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J. Biol. Chem., Vol. 281, Issue 40, 30036-30045, October 6, 2006

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Ribosomal Stress Couples the Unfolded Protein Response to p53-dependent Cell Cycle Arrest^*

Fang Zhang, Robert B. Hamanaka, Ekaterina Bobrovnikova-Marjon, John D. Gordan, Mu-Shui Dai, Hua Lu, M. Celeste Simon^¶, and J. Alan Diehl¹

From the Leonard and Madlyn Abramson Family Cancer Research Institute and ^¶Howard Hughes Medical Institute, University of Pennsylvania Cancer Center, Philadelphia, Pennsylvania 19104 and the Department of Biochemistry and Molecular Biology, School of Medicine, Oregon Health and Science University, Portland, Oregon 972001

Protein misfolding in the endoplasmic reticulum (ER) triggers a signaling pathway termed the unfolded protein response path-way (UPR). UPR signaling is transduced through the transmembrane ER effectors PKR-like ER kinase (PERK), inositol requiring kinase-1 (IRE-1), and activating transcription factor 6 (ATF6). PERK activation triggers phosphorylation of eIF2 leading to repression of protein synthesis, thereby relieving ER protein load and directly inhibiting cyclin D1 translation thereby contributing to cell cycle arrest. However, PERK^-/- murine embryonic fibroblasts have an attenuated G₁/S arrest that is not attributable to cyclin D1 loss, suggesting a cyclin D1-independent mechanism. Here we show that the UPR triggers p53 accumulation and activation. UPR induction promotes enhanced interaction between the ribosome proteins (rpL5, rpL11, and rpL23) and Hdm2 in a PERK-dependent manner. Interaction with ribosomal proteins results in inhibition of Hdm2-mediated ubiquitination and degradation of p53. Our data demonstrate that ribosomal subunit:Hdm2 association couples the unfolded protein response to p53-dependent cell cycle arrest.

Received for publication, May 16, 2006 , and in revised form, July 26, 2006.

^* This work was supported by National Institutes of Health Grant P01 CA104838, a leukemia lymphoma scholar award, and the Abramson Family Cancer Research Institute (to J. A. D.), and by Grants CA093614 and CA095441 (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: The Leonard and Madlyn Abramson Family Cancer Research Institute, Dept. of Cancer Biology, 454 BRB II/III, 421 Curie Blvd., Philadelphia, PA 19104. Tel.: 215-746-6389; Fax: 215-746-5511; E-mail: adiehl{at}mail.med.upenn.edu.

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