ATF4 activation by the p38MAPK-eIF4E axis mediates apoptosis and autophagy induced by selenite in Jurkat cells

FEBS Lett. 2013 Aug 2;587(15):2420-9. doi: 10.1016/j.febslet.2013.06.011. Epub 2013 Jun 19.


Previous studies have shown that selenite exerts pro-apoptosis and pro-autophagy effects and is associated with the activation of ER stress in T-cell acute lymphoblastic leukemia (T-ALL). Herein we demonstrate the underlying mechanisms by which the activation of p38MAPK plays essential roles in apoptosis and autophagy and the coordination of cellular metabolic processes during leukemia therapy. MKK3/6-dependent activation of p38MAPK is required for the phosphorylation of eIF4E, thus initiating the translation of ER stress-related transcription factor ATF4. Upregulated ATF4 results in the transcriptional initiation of the apoptosis-related chop gene and autophagy-related map1lc3b gene, through which selenite links ER stress to apoptosis and autophagy during leukemia treatment. Moreover, autophagy induction enhances cell apoptosis under this condition.

Keywords: 17-AAG; 17-allylamino-demethoxygeldamycin; ATF4; Apoptosis; Autophagy; Hsp90; Sodium selenite; eIF2α; eIF4E; eukaryotic translation initiation factor 2 subunit alpha; eukaryotic translation initiation factor 4E; heat shock protein 90; p38MAPK; s.c.; subcutaneous injection.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factor 4 / metabolism*
  • Apoptosis / drug effects*
  • Autophagy / drug effects*
  • Endoplasmic Reticulum / drug effects
  • Enzyme Activation
  • Eukaryotic Initiation Factor-4E / metabolism*
  • Humans
  • Jurkat Cells
  • Real-Time Polymerase Chain Reaction
  • Sodium Selenite / pharmacology*
  • p38 Mitogen-Activated Protein Kinases / metabolism*


  • ATF4 protein, human
  • Eukaryotic Initiation Factor-4E
  • Activating Transcription Factor 4
  • p38 Mitogen-Activated Protein Kinases
  • Sodium Selenite