Aberrant cell cycle checkpoint function and early embryonic death in Chk1−/− mice
- Hiroyuki Takai1,6,
- Kaoru Tominaga1,6,7,
- Noboru Motoyama1,8,
- Yohji A. Minamishima2,4,
- Hiroyasu Nagahama2,4,
- Tadasuke Tsukiyama2,4,
- Kyoji Ikeda1,
- Keiko Nakayama3,4,
- Makoto Nakanishi1,5,8, and
- Kei-ichi Nakayama2,3,4
- 1Department of Geriatric Research, National Institute for Longevity Sciences, Aichi 474-8522, Japan; 2Department of Molecular and Cellular Biology and 3Laboratory of Embryonic and Genetic Engineering, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan; 4CREST, Japan Science and Technology Corporation, Saitama 332-0012, Japan; 5Department of Biochemistry, Nagoya City University Medical School, Nagoya 467-8601, Japan
Abstract
The recent discovery of checkpoint kinases has suggested the conservation of checkpoint mechanisms between yeast and mammals. In yeast, the protein kinase Chk1 is thought to mediate signaling associated with the DNA damage checkpoint of the cell cycle. However, the function of Chk1 in mammals has remained unknown. Targeted disruption of Chk1 in mice showed thatChk1 −/− embryos exhibit gross morphologic abnormalities in nuclei as early as the blastocyst stage. In culture, Chk1 −/− blastocysts showed a severe defect in outgrowth of the inner cell mass and died of apoptosis. DNA replication block and DNA damage failed to arrest the cell cycle before initiation of mitosis inChk1 −/− embryos. These results may indicate that Chk1 is indispensable for cell proliferation and survival through maintaining the G2 checkpoint in mammals.
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Footnotes
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↵6 These authors contributed equally to this work.
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↵7 Present address: Huffington Center on Aging, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
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↵8 Corresponding author.
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E-MAIL mkt-naka{at}med.nagoya-cu.ac.jp; FAX 81 52 842 3955.
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E-MAIL motoyama{at}nils.go.jp; FAX 81 562 446595.
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- Received March 15, 2000.
- Accepted May 1, 2000.
- Cold Spring Harbor Laboratory Press
