A central paradigm to DNA damage response is the accumulation of the tumor suppressor p53 and a p53-mediated cell cycle response. Thus, p53 has been proposed to be a """"""""sensor"""""""" to trigger an appropriate response in DNA-damaged cells. p53 accumulation mediates either a growth arrest at the G1/S boundary, or apoptotic cell death and is proposed to prevent the proliferation of malignant cells. p53 undergoes postranslational modifications, including phosphorylation and acetylation. DNA damage causes de novo phosphorylation in the amino-terminal region of p53. However, the mechanism by which p53 is stabilized and activated has not been established. The purpose of this research proposal is to test the hypothesis that DNA damage- induced phosphorylation is mechanistically significant for p53 function in vivo. Thus, in order to test the significance of amino-terminal phosphorylation and how it relates to p53 stability and function in a physiological context, I propose to generate mice and cells that contained an altered site of DNA- damage-induced phosphorylation. I will analyze these mice to determine the contribution of phosphate at Serine 18 in the function of p53 in DNA damage-induced G1 arrest, cell growth, and tumor suppression.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32CA084673-02
Application #
6377734
Study Section
Special Emphasis Panel (ZRG1-SSS-1 (01))
Program Officer
Lohrey, Nancy
Project Start
2001-04-01
Project End
Budget Start
2001-04-01
Budget End
2002-03-31
Support Year
2
Fiscal Year
2001
Total Cost
$41,996
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
660735098
City
Worcester
State
MA
Country
United States
Zip Code
01655