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J. Biol. Chem., Vol. 283, Issue 37, 25485-25491, September 12, 2008

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Cleavage-mediated Activation of Chk1 during Apoptosis^*

From the Laboratory of Human Molecular Genetics, Graduate School of Natural Science and Technology, Kanazawa University, Kanazawa 920-1192, Japan

The Chk1 kinase is highly conserved from yeast to humans and is well known to function in the cell cycle checkpoint induced by genotoxic or replication stress. The activation of Chk1 is achieved by ATR-dependent phosphorylation with the aid of additional factors. Robust genotoxic insults induce apoptosis instead of the cell cycle checkpoint, and some of the components in the ATR-Chk1 pathway are cleaved by active caspases, although it has been unclear whether the attenuation of the ATR-Chk1 pathway has some role in apoptosis induction. Here we show that Chk1 is activated by caspase-dependent cleavage when the cells undergo apoptosis. Treatment of chicken DT40 cells with various genotoxic agents, UV light, etoposide, or camptothecin induced Chk1 cleavage, which was inhibited by a pan-caspase inhibitor, benzyloxycarbonyl-VAD-fluoromethyl ketone. The cleavage of Chk1 was similarly observed in human Jurkat cells treated with a non-genotoxic apoptosis inducer, staurosporine. We have determined the cleavage site(s), Asp-299 in chicken and Asp-299 and Asp-351 in human cells. We further show that a truncated form of human Chk1 mimicking the N-terminal cleavage fragment (residues 1–299) possesses strikingly elevated kinase activity. Moreover, the ectopic expression of Chk1-(1–299) in human U2OS cells induces abnormal nuclear morphology with localized chromatin condensation and phosphorylation of histone H2AX. These results suggest that Chk1 is activated by caspase-mediated cleavage during apoptosis and might be implicated in enhancing apoptotic reactions rather than attenuating the ATR-Chk1 pathway.

Received for publication, April 23, 2008 , and in revised form, June 9, 2008.

^* This work was supported in part by grants-in-aid for scientific research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Laboratory of Human Molecular Genetics, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan. Tel.: 81-76-234-4487; Fax: 81-76-234-4427; E-mail: matsukas{at}kenroku.kanazawa-u.ac.jp.

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