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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Tumor Cell Biology Study Section (TCB)
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Arya, Suresh
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Rush University Medical Center
Anatomy/Cell Biology
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United States
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Perez, Ricardo E; Shen, Hong; Duan, Lei et al. (2016) Modeling the Etiology of p53-mutated Cancer Cells. J Biol Chem 291:10131-47
Duan, Lei; Perez, Ricardo E; Davaadelger, Batzaya et al. (2015) p53-regulated autophagy is controlled by glycolysis and determines cell fate. Oncotarget 6:23135-56
Duan, Lei; Danzer, Brian; Levenson, Victor V et al. (2014) Critical roles for nitric oxide and ERK in the completion of prosurvival autophagy in 4OHTAM-treated estrogen receptor-positive breast cancer cells. Cancer Lett 353:290-300
Duan, Lei; Ying, Guoguang; Danzer, Brian et al. (2014) The prolyl peptidases PRCP/PREP regulate IRS-1 stability critical for rapamycin-induced feedback activation of PI3K and AKT. J Biol Chem 289:21694-705
Davaadelger, Batzaya; Shen, Hong; Maki, Carl G (2014) Novel roles for p53 in the genesis and targeting of tetraploid cancer cells. PLoS One 9:e110844
Duan, Lei; Perez, Ricardo E; Hansen, Michael et al. (2014) Increasing cisplatin sensitivity by schedule-dependent inhibition of AKT and Chk1. Cancer Biol Ther 15:1600-12
Shen, Hong; Perez, Ricardo E; Davaadelger, Batzaya et al. (2013) Two 4N cell-cycle arrests contribute to cisplatin-resistance. PLoS One 8:e59848
Aziz, Moammir H; Shen, Hong; Maki, Carl G (2012) Glucocorticoid receptor activation inhibits p53-induced apoptosis of MCF10Amyc cells via induction of protein kinase C?. J Biol Chem 287:29825-36
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

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