
Support Year
4
Fiscal Year
2008
Total Cost
$157,497
Indirect Cost
Name
Tufts University
Department
Type
DUNS #
079532263
City
Boston
State
MA
Country
United States
Zip Code
02111