Cooperative functions of Chk1 and Chk2 reduce tumour susceptibility in vivo

Hiroyuki Niida, Kazuhiro Murata, Midori Shimada, Kumiko Ogawa, Kumiko Ohta, Kyoko Suzuki, Hidetsugu Fujigaki, Aik Kia Khaw, Birendranath Banerjee, M. Prakash Hande, Tomomi Miyamoto, Ichiro Miyoshi, Tomoyuki Shirai, Noboru Motoyama, Mireille Delhase, Ettore Appella, Makoto Nakanishi

Research output: Contribution to journalArticle

36 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)3558-3570
Number of pages13
JournalEMBO Journal
Volume29
Issue number20
DOIs
Publication statusPublished - 01-10-2010

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Tumors
DNA Damage
S Phase Cell Cycle Checkpoints
DNA
Neoplasms
1-phenyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline
Phosphotransferases
Oncogenes
DNA Repair
Fibroblasts
Alleles
Repair
Phenotype
Mutation

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

Cite this

Niida, H., Murata, K., Shimada, M., Ogawa, K., Ohta, K., Suzuki, K., ... Nakanishi, M. (2010). Cooperative functions of Chk1 and Chk2 reduce tumour susceptibility in vivo. EMBO Journal, 29(20), 3558-3570. https://doi.org/10.1038/emboj.2010.218
Niida, Hiroyuki ; Murata, Kazuhiro ; Shimada, Midori ; Ogawa, Kumiko ; Ohta, Kumiko ; Suzuki, Kyoko ; Fujigaki, Hidetsugu ; Khaw, Aik Kia ; Banerjee, Birendranath ; Hande, M. Prakash ; Miyamoto, Tomomi ; Miyoshi, Ichiro ; Shirai, Tomoyuki ; Motoyama, Noboru ; Delhase, Mireille ; Appella, Ettore ; Nakanishi, Makoto. / Cooperative functions of Chk1 and Chk2 reduce tumour susceptibility in vivo. In: EMBO Journal. 2010 ; Vol. 29, No. 20. pp. 3558-3570.
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Niida, H, Murata, K, Shimada, M, Ogawa, K, Ohta, K, Suzuki, K, Fujigaki, H, Khaw, AK, Banerjee, B, Hande, MP, Miyamoto, T, Miyoshi, I, Shirai, T, Motoyama, N, Delhase, M, Appella, E & Nakanishi, M 2010, 'Cooperative functions of Chk1 and Chk2 reduce tumour susceptibility in vivo', EMBO Journal, vol. 29, no. 20, pp. 3558-3570. https://doi.org/10.1038/emboj.2010.218

Cooperative functions of Chk1 and Chk2 reduce tumour susceptibility in vivo. / Niida, Hiroyuki; Murata, Kazuhiro; Shimada, Midori; Ogawa, Kumiko; Ohta, Kumiko; Suzuki, Kyoko; Fujigaki, Hidetsugu; Khaw, Aik Kia; Banerjee, Birendranath; Hande, M. Prakash; Miyamoto, Tomomi; Miyoshi, Ichiro; Shirai, Tomoyuki; Motoyama, Noboru; Delhase, Mireille; Appella, Ettore; Nakanishi, Makoto.

In: EMBO Journal, Vol. 29, No. 20, 01.10.2010, p. 3558-3570.

Research output: Contribution to journalArticle

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T1 - Cooperative functions of Chk1 and Chk2 reduce tumour susceptibility in vivo

AU - Niida, Hiroyuki

AU - Murata, Kazuhiro

AU - Shimada, Midori

AU - Ogawa, Kumiko

AU - Ohta, Kumiko

AU - Suzuki, Kyoko

AU - Fujigaki, Hidetsugu

AU - Khaw, Aik Kia

AU - Banerjee, Birendranath

AU - Hande, M. Prakash

AU - Miyamoto, Tomomi

AU - Miyoshi, Ichiro

AU - Shirai, Tomoyuki

AU - Motoyama, Noboru

AU - Delhase, Mireille

AU - Appella, Ettore

AU - Nakanishi, Makoto

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N2 - 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.

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Niida H, Murata K, Shimada M, Ogawa K, Ohta K, Suzuki K et al. Cooperative functions of Chk1 and Chk2 reduce tumour susceptibility in vivo. EMBO Journal. 2010 Oct 1;29(20):3558-3570. https://doi.org/10.1038/emboj.2010.218