Activation of the p53 tumor suppressor is an important part of the response that cells mount to a variety of genotoxic and nongenotoxic stimuli and a key step in that activation process is the accumulation of p53 in the nuclei of affected cells. The mechanism that regulates p53 subcellular localization is only poorly understood. However, the observation that some p53 is excluded from the nucleus in the cells of some tumors suggests that this may be another mechanism by which p53 can be inactivated and points to the importance of understanding how p53 subcellular localization is controlled. In order to gain insight into the p53 protein trafficking we adopted a model system in which the accumulation of a tsp53 in the nucleus inhibited cell proliferation and selected for mutants that were resistant to these affects. Preliminary studies indicate that the mutant cell lines are defective for p53 nuclear trafficking and are significantly more sensitive to killing by heat shock. These observations combined with reports indicating that heat shock proteins play a role in the trafficking of proteins into the nucleus lead us to propose the hypothesis that heat shock proteins function in transportation of p53 into the nucleus in cells exposed to stressful stimuli. To elucidate regulation of p53 subcellular localization we will 1) characterize functioning of the p53 nuclear localization signally by determining whether activity of this motif is controlled by phosphorylation and/or by interaction with hsc70 2) determine whether p53 phosphorylation or interaction with hsc70 is aberrant in our mutant cells where p53 nuclear trafficking is defective 3) determine whether mutations that inactivate p53 promote interaction between p53 and heat shock proteins or whether heat shock proteins suppress p53 activity by anchoring the protein in the cytoplasm.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA090776-01A2
Application #
6680550
Study Section
Special Emphasis Panel (ZRG1-PTHB (05))
Program Officer
Pelroy, Richard
Project Start
2003-07-08
Project End
2007-06-30
Budget Start
2003-07-08
Budget End
2004-06-30
Support Year
1
Fiscal Year
2003
Total Cost
$313,280
Indirect Cost
Name
University of Arizona
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
806345617
City
Tucson
State
AZ
Country
United States
Zip Code
85721
Chambers, Setsuko K; Martinez, Jesse D (2012) The significance of p53 isoform expression in serous ovarian cancer. Future Oncol 8:683-6
Li, Qiang; Martinez, Jesse D (2011) Loss of HSF1 results in defective radiation-induced G(2) arrest and DNA repair. Radiat Res 176:17-24
Li, Qiang; Martinez, Jesse D (2011) P53 is transported into the nucleus via an Hsf1-dependent nuclear localization mechanism. Mol Carcinog 50:143-52
Feldman, Rebecca; Martinez, Jesse D (2009) Growth suppression by ursodeoxycholic acid involves caveolin-1 enhanced degradation of EGFR. Biochim Biophys Acta 1793:1387-94
Li, Qiang; Feldman, Rebecca A; Radhakrishnan, Vijayababu M et al. (2008) Hsf1 is required for the nuclear translocation of p53 tumor suppressor. Neoplasia 10:1138-45
Li, Q; Falsey, R R; Gaitonde, S et al. (2007) Genetic analysis of p53 nuclear importation. Oncogene 26:7885-93
Mayelzadeh, F; Martinez, J D (2007) DNA binding and selective gene induction by different forms of the p53 protein. Oncogene 26:2955-63
Holm, Richard P (2006) Frankenstein, a story of scientific discovery turned to dread, with a lesson in ethics. Pharos Alpha Omega Alpha Honor Med Soc 69:30-4