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J. Biol. Chem., Vol. 282, Issue 50, 36671-36681, December 14, 2007

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A Suppressive Role of the Prolyl Isomerase Pin1 in Cellular Apoptosis Mediated by the Death-associated Protein Daxx^*

Akihide Ryo¹, Akiko Hirai, Mayuko Nishi, Yih-Cherng Liou², Kilian Perrem^¶, Sheng-Cai Lin^||, Hisashi Hirano^**, Sam W. Lee, and Ichiro Aoki

From the Department of Pathology, Yokohama City University School of Medicine, 3-9 Fuku-ura, Kanazawa-ku, Yokohama 236-0004, Japan, the Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore, the ^¶Molecular Oncology Laboratory, Department of Pathology, Royal College of Surgeons in Ireland, Smurfit Building, Beaumont Hospital, Dublin 9, Ireland, the ^||Key Laboratory of the Ministry of Education for Cell Biology, School of Life Sciences, Xiamen University, Fujian 361005, Xiamen, China, the ^**International Graduate School of Arts and Sciences, Yokohama City University, Yokohama 230-0045, Japan, and the Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129

The death-associated protein Daxx is a multifunctional factor that regulates a variety of cellular processes, including transcription and apoptosis. Several previous reports have indicated that Daxx is induced upon oxidative stress and is then subjected to phosphorylation-based functional modification. However, the precise molecular events underlying these phosphorylation events remain largely unknown. We report in our current study that the peptidyl-prolyl isomerase Pin1 is highly overexpressed in malignant human gliomas and inhibits Daxx-mediated cellular apoptosis. The targeted inhibition of Pin1 by small interfering RNA in A172 glioblastoma cells significantly enhances the apoptotic response induced by hydrogen peroxide or stimulatory Fas antibodies. This is in turn accompanied by the increased induction of Daxx and the activation of the apoptosis signal-regulating kinase 1/c-Jun N-terminal kinase pathway. Furthermore, Pin1 binds to the phosphorylated Ser¹⁷⁸-Pro motif in the Daxx protein, and Pin1 overexpression results in the rapid degradation of Daxx via the ubiquitin-proteasome pathway. Moreover, a Daxx-S178A mutant, which cannot interact with Pin1, demonstrates higher proapoptotic activity and is refractory to Pin1-mediated antiapoptotic effects. We further found that the expression levels of Pin1 inversely correlate with the degree of Daxx nuclear accumulation in human glioblastoma tissues. These results together indicate that Pin1-mediated prolyl isomerization plays an important role in the negative regulation of Daxx and thereby inhibits the oxidative stress-induced cellular apoptotic response, particularly in malignant tumor cells where Pin1 is often overexpressed.

Received for publication, May 21, 2007 , and in revised form, September 17, 2007.

^* This work was supported in part by a special fellow grant from the Leukemia and Lymphoma Society and by grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan (to A. R.). 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.

² Supported by grants from the National Science Foundation of China and the Biomedical Research Council of Singapore.

¹ To whom correspondence should be addressed. Tel.: 81-45-787-2587; Fax: 81-45-786-0191; E-mail: aryo{at}yokohama-cu.ac.jp.

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