| Institution: | 1. Department of Cell Biology, Nagoya City University, Kawasumi, Mizuho‐cho, Mizuho‐ku, Nagoya, Japan;2. Department of Biochemistry, Hamamatsu University School of Medicine, Handayama, Higashi‐ku, Hamamatsu, Shizuoka, Japan;3. Department of Experimental Pathology and Tumor Biology, Nagoya City University, Kawasumi, Mizuho‐cho, Mizuho‐ku, Nagoya, Japan;4. Department of Cognitive Brain Science, National Center for Geriatrics and Gerontology, Obu, Aichi, Japan;5. Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA;6. Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore;7. Department of Comparative and Experimental Medicine and Center for Animal Science, Graduate School of Medical Sciences, Nagoya City University, Kawasumi, Mizuho‐cho, Mizuho‐ku, Nagoya, Japan |
| 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. |
