Research Project
Grant-in-Aid for Scientific Research on Priority Areas
Chkl regulates both DNA damage and replication checkpoints in mammals. Although Chk1 is crucial for embryonic cell survival, its function in normal cell cycle remains largely unknown. With the use of a Cre/lox-conditional mouse line, we demonstrate here the essential and indispensable role of Chk1 in regulation of S-phase progression and prevention of mitotic initiation in embryonic cell cycle. An analysis using laser scanning cytometer revealed that Chk1 deficiency resulted in premature mitosis with the premature chromosome condensation and the phosphorylation of histone H3 at serine10 due to abnormal activation of cyclin B-Cdc2, and led to the activation of caspases 3 and 9 triggered by cytoplasmic release of cytochrome c. This deficiency was associated with foci formation by the phosphorylated histone, H2AX (gH2AX), specifically at S phase. Ectopic expression of Cdc2AF, a mutant that cannot be phosphorylated at inhibitory sites, also induced premature mitosis and foci formation by gH2AX at S phase in both ES cells and HCT116 cells. Inhibition of ATM and ATR with caffeine protected against cell death from premature mitosis. p53-deficient cells were highly resistant to lethality from premature mitosis as well. Our results therefore suggest that ATM/ATR-p53 is required for mitotic catastrophe that eliminates cells escaping Chk1-dependent mitotic regulation. Loss of this function might be important in mammalian tumorigenesis.
All 2006 2005 2004 2003 2002 2001 Other
All Journal Article (59 results) Publications (20 results)
Mutagenesis. 21
Pages: 3-9
J. Biol. Chem. 280
Pages: 32640-32648
Pages: 39246-39252
Proc. Natl. Acad. Sci. 102
Pages: 5797-5801
J. Immunol. 174
Pages: 1507-1512
Pages: 27-30
J.Biol.Chem. 280
Proc.Natl.Acad.Sci. 102
J.Immunol. 174
J. Biol. Chem. 279
Pages: 47372-47378
Oncogene. 23
Pages: 7691-7700
Pages: 31164-31170
Pages: 25093-25100
Microbiol Immunol. 48
Pages: 137-145
10012077282
Blood. 103
Pages: 283-290
J.Biol.Chem. 279
Mol. Cell. Biol. 23
Pages: 7780-7793
Gene. 304
Pages: 57-64
Biochem. Biophys. Res. Commun. 308
Pages: 306-312
J. Biol. Chem. 278
Pages: 24644-24650
J. Surg. Res. 111
Pages: 196-202
EMBO J. 21
Pages: 5195-5205
Nat. Cell Biol. 4
Pages: 384-388
Mol. Cell. Biol. 22
Pages: 2769-2776
Biochem. Biophys. Res. Commun. 293
Pages: 753-758
Hepatology Res. 22
Pages: 37-44
10012276513
EMBO J. 20
Pages: 2367-2375
Mol. Cell. Biol. 21
Pages: 5214-5222
J. Biol. Chem. 276
Pages: 29200-29209
Mol. Brain Res. 89
Pages: 94-102
Intervirology 44
Pages: 43-47
Proc.Natl.Acad.Sci. (In press)
J.Immunol. (In press)
J.Biol.Chem. (In press)