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J. Biol. Chem., Vol. 280, Issue 29, 26776-26787, July 22, 2005

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A Chromatin-associated and Transcriptionally Inactive p53-Mdm2 Complex Occurs in mdm2 SNP309 Homozygous Cells^*

Nicoleta C. Arva, Tamara R. Gopen, Kathryn E. Talbott¶, Latoya E. Campbell||, Agustin Chicas**, David E. White, Gareth L. Bond, Arnold J. Levine, and Jill Bargonetti

From the Institute for Biomolecular Structure and Function and Department of Biological Sciences, Hunter College and Graduate School, City University of New York, New York, New York 10021 and the Cancer Institute of New Jersey, University of Medicine and Dentistry of New Jersey, New Brunswick, New Jersey 08903

In cancer cells, the function of the tumor suppressor protein p53 is usually blocked. Impairment of the p53 pathway results in tumor cells with endogenous overexpression of Mdm2 via a naturally occurring single nucleotide polymorphism (SNP) in the mdm2 gene at position 309. Here we report that in mdm2 SNP309 cells, inactivation of p53 results in a chromatin-associated Mdm2-p53 complex without clearance of p53 by protein degradation. Nuclear accumulation of p53 protein in mdm2 SNP309 cells results after 6 h of camptothecin, etoposide, or mitomycin C treatment, with the p53 protein phosphorylated at Ser¹⁵. Chromatin immunoprecipitation demonstrated p53 and Mdm2 bound to p53 responsive elements. Interestingly, although the p53 protein was able to bind to DNA, quantitative PCR showed compromised transcription of endogenous target genes. Additionally, exogenously introduced p53 was incapable of activating transcription from p53 responsive elements in SNP309 cells, confirming the trans-acting nature of the inhibitor. Inhibition of Mdm2 by siRNA resulted in transcriptional activation of these p53 targets. Our data suggest that overproduction of Mdm2, resulting from a naturally occurring SNP, inhibits chromatin-bound p53 from activating the transcription of its target genes.

Received for publication, May 11, 2005

^* This work was supported by Grants MCB-0212761 and MCB-9722262 from the National Science Foundation (to J. B.). 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.

Both authors contributed equally to this work.

^¶ Supported in part through National Institutes of Health SCORE (1S06 GM60754).

^|| Student of the Hunter College Minority Access to Research Careers Program.

^** Supported by the Research Centers in Minority Institutions Award RR-03037 from the National Center for Research Resources of the National Institutes of Health, which supports infrastructure and instrumentation in the Biological Sciences Department at Hunter College.

To whom correspondence should be addressed: Dept. of Biological Sciences, Hunter College and Graduate School, City University of New York, 695 Park Ave., New York, NY 10021. Tel.: 212-650-3519; Fax: 212-772-5227; E-mail: bargonetti{at}genectr.hunter.cuny.edu.

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