論文

査読有り
2008年9月

Cleavage-mediated activation of Chk1 during apoptosis

JOURNAL OF BIOLOGICAL CHEMISTRY
  • Kenkyo Matsuura
  • ,
  • Mitsuo Wakasugi
  • ,
  • Katsumi Yamashita
  • ,
  • Tsukasa Matsunaga

283
37
開始ページ
25485
終了ページ
25491
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1074/jbc.M803111200
出版者・発行元
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC

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.

Web of Science ® 被引用回数 : 34

リンク情報
DOI
https://doi.org/10.1074/jbc.M803111200
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/18550533
Web of Science
https://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=JSTA_CEL&SrcApp=J_Gate_JST&DestLinkType=FullRecord&KeyUT=WOS:000259012700044&DestApp=WOS_CPL
URL
http://europepmc.org/abstract/med/18550533
URL
http://orcid.org/0000-0003-4612-6031
ID情報
  • DOI : 10.1074/jbc.M803111200
  • ISSN : 0021-9258
  • ORCIDのPut Code : 45674063
  • PubMed ID : 18550533
  • Web of Science ID : WOS:000259012700044

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