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J. Biol. Chem., Vol. 280, Issue 28, 25953-25959, July 15, 2005

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Phosphorylation of Human p53 at Serine 46 Determines Promoter Selection and whether Apoptosis Is Attenuated or Amplified^*

Lindsey D. Mayo, Young Rok Seo¶, Mark W. Jackson||, Martin L. Smith¶, Javier Rivera Guzman¶, Chandrashekhar K. Korgaonkar¶, and David B. Donner¶**

From the Departments of Radiation Oncology and Pharmacology, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio 44106, ^¶Department of Microbiology and Immunology and Walther Oncology Center, Indiana University School of Medicine, Indianapolis, Indiana 46202, and ^||Department of Molecular Biology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44159

The capacity of DNA damaging agents to induce apoptosis is regulated by target gene induction by p53. We found that p53 targeted MDM2 in cells in which DNA repair was occurring, but persistent DNA damage induced by chemotherapy led p53 to selectively target PTEN. High dose chemotherapy induced the phosphorylation of p53 on serine 46, whereas low dose chemotherapy did not. A nonphosphorylatable serine 46 to alanine p53 mutant (S46A) targeted the MDM2 promoter in preference to that for PTEN. A serine 46 to aspartate mutant (S46D, a phosphorylation mimic) targeted PTEN in preference to MDM2. These observations show that phosphorylation of serine 46 in p53 is sufficient for it to induce the PTEN (phosphatase and tensin homolog deleted on chromosome ten) tumor suppressor protein in preference to MDM2. S46A induced significantly less cell death than the S46D in cells. The phosphorylation-induced change of p53 promoter targeting suppresses the induction of MDM2 and the formation of the autoregulatory feedback loop. Induction of PTEN by p53 followed by expression of PTEN inhibits AKT-induced translocation of MDM2 into the nucleus and sustains p53 function. The protection of p53 from MDM2 by PTEN and the damage-induced activation of PTEN by phosphorylated p53 leads to the formation of an apoptotic amplification cycle in which p53 and PTEN coordinately increase cellular apoptosis.

Received for publication, March 18, 2005 , and in revised form, April 18, 2005.

^* This work was supported by a grant from the General Motors Cancer Research Foundation (to L. D. M.) and National Institutes of Health Grants CA 67891 and CA 73023 (to D. B. D.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence may be addressed. E-mail: lindsey.mayo{at}cwru.edu. ** To whom correspondence may be addressed. E-mail: ddonner{at}iupui.edu.

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