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

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. (C) 2013 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.