Wild-type p53 is a potent tumor suppressor that is activated by DNA damage and other stresses. There has been considerable interest in restoring wild-type p53 function as a therapeutic strategy. This goal has led to the development of the Nutlin-3 (Nutlin), a small molecule that activates wild-type p53 by blocking its interaction with MDM2, the primary negative regulator of p53 activity in cells. Notably, Nutlin activates p53 through a non-genotoxic mechanism, and thus its use as a therapeutic agent may spare tissues of deleterious side-effects associated with common DNA damaging drugs. Effective use of Nutlin requires that its effects on cells be fully understood. We have examined the response of various p53 wild-type cell lines to transient Nutlin treatment. We find that p53 activation by Nutlin can promote growth arrest or apoptosis in cells dependent on activation of survival pathways, and we have identified a candidate survival factor that protects cells from Nutlin-induced apoptosis. We also find that Nutlin has surprising effects on cytoskeletal organization and control of DNA endoreduplication. The purpose of this grant is to determine the effects of Nutlin-mediated p53 activation on these various cellular responses.

Public Health Relevance

Cell growth can be considered similar to driving a car;there are accelerators that increase cell growth and brakes that prevent cells from growing too fast. The p53 protein is an important cell brake that prevents normal cells from becoming cancer, and p53 is inactive in most human cancers. We are studying the effects of p53 activation by Nutlin-3a, a small molecule that specifically activates wild-type p53 in a subset of cancers.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA137598-05
Application #
8471662
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Arya, Suresh
Project Start
2009-07-13
Project End
2014-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
5
Fiscal Year
2013
Total Cost
$283,799
Indirect Cost
$94,600
Name
Rush University Medical Center
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
068610245
City
Chicago
State
IL
Country
United States
Zip Code
60612
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Shen, Hong; Perez, Ricardo E; Davaadelger, Batzaya et al. (2013) Two 4N cell-cycle arrests contribute to cisplatin-resistance. PLoS One 8:e59848
Aziz, M H; Shen, H; Maki, C G (2011) Acquisition of p53 mutations in response to the non-genotoxic p53 activator Nutlin-3. Oncogene 30:4678-86
Shen, Hong; Maki, Carl G (2011) Pharmacologic activation of p53 by small-molecule MDM2 antagonists. Curr Pharm Des 17:560-8
Moran, Diarmuid M; Maki, Carl G (2010) Nutlin-3a induces cytoskeletal rearrangement and inhibits the migration and invasion capacity of p53 wild-type cancer cells. Mol Cancer Ther 9:895-905