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A more recent version of this article appeared on July 22, 2005
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Papers In Press, published online ahead of print May 20, 2005
J. Biol. Chem, 10.1074/jbc.M505203200
Submitted on May 11, 2005
Accepted on May 20, 2005

A chromatin associated and transcriptionally inactive p53-MDM2 complex occurs in MDM2 SNP 309 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

Biology Dept., Hunter College, New York, NY 10021

Corresponding Author: bargonetti{at}genectr.hunter.cuny.edu

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 over-expression 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 with 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 hours of camptothecin, etoposide or mitomycin C treatment, with the p53 protein phosphorylated at Ser-15. Chromatin immuno-precipitation 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. Inhibiting Mdm2 by siRNA resulted in transcriptional activation of these p53 targets. Our data suggest that over-production of Mdm2 resulting from a naturally occurring SNP inhibits chromatin-bound p53 from activating the transcription of its target genes.


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