c-Jun Downregulation by HDAC3-Dependent Transcriptional Repression Promotes Osmotic Stress-Induced Cell Apoptosis

• Published in: Molecular cell 2007-01, Vol.25 (2), p.219-232
• Main Authors: Xia, Yan, Wang, Ji, Liu, Ta-Jen, Yung, W.K. Alfred, Hunter, Tony, Lu, Zhimin
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis - drug effects; Apoptosis - physiology; Aspartic Acid - chemistry; Base Sequence; Caspase 7 - metabolism; Caspase 8 - metabolism; Cell Line; CELLCYCLE; DNA; DNA, Complementary - genetics; Down-Regulation - drug effects; Enzyme Activation; Fas Ligand Protein - metabolism; Histone Deacetylases - chemistry; Histone Deacetylases - metabolism; Humans; JNK Mitogen-Activated Protein Kinases - genetics; JNK Mitogen-Activated Protein Kinases - metabolism; MAP Kinase Kinase 1 - metabolism; MAP Kinase Kinase 2 - metabolism; Mice; Mitogen-Activated Protein Kinase 8 - metabolism; Mitogen-Activated Protein Kinase 9 - metabolism; Models, Biological; NIH 3T3 Cells; Osmotic Pressure; Peptide Fragments - genetics; Peptide Fragments - metabolism; Promoter Regions, Genetic; Sorbitol - pharmacology
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2007.01.005

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.