c-Jun downregulation by HDAC3-dependent transcriptional repression promotes osmotic stress-induced cell apoptosis.
c-Jun, a major transcription factor in the activating protein 1 (AP-1) family of regulatory proteins, is activated by many physiologic and pathologic stimuli. However, whether c-jun is regulated by epigenetic modification of chromatin structure is not clear. We showed here that c-jun was transcriptionally repressed in response to osmotic stress via a truncated HDAC3 generated by caspase-7-dependent cleavage at aspartic acid 391. The activation of caspase-7, which is independent of cytochrome c release and activation of caspase-9 and caspase-12, depends on activation of caspase-8, which in turn requires MEK2 activity and secretion of FAS ligand. The cell apoptosis induced by the truncated HDAC3 or enhanced by c-Jun deficiency during osmotic stress was suppressed by exogenous expression of c-Jun, indicating that the downregulation of c-Jun by HDAC3-dependent transcriptional repression plays a role in regulating cell survival and apoptosis.
Xia
Yan
Y
Brain Tumor Center and Department of Neuro-Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Wang
Ji
J
Liu
Ta-Jen
TJ
Yung
W K Alfred
WK
Hunter
Tony
T
Lu
Zhimin
Z
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001224:Aspartic Acid / Q000737:chemistry; D001483:Base Sequence; D053179:Caspase 7 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D002460:Cell Line; D018076:DNA, Complementary / Q000235:genetics; D015536:Down-Regulation / Q000187:drug effects; D004789:Enzyme Activation; D053222:Fas Ligand Protein / Q000378:metabolism; D006655:Histone Deacetylases / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D048369:MAP Kinase Kinase 1 / Q000378:metabolism; D048370:MAP Kinase Kinase 2 / Q000378:metabolism; D051379:Mice; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism; D048056:Mitogen-Activated Protein Kinase 9 / Q000378:metabolism; D008954:Models, Biological; D041681:NIH 3T3 Cells; D009997:Osmotic Pressure; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D013012:Sorbitol / Q000494:pharmacology; D000099186:Histone Deacetylase 3
D001224:Aspartic Acid; D053179:Caspase 7; D053181:Caspase 8; D018076:DNA, Complementary; D053222:Fas Ligand Protein; D006655:Histone Deacetylases; D048031:JNK Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; D048055:Mitogen-Activated Protein Kinase 8; D048056:Mitogen-Activated Protein Kinase 9; D010446:Peptide Fragments; D013012:Sorbitol; D000099186:Histone Deacetylase 3; C505658:Fasl protein, mouse; C482127:Map2k1 protein, mouse; C482129:Map2k2 protein, mouse; C505526:Casp8 protein, mouse