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J. Biol. Chem., Vol. 278, Issue 52, 52890-52900, December 26, 2003

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Defective p53 Post-translational Modification Required for Wild Type p53 Inactivation in Malignant Epithelial Cells with mdm2 Gene Amplification^*

Chad D. Knights, Yuangang Liu, Ettore Appella¶, and Molly Kulesz-Martin||

From the Department of Dermatology, Oregon Health & Science University, Portland, Oregon 97239, the Program of Biochemistry and Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, State University of New York, Buffalo, New York 14263, and the ^¶Laboratory of Cell Biology, Division of Basic Sciences, NCI, National Institutes of Health, Bethesda, Maryland 20892

Mdm2 gene amplification occurs in benign and chemotherapy-responsive malignant tumors with wtp53 genes as well as in breast and epithelial cancers. Mdm2 amplification in benign tumors suggests that it is not sufficient for p53 inactivation in cancer, implying that other defects in the p53 pathway are required for malignancy. We investigated mechanisms of wtp53 protein inactivation in malignant conversion of epithelial cells by comparing clonally related initiated cells with their derivative cancerous cells that have mdm2 amplification. Deficiencies in p53 accumulation and activities in response to DNA damage were not due simply to Mdm2 destabilization of p53 protein, but to continued association of DNA-bound p53 with Mdm2 protein and lack of binding and acetylation by p300 protein. The aberrant interactions were not because of mdm2 amplification alone, because DNA-bound p53 protein from initiated cells failed to bind ectopically expressed Mdm2 or endogenous overexpressed Mdm2 from cancerous cells. Phosphorylations of endogenous p53 at Ser¹⁸, -23, or -37 were insufficient to dissociate Mdm2, because each was induced by UV in cancerous cells. Interestingly, phospho-mimic p53-T21E did dissociate the Mdm2 protein from DNA-bound p53 and recovered p300 binding and p21 induction in the cancerous cells. Thus wtp53 in malignant cells with mdm2 amplification can be inactivated by continued association of DNA-bound p53 protein with Mdm2 and failure of p300 binding and acetylation, coupled with a defect in p53 phosphorylation at Thr²¹. These findings suggest therapeutic strategies that address both p53/Mdm2 interaction and associated p53 protein defects in human tumors that have amplified mdm2 genes.

Received for publication, January 10, 2003 , and in revised form, September 25, 2003.

^* This work was supported by NCI National Institutes of Health Grant CA31101, Oregon Health and Science University Cancer Institute Grant CA69533, the Medical Research Foundation of Portland, OR, The Mark Diamond Research Fund of Roswell Park Cancer Institute, Buffalo (to C. D. K.), and a Tartar Trust Fellowship of the Oregon Health and Science University (to C. D. K.). 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.

The on-line version of this article (available at http://www.jbc.org) contains Figs. S1-S4.

^|| To whom correspondence should be addressed: Dept. of Dermatology, OP06, Oregon Health & Science University, 3181 S.W. Sam Jackson Park Rd., Portland, OR 97239-3098. Tel.: 503-494-9933; Fax: 503-418-4266; E-mail: kuleszma{at}ohsu.edu.

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