Cdc34-mediated Degradation of ATF5 Is Blocked by Cisplatin

• Published in: The Journal of biological chemistry 2008-07, Vol.283 (27), p.18773-18781
• Main Authors: Wei, Yuanyan, Jiang, Jianhai, Liu, Dan, Zhou, Jin, Chen, Xiaoning, Zhang, Si, Zong, Hongliang, Yun, Xiaojing, Gu, Jianxin
• Format: Article
• Language: English
• Subjects: Activating Transcription Factors - genetics; Activating Transcription Factors - metabolism; Active Transport, Cell Nucleus - drug effects; Active Transport, Cell Nucleus - physiology; Anaphase-Promoting Complex-Cyclosome; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Apoptosis - physiology; Cell Differentiation - drug effects; Cell Differentiation - physiology; Cell Line; Cell Nucleus - enzymology; Cisplatin - pharmacology; Cytoplasm - enzymology; Cytoplasm - physiology; Down-Regulation - drug effects; Down-Regulation - physiology; Humans; Proteasome Endopeptidase Complex - genetics; Proteasome Endopeptidase Complex - metabolism; Ubiquitin - genetics; Ubiquitin - metabolism; Ubiquitin-Conjugating Enzymes; Ubiquitin-Protein Ligase Complexes - genetics; Ubiquitin-Protein Ligase Complexes - metabolism; Ubiquitination - drug effects; Ubiquitination - physiology
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M707879200

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.