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Area of Science:

  • Molecular Biology
  • Cellular Stress Response
  • Cancer Therapeutics

Background:

  • Endoplasmic reticulum (ER) stress triggers adaptive responses via gene expression reprogramming.
  • Activating transcription factor 4 (ATF4) is a key transcription factor induced by ER stress.
  • ER stress-induced ATF4 translation is mediated by phosphorylated translation initiation factor 2 alpha (p-eIF2α).

Purpose of the Study:

  • To identify factors involved in p-eIF2α-mediated ATF4 translation.
  • To investigate the role of RNA-binding proteins in ER stress-induced ATF4 expression.
  • To elucidate the mechanism of ATF4 regulation by DDX3 in cancer cells.

Main Methods:

  • Depletion experiments using RNA interference to assess DDX3 function.
  • Luciferase and polyribosomes assays to study mRNA translation.
  • Protein-interaction assays to determine binding partners.

Main Results:

  • DDX3 was identified as an RNA-binding protein that promotes ATF4 expression in cancer cells treated with sorafenib.
  • DDX3 depletion inhibited p-eIF2α-mediated ATF4 expression.
  • DDX3 was shown to drive ATF4 mRNA translation under ER stress and bind the eIF4F complex.

Conclusions:

  • DDX3 is essential for p-eIF2α-mediated ATF4 mRNA translation during ER stress.
  • The eIF4F complex is required for ER stress-induced ATF4 expression.
  • DDX3 acts as a crucial component of the eIF4F complex in regulating ATF4 translation.