title: Activation of the c-Jun N-terminal kinase pathway by MST1 is essential and sufficient for the induction of chromatin condensation during apoptosis.
abstract: Chromatin condensation is the most recognizable nuclear hallmark of apoptosis. Cleavage and activation of MST1 by caspases induce chromatin condensation. It was previously reported that, during apoptosis, activated MST1 induced c-Jun N-terminal kinase (JNK) activation and also phosphorylated histone H2B. However, which of these mechanisms underlies MST1's induction of chromatin condensation has yet to be clarified. Here, we report that MST1-mediated activation of JNK is both essential and sufficient for chromatin condensation. MST1 activation did not result in chromatin condensation in mitogen-activate protein kinase kinase 4 (MKK4)/MKK7 double knockout (MKK4/7 DKO) embryonic stem (ES) cells, which genetically lack the ability to activate JNK. On the other hand, constitutively active JNK was able to induce chromatin condensation in MKK4/7 DKO ES cells. In contrast, histone H2B phosphorylation did not correlate with chromatin condensation in wild-type ES cells. Finally, inhibition of JNK as well as inhibitor of caspase-activated DNase blocked chromatin condensation during Fas-mediated apoptosis of Jurkat cells. Taken together, our results indicate that caspase-mediated cleavage of MST1, followed by MST1-mediated activation of the JNK pathway, is the mechanism responsible for inducing chromatin condensation during apoptosis.
authors.affiliation: Department of Developmental and Regenerative Biology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Ura
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nishina
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Gotoh
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Katada
mesh_terms: D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002843:Chromatin / Q000378:metabolism*; D004789:Enzyme Activation; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008954:Models, Biological; D010768:Phosphoserine / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D014158:Transcription, Genetic; D019014:fas Receptor / Q000378:metabolism
chemical_list: D002843:Chromatin; D006657:Histones; D011518:Proto-Oncogene Proteins; D019014:fas Receptor; C082332:macrophage stimulating protein; D010768:Phosphoserine; D017228:Hepatocyte Growth Factor; D048031:JNK Mitogen-Activated Protein Kinases; D020169:Caspases