Regulation of cell cycle checkpoints that monitor DNA damage and DNA replication block.

2005 Fiscal Year Final Research Report Summary

• Project/Area Number: 13043043
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: NAGOYACITY UNIVERSITY
• Principal Investigator: NAKANISHI Makoto Nagoya City University, Graduate School of Medical Sciences, Professor, 大学院医学研究科, 教授 (40217774)
• Project Period (FY): 2001 – 2005
• Keywords: gene / nucleic acid / cancer / genome / signal transduction

Research Abstract

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.

Research Products

• [Journal Article] DNA damage checkpoint in mammals. (2006)
  • Author(s): Niida, H., Nakanishi, M.
  • Journal Title: Mutagenesis. 21 Pages: 3-9
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Regulation of Cdc2p and Cdc13p is required for cell cycle arrest induced by defective RNA splicing in fission yeast. (2005)
  • Author(s): Shimada, M., Namikawa-Yamada, C., Nakanishi, M., Murakami, H.
  • Journal Title: J. Biol. Chem. 280 Pages: 32640-32648
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Depletion of Chk1 leads to premature activation of cdc2-cyclin B and mitotic catastrophy. (2005)
  • Author(s): Niida, H., Tsuge, S., Katsuno, Y., Konishi, A., Takeda, N., Nakanishi, M.
  • Journal Title: J. Biol. Chem. 280 Pages: 39246-39252
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] A checkpoint control linking meiotic S phase and recombination initiation in fission yeast. (2005)
  • Author(s): Tonami, Y., Murakami, H., Shirahige, K., Nakanishi, M.
  • Journal Title: Proc. Natl. Acad. Sci. 102 Pages: 5797-5801
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] A20 is a negative regulator of interferon regulatory factor 3 signaling. (2005)
  • Author(s): Saitoh, T., Yamamoto, M., Miyagi, M., Taira, K., Nakanishi, M., Fujita, T., Akira, S., Yamamoto, N., Yamaoka, S.
  • Journal Title: J. Immunol. 174 Pages: 1507-1512
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] NF-KappaB-activating kinase (NAK)-associatea protein (NAP) 1 participates in Toll-like receptor (TLR)3/Toll-IL-1 homology domain-containing adapter molecule (TICAM)-1-mediated IRF3 activation. (2005)
  • Author(s): Sasai, M., Oshiumi, H., Matsumoto, M., Inoue, N., Fujita F., Nakanishi, M., Seya T.
  • Journal Title: J. Immunol. 174 Pages: 27-30
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Regulation of Cdc2p and Cdcl3p is required for cell cycle arrest induced by defective RNA splicing in fission yeast. (2005)
  • Author(s): Shimada, M., Namikawa-Yamada, C., Nakanishi, M., Murakami, H.
  • Journal Title: J. Biol. Chem. 280 Pages: 32640-32648
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Depletion of Chkl leads to premature activation of cdc2-cyclin B and mitotic catastrophy. (2005)
  • Author(s): Niida, H., Tsuge, S., Katsuno, Y., Konishi, A., Takeda, N., Nakanishi, M.
  • Journal Title: J. Biol. Chem. 280 Pages: 39246-39252
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] NF-kappaB-activating kinase (NAK)- associated protein (NAP) 1 participates in Toll-like receptor (TLR)3/Toll-IL-1 homology domain-containing adapter molecule (TICAM)-1-mediated IRF3 activation. (2005)
  • Author(s): Sasai, M., Oshiumi, H., Matsumoto, M., Inoue, N., Fujita, F., Nakanishi, M., Seya T.
  • Journal Title: J. Immunol. 174 Pages: 27-30
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] DNA replication checkpoint control mediated by the spindle checkpoint protein Mad2p in fission yeast. (2004)
  • Author(s): Sugimoto, I., Murakami, H., Tonami, Y., Moriyama, A., Nakanishi.M.
  • Journal Title: J. Biol. Chem. 279 Pages: 47372-47378
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Activation of ATM and Chk2 kinases in relation to the amount of DNA strand breaks. (2004)
  • Author(s): Buscemi, G., Perego, P., Carenini, N., Nakanishi, M., Chessa, L., Chen, J., Khanna, K.K., Delia, D.
  • Journal Title: Oncogene. 23 Pages: 7691-7700
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Human SAD1 kinase is involved in UV-induced DNA damage checkpoint function. (2004)
  • Author(s): Lu, R., Niida, H., Nakanishi, M.
  • Journal Title: J. Biol. Chem. 279 Pages: 31164-31170
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Negative regulation of Chk2 expression by p53 is dependent on the CCAAT-binding transcription factor NF-Y. (2004)
  • Author(s): Matsui, T., Katsuno, Y., Inoue, Y., Fujita, F., Joh, T., Niida, H., Murakami, H., Itoh, M., Nakanishi.M.
  • Journal Title: J. Biol. Chem. 279 Pages: 25093-25100
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Susceptibility to killer T cells of gastric cancer cells enhanced by Mitomycin-C involves induction of ATBF1 and activation of p21(Waf1/ Cip1) promoter. (2004)
  • Author(s): Miura, Y., Kataoka, H., Joh, T., Tada, T., Asai, K., Nakanishi, M., Okada, N., Okada.H.
  • Journal Title: Microbiol Immunol. 48 Pages: 137-145
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Identification and characterization of polymorphic variations of the ataxia telangiectasia mutated (ATM) gene in childhood Hodgkin disease. (2004)
  • Author(s): Takagi, M., Tsuchida, R, Oguchi, K, Shigeta, T., Nakada, S., Shimizu, K., Ohki, M., Delia, D., Chessa, L., Taya, Y., Nakanishi.M., Tsunematsu, Y., Bessho, F., Isoyama, K., Hayashi, Y., Kudo, K., Okamura, J., Mizutani, S.
  • Journal Title: Blood. 103 Pages: 283-290
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] DNA replication checkpoint control mediated by the spindle checkpoint protein Mad2p in fission yeast. (2004)
  • Author(s): Sugimoto, I., Murakami, H., Tonami, Y., Moriyama, A., Nakanishi, M.
  • Journal Title: J. Biol. Chem. 279 Pages: 47372-47378
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Negative regulation of Chk2 expression by p53 is dependent on the CCAAT-binding transcription factor NF-Y. (2004)
  • Author(s): Matsui, T., Katsuno, Y., Inoue, Y., Fujita, F., Joh, T., Niida, H., Murakami, H., Itoh, M., Nakanishi, M.
  • Journal Title: J. Biol. Chem. 279 Pages: 25093-25100
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Susceptibility to killer T cells of gastric cancer cells enhanced by Mitomycin-C involves induction of ATBF 1 and activation of p21(Wafl/Cipl) promoter. (2004)
  • Author(s): Miura, Y., Kataoka, H., Joh, T., Tada, T., Asai, K., Nakanishi, M., Okada, N., Okada, H.
  • Journal Title: Microbiol Immunol. 48 Pages: 137-145
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Identification and characterization of polymorphic variations of the ataxia telangiectasia mutated (ATM) gene in childhood Hodgkin disease. (2004)
  • Author(s): Takagi, M., Tsuchida, R., Oguchi, K., Shigeta, T., Nakada, S., Shimizu, K., Ohki, M., Delia, D., Chessa, L., Taya, Y., Nakanishi, M.Tsunematsu, Y., Bessho, F., Isoyama, K., Hayashi, Y., Kudo, K., Okamura, J., Mizutani, S.
  • Journal Title: Blood. 103 Pages: 283-290
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Identification of NAP1, a regulatory subunit of IkappaB kinase-related kinases that potentiates NF-kappaB signaling. (2003)
  • Author(s): Fujita, F., Taniguchi, Y., Kato, T., Narita, Y., Furuya, A., Ogawa, T., Sakurai, H., Joh, T., Itoh, M., Delhase, M., Karin, M., Nakanishi, M.
  • Journal Title: Mol. Cell. Biol. 23 Pages: 7780-7793
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Genomic structure and characterization of the promoter region of the human NAK gene. (2003)
  • Author(s): Li, S.F., Fujita, F., Hirai, M., Lu, R., Niida, H., Nakanishi, M.
  • Journal Title: Gene. 304 Pages: 57-64
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Stretch-induced IL-6 secretion from endothelial cells requires NF-kappaB activation. (2003)
  • Author(s): Kobayashi, S., Nagino, M., Komatsu, S., Naruse, Kl., Nimura, Y., Nakanishi, M., Sokabe, M.
  • Journal Title: Biochem. Biophys. Res. Commun. 308 Pages: 306-312
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Ishimi, Y., Komamura, Kohno, Y., Kwon, H.J., Yamada, K., and Nakanishi, M. (2003)
  • Author(s): Ishimi, Y., Komamura, Kohno, Y., Kwon, H.J., Yamada, K., Nakanishi, M.
  • Journal Title: J. Biol. Chem. 278 Pages: 24644-24650
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Loss of p27(Kip1) accelerates DNA replication after partial hepatectomy in mice. (2003)
  • Author(s): Hayashi, E., Yasui, A., Oda, K., Nagino, M., Nimura, Y., Nakanishi, M., Motoyama, N., Ikeda, K., Matsuura, A.
  • Journal Title: J. Surg. Res. 111 Pages: 196-202
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Identification of NAP1, a regulatory subunit of IkappaB kinase- related kinases that potentiates NF-kappaB signaling. (2003)
  • Author(s): Fujita, F., Taniguchi, Y., Kato, T., Narita, Y., Furuya, A., Ogawa, T., Sakurai, H., Joh, T., Itoh, M., Delhase, M., Karin, M., Nakanishi, M.
  • Journal Title: Mol. Cell. Biol. 23 Pages: 7780-7793
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Identification of MCM4 as a target of the DNA replication block checkpoint system. (2003)
  • Author(s): Ishimi, Y, Komamura, Kohno, Y., Kwon, H.J., Yamada, K., Nakanishi, M.
  • Journal Title: J. Biol. Chem. 278 Pages: 24644-24650
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Loss of p27(Kip 1) accelerates DNA replication after partial hepatectomy in mice. (2003)
  • Author(s): Hayashi, E., Yasui, A., Oda, K., Nagino, M., Nimura, Y., Nakanishi, M., Motoyama, N., Ikeda, K., Matsuura, A.
  • Journal Title: J. Surg. Res. 111 Pages: 196-202
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Chk2-deficient mice exhibit radioresistance and defective p53-mediated transcription. (2002)
  • Author(s): Takai, H., Naka, K., Okada, Y., Watanabe, M., Harada, N., Saito, S., Anderson, C.W., Appela, E., Nakanishi, M., Suzuki, H., Nagashima, K., Sawa, H., Ikeda, K., Motoyama, N.
  • Journal Title: EMBO J. 21 Pages: 5195-5205
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Maintenance of replication forks and the S-phase checkpoint by Cdc18p and Orp1p. (2002)
  • Author(s): Murakami, H., Yanow, S.K., Griffiths, D., Nakanishi, M., Nurse, P.
  • Journal Title: Nat. Cell Biol. 4 Pages: 384-388
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Hydrocephalus, Situs Inversus, Chronic Sinusitis, and Male Infertility in DNA Polymerase lambda-Deficient Mice : Possible Implication for the Pathogenesis of Immotile Cilia Syndrome. (2002)
  • Author(s): Kobayashi, Y., Watanabe, M., Okada, Y., Sawa, H., Takai, H., Nakanishi, M., Kawase, Y., Suzuki, H., Nagashima, K., Ikeda, K., Motoyama, N.
  • Journal Title: Mol. Cell. Biol. 22 Pages: 2769-2776
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Identification and characterization of Nek6 protein kinase, a potential human homolog of NIMA histone H3 kinase. (2002)
  • Author(s): Hashimoto, Y., Akita, H., Hibino, M., Kohri, K., Nakanishi, M.
  • Journal Title: Biochem. Biophys. Res. Commun. 293 Pages: 753-758
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Different hepatitis B virus genotype distributions among asymptomatic carriers and patients with liver diseases in Nanning, southern China. (2002)
  • Author(s): Ding, X., Mizokami, M., Ge, X., Orito, E., lino, S., Ueda R., Nakanishi, M.
  • Journal Title: Hepatology Res. 22 Pages: 37-44
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Maintenance of replication forks and the S-phase checkpoint by Cdcl8p and Oiplp. (2002)
  • Author(s): Murakami, H., Yanow, S.K., Griffiths, D., Nakanishi, M., Nurse, P.
  • Journal Title: Nat. Cell Biol. 4 Pages: 384-388
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] and Male Infertility in DNA Polymerase lambda-Deficient Mice : Possible Implication for the Pathogenesis of Immotile Cilia Syndrome. (2002)
  • Author(s): Kobayashi, Y., Watanabe, M., Okada, Y., Sawa, H., Takai, H., Nakanishi, M., Kawase, Y., Suzuki, H., Nagashima, K., Ikeda, K., Motoyama, N.Hydrocephalus, Situs Inversus, Chronic Sinusitis
  • Journal Title: Mol. Cell. Biol. 22 Pages: 2769-2776
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Different hepatitis B virus genotype distributions among asymptomatic carriers and patients with liver diseases in Nanning, southern China. (2002)
  • Author(s): Ding, X.Mizokami, M., Ge, X., Orito, E., Iino, S., Ueda R., Nakanishi, M.
  • Journal Title: Hepatology Res. 22 Pages: 37-44
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] A degradation signal located in the C-terminus of p21WAF1/CIP1 is a binding site for the C8 α-subunit of the 20S proteasome. (2001)
  • Author(s): Touitou, R., Richardson, J., Bose, S., Nakanishi, M., Rivett, J., Allday, M.J.
  • Journal Title: EMBO J. 20 Pages: 2367-2375
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Nbs1 dependence of Chk2 activation after DNA-damage. (2001)
  • Author(s): Buscemi, G., Savio, C., Zannini, L., Micciche, F., Masnada, D., Nakanishi, M., Tauchi, H., Komatsu, K., Mizutani, S., Khanna, K.K., Chen, P., Concannon, P., Chessa, L., Delia, D.
  • Journal Title: Mol. Cell. Biol. 21 Pages: 5214-5222
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] C/EBBα cooperates with p21 to inhibit cdk2 kinase activity and induces growth arrest independent of DNA binding. (2001)
  • Author(s): Harris, T.E., Albrecht, J.H., Nakanishi, M., Darlington, G.J.
  • Journal Title: J. Biol. Chem. 276 Pages: 29200-29209
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Regulation of aquaporin-4 expression in astrocytes. (2001)
  • Author(s): Yoneda, K., Yamamoto, N., Asai, K., Sobue, K., Fujita, Y., Fujita, M., Mase, M., Yamada, K., Nakanishi, M., Tada, T., Miura, Y., Kato, T.
  • Journal Title: Mol. Brain Res. 89 Pages: 94-102
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Hepatitis B virus genotype distribution among chronic hepatitis B virus carriers in Shanghai, China. (2001)
  • Author(s): Ding, A., Mizokami, M., Yao, G., Xu, G., Orito, E., Ueda, R., Nakanishi, M.
  • Journal Title: Intervirology 44 Pages: 43-47
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] A degradation signal located in the C-terminus of p21WAF1/CIP1 is a binding site for the C8a-subunit of the 20S proteasome. (2001)
  • Author(s): Touitou, R., Richardson, J., Bose, S., Nakanishi, M., Rivett, J., Allday, M.J.
  • Journal Title: EMBO J. 20 Pages: 2367-2375
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Nbsl dependence of Chk2 activation after DNA-damage. (2001)
  • Author(s): Buscemi, G., Savio, C., Zannini, L., Micciche, F., Masnada, D., Nakanishi, M., Tauchi, H., Komatsu, K., Mizutani, S., Khanna, K.K., Chen, P., Concannon, P., Chessa, L., Delia, D.
  • Journal Title: Mol. Cell. Biol. 21 Pages: 5214-5222
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] C/EBPa cooperates with p21 to inhibit cdk2 kinase activity and induces growth arrest independent of DNA binding. (2001)
  • Author(s): Harris, T.E., Albrecht, J.H., Nakanishi, M., Darlington, G.J.
  • Journal Title: J. Biol. Chem. 276 Pages: 29200-29209
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Regulation of aquaporin-4 expression in astrocytes. (2001)
  • Author(s): Yoneda, K., Yamamoto, N.Asai, K., Sobue, K., Fujita, Y., Fujita, M., Mase, M., Yamada, K., Nakanishi, M., Tada, T., Miura, Y., Kato, T.
  • Journal Title: Mol. Brain Res. 89 Pages: 94-102
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Hepatitis B virus genotype distribution among chronic hepatitis B virus carriers in Shanghai, China. (2001)
  • Author(s): Ding, X., Mizokami, M., Yao, G., Xu, G., Orito, E., Ueda, R., Nakanishi, M.
  • Journal Title: Intervirology 44 Pages: 43-47
  • Description: 「研究成果報告書概要(欧文)」より