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J. Biol. Chem., Vol. 282, Issue 11, 8052-8059, March 16, 2007

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5-Fluorouracil Activation of p53 Involves an MDM2-Ribosomal Protein Interaction^*

From the Department of Biochemistry and Molecular Biology, School of Medicine, Oregon Health & Science University, Portland, Oregon 97239

5-Fluorouracil (5-FU) is a widely used chemotherapeutic drug for the treatment of a variety of solid tumors. The anti-tumor activity of 5-FU has been attributed in part to its ability to induce p53-dependent cell growth arrest and apoptosis. However, the molecular mechanisms underlying p53 activation by 5-FU remain largely obscure. Here we report that 5-FU treatment leads to p53 stabilization and activation by blocking MDM2 feedback inhibition through ribosomal proteins. 5-FU treatment increased the fraction of ribosome-free L5, L11, and L23 ribosomal proteins and their interaction with MDM2, leading to p53 activation and G₁/S arrest. Conversely, individual knockdown of these ribosomal proteins by small interfering RNA prevented the 5-FU-induced p53 activation and reversed the 5-FU-induced G₁/S arrest. These results demonstrate that 5-FU treatment triggers a ribosomal stress response so that ribosomal proteins L5, L11, and L23 are released from ribosome to activate p53 by ablating the MDM2-p53 feedback circuit.

Received for publication, November 15, 2006 , and in revised form, January 22, 2007.

^* This work is supported by National Institutes of Health NCI Grants CA095441, CA93614, and CA079721 (to H. L.). 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.

¹ To whom correspondence should be addressed: 3181 S.W. Sam Jackson Park Rd., Portland, OR 97239. Tel.: 503-494-7414; Fax: 503-494-8393; E-mail: luh{at}ohsu.edu.

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