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J. Biol. Chem., Vol. 283, Issue 18, 12387-12392, May 2, 2008

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Mycophenolic Acid Activation of p53 Requires Ribosomal Proteins L5 and L11^*

Xiao-Xin Sun, Mu-Shui Dai¹, and Hua Lu²

From the Department of Biochemistry and Molecular Biology, Indiana University School of Medicine and Simon Cancer Center, Indianapolis, Indiana 46202 and the Department of Biochemistry and Molecular Biology, School of Medicine, Oregon Health & Science University, Portland, Oregon 97239

Mycophenolate mofetil (MMF), a prodrug of mycophenolic acid (MPA), is widely used as an immunosuppressive agent. MPA selectively inhibits inosine monophosphate dehydrogenase (IMPDH), a rate-limiting enzyme for the de novo synthesis of guanine nucleotides, leading to depletion of the guanine nucleotide pool. Its chemotherapeutic effects have been attributed to its ability to induce cell cycle arrest and apoptosis. MPA treatment has also been shown to induce and activate p53. However, the mechanism underlying the p53 activation pathway is still unclear. Here, we show that MPA treatment results in inhibition of pre-rRNA synthesis and disruption of the nucleolus. This treatment enhances the interaction of MDM2 with L5 and L11. Interestingly, knockdown of endogenous L5 or L11 markedly impairs the induction of p53 and G₁ cell cycle arrest induced by MPA. These results suggest that MPA may trigger a nucleolar stress that induces p53 activation via inhibition of MDM2 by ribosomal proteins L5 and L11.

Received for publication, February 21, 2008

^* This work was supported in part by NCI, National Institutes of Health Grants CA095441, CA93614, CA079721, and CA127724 (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 Supported by NCI, National Institutes of Health Grant K99-CA127134 and a Biomedical Research Grant (BRG) from Indiana University.

² To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Biology, Indiana University School of Medicine, 635 Barnhill Dr., Indianapolis, IN 46202. Tel.: 317-278-0920; Fax: 317-274-4686; E-mail: hualu{at}iupui.edu.

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