The proposed research addresses molecular mechanisms controlling cell proliferation, with an emphasis on the members of the p21 or CIP/KIP family of CDK inhibitors. The proposal includes three diverse aims.
The first aim of the proposal will be to pursue mechanisms controlling the stability of these inhibitors. In particular, the applicant will continue ongoing studies of a recently identified protein, known as ROC1, which appears to play a role in the ubiquitination of G1 regulatory proteins. The investigator proposes to use biochemical approaches to characterize the role of ROC1 in the degradation of CIP/KIP inhibitors, with an emphasis on the identification of proteins involved in targeting ROC1 to these inhibitors for ubiquitin-dependent degradation. In the second aim, the applicant will analyze the phenotypes of mice bearing double mutations in different CDK inhibitors, with the goal of unveiling overlaps in the function of different inhibitors in vivo. The third and final aim will focus on the control of cell proliferation by the p53 regulator, ARF. Preliminary results indicate that ARF associates with p53 and another p53 regulator, MDM2, in concentrated """"""""nuclear bodies"""""""" in the nucleus, and the investigator proposes to clarify the function of these bodies by searching for ARF-associated proteins and by purifying and identifying the components of these nuclear bodies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA065572-09
Application #
6628287
Study Section
Cell Development and Function Integrated Review Group (CDF)
Program Officer
Spalholz, Barbara A
Project Start
1995-03-01
Project End
2005-01-31
Budget Start
2003-02-10
Budget End
2004-01-31
Support Year
9
Fiscal Year
2003
Total Cost
$277,530
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Biochemistry
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
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Zhang, Yanping; Wolf, Gabrielle White; Bhat, Krishna et al. (2003) Ribosomal protein L11 negatively regulates oncoprotein MDM2 and mediates a p53-dependent ribosomal-stress checkpoint pathway. Mol Cell Biol 23:8902-12
Shumway, Stuart D; Li, Yong; Xiong, Yue (2003) 14-3-3beta binds to and negatively regulates the tuberous sclerosis complex 2 (TSC2) tumor suppressor gene product, tuberin. J Biol Chem 278:2089-92

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