Cooperative functions of Chk1 and Chk2 reduce tumour susceptibility in vivo.
Although the linkage of Chk1 and Chk2 to important cancer signalling suggests that these kinases have functions as tumour suppressors, neither Chk1+/- nor Chk2-/- mice show a predisposition to cancer under unperturbed conditions. We show here that Chk1+/-Chk2-/- and Chk1+/-Chk2+/- mice have a progressive cancer-prone phenotype. Deletion of a single Chk1 allele compromises G2/M checkpoint function that is not further affected by Chk2 depletion, whereas Chk1 and Chk2 cooperatively affect G1/S and intra-S phase checkpoints. Either or both of the kinases are required for DNA repair depending on the type of DNA damage. Mouse embryonic fibroblasts from the double-mutant mice showed a higher level of p53 with spontaneous DNA damage under unperturbed conditions, but failed to phosphorylate p53 at S23 and further induce p53 expression upon additional DNA damage. Neither Chk1 nor Chk2 is apparently essential for p53- or Rb-dependent oncogene-induced senescence. Our results suggest that the double Chk mutation leads to a high level of spontaneous DNA damage, but fails to eliminate cells with damaged DNA, which may ultimately increase cancer susceptibility independently of senescence.
Niida
Hiroyuki
H
Department of Cell Biology, Nagoya City University, Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Japan.
Murata
Kazuhiro
K
Shimada
Midori
M
Ogawa
Kumiko
K
Ohta
Kumiko
K
Suzuki
Kyoko
K
Fujigaki
Hidetsugu
H
Khaw
Aik Kia
AK
Banerjee
Birendranath
B
Hande
M Prakash
MP
Miyamoto
Tomomi
T
Miyoshi
Ichiro
I
Shirai
Tomoyuki
T
Motoyama
Noboru
N
Delhase
Mireille
M
Appella
Ettore
E
Nakanishi
Makoto
M
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002453:Cell Cycle / Q000502:physiology*; D002478:Cells, Cultured; D016922:Cellular Senescence; D000071877:Checkpoint Kinase 1; D064447:Checkpoint Kinase 2; D002869:Chromosome Aberrations; D004249:DNA Damage; D004260:DNA Repair; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D017353:Gene Deletion; D053208:Kaplan-Meier Estimate; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*
D011494:Protein Kinases; D064447:Checkpoint Kinase 2; D000071877:Checkpoint Kinase 1; C000605869:Chek1 protein, mouse; C578633:Chek2 protein, mouse; D017346:Protein Serine-Threonine Kinases