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J. Biol. Chem., Vol. 283, Issue 27, 18773-18781, July 4, 2008

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Cdc34-mediated Degradation of ATF5 Is Blocked by Cisplatin^*

From the Gene Research Center, Key Laboratory of Medical Molecular Virology Ministry of Education and Health and Key Laboratory of Glycoconjuates Research, Ministry of Public Health, Shanghai Medical College and Institutes of Biomedical Sciences of Fudan University, Shanghai, China 200032

ATF5, a member of activating transcription factor (ATF)/cAMP-response element-binding protein (CREB) family of b-ZIP transcription factors, contributes to neural cell differentiation and is involved in cell apoptosis in response to cisplatin and a number of environment factors. However, the mechanisms governing the regulation of ATF5 protein during apoptosis are largely unknown. In this study we reported that ATF5 protein was a substrate of the ubiquitin-proteasome pathway. Interestingly, the ubiquitin-dependent degradation of exogenous ATF5 protein was independent of lysine residues. Instead, the addition of a large N-terminal enhanced green fluorescence protein tag increased the stability of ATF5 protein, and the free amino acid group of the N-terminal methionine of ATF5 protein was a site for ubiquitinylation, indicating that exogenous ATF5 was degraded via the ubiquitin-proteasome system through N-terminal ubiquitinylation. Furthermore, cisplatin increased ATF5 protein expression via preventing its ubiquitin-dependent degradation, which might be associated with its promoting the nucleus-to-cytoplasm translocation of E2 ubiquitin-conjugating enzyme Cdc34 and reducing the interaction between ATF5 and Cdc34. In summary, a down-regulation of proteasome-mediated degradation of ATF5 might contribute to cisplatin-induced apoptosis, providing a new mechanism of cisplatin-induced apoptosis.

Received for publication, September 20, 2007 , and in revised form, May 5, 2008.

^* This work was supported by National Natural Scientific Foundation of China Grants 30700132, 30470442, and 30330320; Shanghai Educational Development Foundation Grant 2007CG02; Shanghai Leading Academic Discipline Project B110; CNHLPP Grant 2004BA711A19; and Development of Science and Technology of Shanghai Grants ZR14011 and 02DJ14002. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed. Tel.: 86-21-54237704; Fax: 86-21-65649416; E-mail: jxgu{at}shmu.edu.cn.

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