Cdc34-mediated degradation of ATF5 is blocked by cisplatin

J Biol Chem. 2008 Jul 4;283(27):18773-81. doi: 10.1074/jbc.M707879200. Epub 2008 May 5.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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


  • ATF5 protein, human
  • Activating Transcription Factors
  • Antineoplastic Agents
  • Ubiquitin
  • CDC34 protein, human
  • Ubiquitin-Conjugating Enzymes
  • Ubiquitin-Protein Ligase Complexes
  • Anaphase-Promoting Complex-Cyclosome
  • Proteasome Endopeptidase Complex
  • Cisplatin