Cdc34-mediated degradation of ATF5 is blocked by cisplatin.
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.
Wei
Yuanyan
Y
Gene Research Center, Key Laboratory of Medical Molecular Virology Ministry of Education and Health, Ministry of Public Health, Shanghai Medical College and Institutes of Biomedical Sciences of Fudan University, Shanghai, China.
Jiang
Jianhai
J
Liu
Dan
D
Zhou
Jin
J
Chen
Xiaoning
X
Zhang
Si
S
Zong
Hongliang
H
Yun
Xiaojing
X
Gu
Jianxin
J
D051696:Activating Transcription Factors / Q000235:genetics / Q000378:metabolism*; D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000502:physiology; D064173:Anaphase-Promoting Complex-Cyclosome; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D002467:Cell Nucleus / Q000201:enzymology*; D002945:Cisplatin / Q000494:pharmacology*; D003593:Cytoplasm / Q000201:enzymology / Q000502:physiology; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism; D044763:Ubiquitin-Conjugating Enzymes; D043743:Ubiquitin-Protein Ligase Complexes / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination / Q000187:drug effects / Q000502:physiology
C507532:ATF5 protein, human; D051696:Activating Transcription Factors; D000970:Antineoplastic Agents; D025801:Ubiquitin; C577447:CDC34 protein, human; D044763:Ubiquitin-Conjugating Enzymes; D043743:Ubiquitin-Protein Ligase Complexes; D064173:Anaphase-Promoting Complex-Cyclosome; D046988:Proteasome Endopeptidase Complex; D002945:Cisplatin