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SIRT1 suppresses activating transcription factor 4 (ATF4) expression in response to proteasome inhibition

Seon Rang Woo1, Jeong-Eun Park, Yang Hyun Kim

  • 1Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul 139-706, Republic of Korea.

Journal of Microbiology and Biotechnology
|October 9, 2013
PubMed

Insights

SIRT1 (a deacetylase) suppresses activating transcription factor 4 (ATF4) protein synthesis during proteasome inhibition stress. This regulation occurs post-transcriptionally, impacting cellular stress responses.

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Activating transcription factor 4 (ATF4) is a key regulator activated by cellular stress.
  • Proteasome inhibition triggers endoplasmic reticulum stress and the unfolded protein response, where ATF4 plays a crucial role.
  • Nutrient restriction, ER homeostasis, and oxidative stress activate ATF4 synthesis.

Purpose of the Study:

  • To investigate the role of SIRT1 in regulating ATF4 synthesis under stress conditions.
  • To determine the mechanism by which SIRT1 affects ATF4 levels during proteasome inhibition.

Main Methods:

  • Utilized siRNA to deplete SIRT1 in HeLa cells.
  • Employed SIRT1-overexpressing plasmids for overexpression studies.
  • Administered the proteasome inhibitor MG132.
  • Analyzed ATF4 protein and mRNA levels via Western blotting and RT-PCR.

Main Results:

  • SIRT1 depletion significantly increased ATF4 protein levels during MG132 treatment.
  • SIRT1 overexpression decreased ATF4 protein levels in the presence of MG132.
  • ATF4 mRNA levels remained unaffected by SIRT1 modulation, indicating post-transcriptional regulation.

Conclusions:

  • SIRT1 acts as a negative regulator of ATF4 protein synthesis.
  • The suppression of ATF4 by SIRT1 occurs at the post-transcriptional level.
  • SIRT1 plays a significant role in managing cellular stress responses by controlling ATF4 levels.

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