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Analysis of Translation Initiation During Stress Conditions by Polysome Profiling
10:59

Analysis of Translation Initiation During Stress Conditions by Polysome Profiling

Published on: May 19, 2014

Regulated translation initiation controls stress-induced gene expression in mammalian cells

H P Harding1, I Novoa, Y Zhang

  • 1Skirball Institute of Biomolecular Medicine The Department of Medicine, Kaplan Cancer Center New York University School of Medicine, New York, NY 10016, USA.

Molecular Cell
|December 7, 2000
PubMed

Insights

Stress-activated protein kinases regulating eukaryotic initiation factor 2 alpha (eIF2alpha) phosphorylation control gene expression. This study reveals their role in the unfolded protein response and amino acid starvation, impacting protein synthesis.

Area of Science:

  • Molecular Biology
  • Cellular Stress Response
  • Gene Regulation

Background:

  • Protein kinases phosphorylating eukaryotic initiation factor 2 alpha (eIF2alpha) are activated by cellular stress.
  • These kinases negatively regulate global protein synthesis.
  • Their specific roles in stress-induced gene expression were not fully elucidated.

Purpose of the Study:

  • To investigate the function of eIF2alpha kinases in mammalian cells under stress conditions.
  • To elucidate the role of these kinases in the unfolded protein response (UPR) and amino acid starvation.
  • To identify the downstream targets and regulatory pathways controlled by eIF2alpha kinases.

Main Methods:

  • Phenotypic analysis of targeted mutations in murine cells.
  • Investigating the activation of PERK and GCN2 kinases.
  • Analyzing the translational control of Activating Transcription Factor 4 (ATF4) and its downstream target CHOP (GADD153).

Main Results:

  • eIF2alpha kinases play a novel role in regulating gene expression during UPR and amino acid starvation.
  • Activated PERK and GCN2 repress general mRNA translation but selectively enhance ATF4 translation.
  • This leads to the induction of the downstream gene CHOP (GADD153).

Conclusions:

  • Mammalian cells utilize an ancient pathway, homologous to the yeast general control response, to regulate gene expression under diverse stress signals.
  • eIF2alpha phosphorylation by PERK and GCN2 is a key mechanism for coordinating cellular adaptation to stress.
  • This pathway highlights a conserved stress response involving translational control and specific gene induction.

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