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J. Biol. Chem., Vol. 281, Issue 34, 24304-24313, August 25, 2006

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Regulation of the MDM2-p53 Pathway by Ribosomal Protein L11 Involves a Post-ubiquitination Mechanism^*

Mu-Shui Dai, Dingding Shi, Yetao Jin, Xiao-Xin Sun, Yanping Zhang^¶, Steven R. Grossman, and Hua Lu¹

From the Department of Biochemistry and Molecular Biology, School of Medicine, Oregon Health and Science University, Portland, Oregon 97239, Departments of Cancer Biology and Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, and ^¶Department of Radiation Oncology, University of North Carolina, Chapel Hill, North Carolina 27599

Inhibition of the MDM2-p53 feedback loop is critical for p53 activation in response to cellular stresses. The ribosomal proteins L5, L11, and L23 can block this loop by inhibiting MDM2-mediated p53 ubiquitination and degradation in response to ribosomal stress. Here, we show that L11, but not L5 and L23, leads to a drastic accumulation of ubiquitinated and native MDM2. This effect is dependent on the ubiquitin ligase activity of MDM2, but not p53, and requires the central MDM2 binding domain (residues 51–108) of L11. We further show that L11 inhibited 26 S proteasome-mediated degradation of ubiquitinated MDM2 in vitro and consistently prolonged the half-life of MDM2 in cells. These results suggest that L11, unlike L5 and L23, differentially regulates the levels of ubiquitinated p53 and MDM2 and inhibits the turnover and activity of MDM2 through a post-ubiquitination mechanism.

Received for publication, March 20, 2006 , and in revised form, June 26, 2006.

^* This work was supported in part by NCI, National Institutes of Health Grants CA93614, CA095441, and CA079721 (to H. L.) and CA107532 (to S. R. G.). 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: Dept. of Biochemistry and Molecular Biology, OR Health and Science University, 3181 SW 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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