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Molecular and Cellular Biology, August 2007, p. 5514-5522, Vol. 27, No. 15
0270-7306/07/$08.00+0     doi:10.1128/MCB.00199-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Activation of the c-Jun N-Terminal Kinase Pathway by MST1 Is Essential and Sufficient for the Induction of Chromatin Condensation during Apoptosis{triangledown}

Seiji Ura,1,2 Hiroshi Nishina,1* Yukiko Gotoh,3 and Toshiaki Katada2

Department of Developmental and Regenerative Biology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan,1 Department of Physiological Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan,2 Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan3

Received 2 February 2007/ Returned for modification 15 March 2007/ Accepted 17 May 2007

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.

* Corresponding author. Mailing address: Department of Developmental and Regenerative Biology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan. Phone: 81 3 5803 4659. Fax: 81 3 5803 5829. E-mail: nishina.dbio{at}mri.tmd.ac.jp

{triangledown} Published ahead of print on 4 June 2007.

Molecular and Cellular Biology, August 2007, p. 5514-5522, Vol. 27, No. 15
0270-7306/07/$08.00+0     doi:10.1128/MCB.00199-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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