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Cdc34-mediated degradation of ATF5 is blocked by cisplatin

Yuanyan Wei1, Jianhai Jiang, Dan Liu

  • 1Gene 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.

The Journal of Biological Chemistry
|May 7, 2008
PubMed

Insights

Activating transcription factor 5 (ATF5) protein is degraded by the ubiquitin-proteasome system via N-terminal ubiquitination. Cisplatin inhibits this degradation, increasing ATF5 levels and contributing to apoptosis.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • Activating transcription factor 5 (ATF5) is a transcription factor involved in neural cell differentiation and apoptosis.
  • The precise mechanisms regulating ATF5 protein levels during apoptosis are not well understood.
  • Understanding ATF5 regulation is crucial for deciphering its role in various cellular processes.

Purpose of the Study:

  • To investigate the mechanisms of ATF5 protein regulation, particularly its degradation pathway.
  • To elucidate the role of the ubiquitin-proteasome system in controlling ATF5 stability.
  • To determine how cisplatin affects ATF5 protein levels and its implications in apoptosis.

Main Methods:

  • Investigated ATF5 protein as a substrate of the ubiquitin-proteasome pathway.
  • Analyzed the role of lysine residues and N-terminal methionine in ATF5 ubiquitination.
  • Examined the effect of cisplatin on ATF5 protein expression and its interaction with Cdc34.
  • Studied the subcellular localization of Cdc34 in response to cisplatin treatment.

Main Results:

  • ATF5 protein undergoes ubiquitin-dependent degradation independent of lysine residues.
  • N-terminal methionine is a site for ATF5 ubiquitination, indicating N-terminal ubiquitinylation-mediated degradation.
  • Cisplatin treatment increases ATF5 protein expression by inhibiting its proteasomal degradation.
  • Cisplatin promotes nucleus-to-cytoplasm translocation of Cdc34, reducing ATF5-Cdc34 interaction.

Conclusions:

  • ATF5 protein stability is regulated by the N-terminal ubiquitin-proteasome pathway.
  • Cisplatin enhances ATF5 protein levels by disrupting its degradation pathway.
  • Down-regulation of proteasome-mediated ATF5 degradation is a novel mechanism contributing to cisplatin-induced apoptosis.

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