title: Cooperative functions of Chk1 and Chk2 reduce tumour susceptibility in vivo.
abstract: 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.
authors.affiliation: Department of Cell Biology, Nagoya City University, Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Niida
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Murata
authors.forename: Midori
authors.initials: M
authors.lastname: Shimada
authors.forename: Kumiko
authors.initials: K
authors.lastname: Ogawa
authors.forename: Kumiko
authors.initials: K
authors.lastname: Ohta
authors.forename: Kyoko
authors.initials: K
authors.lastname: Suzuki
authors.forename: Hidetsugu
authors.initials: H
authors.lastname: Fujigaki
authors.forename: Aik Kia
authors.initials: AK
authors.lastname: Khaw
authors.forename: Birendranath
authors.initials: B
authors.lastname: Banerjee
authors.forename: M Prakash
authors.initials: MP
authors.lastname: Hande
authors.forename: Tomomi
authors.initials: T
authors.lastname: Miyamoto
authors.forename: Ichiro
authors.initials: I
authors.lastname: Miyoshi
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Shirai
authors.forename: Noboru
authors.initials: N
authors.lastname: Motoyama
authors.forename: Mireille
authors.initials: M
authors.lastname: Delhase
authors.forename: Ettore
authors.initials: E
authors.lastname: Appella
authors.forename: Makoto
authors.initials: M
authors.lastname: Nakanishi
mesh_terms: 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*
chemical_list: D011494:Protein Kinases; D064447:Checkpoint Kinase 2; D000071877:Checkpoint Kinase 1; C000605869:Chek1 protein, mouse; C578633:Chek2 protein, mouse; D017346:Protein Serine-Threonine Kinases