Molecular Mechanism of Mitotic Catastrophe

• Project/Area Number: 17390084
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General medical chemistry
• 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)
• Co-Investigator(Kenkyū-buntansha): MURAKMI Hiroshi Nagoya City University, Graduate School ot Medical Sciences, Associate Professor, 大学院医学研究科, 助教授 (80262020) ; NIIDA Hiroyuki Nagoya City University, Graduate School of Medical Sciences, Assistant Professor, 大学院医学研究科, 助手 (20336671)
• Project Period (FY): 2005 – 2006
• Project Status: Completed (Fiscal Year 2006)
• Budget Amount: ¥14,600,000 (Direct Cost: ¥14,600,000); Fiscal Year 2006: ¥5,600,000 (Direct Cost: ¥5,600,000); Fiscal Year 2005: ¥9,000,000 (Direct Cost: ¥9,000,000)
• Keywords: cell cycle / checkpoint / Apoptosis

Research Abstract

Mitotic catastrophe has been first identified as a lethal phenotype with gross abnormalities of chromosome segregation during mitosis in some fission yeast mutant strains. Similar lethal phenotype was also observed in mammalian cells as a result from premature mitosis or failure to undergo complete mitosis. However, there is no broadly accepted definition of the term "mitotic catastrophe", presumably due to lack of the major processes dictating mitotic catastrophe in molecular and genetic terms. Mitotic catastrophe occurs as a result of uncoupling of the onset of mitosis from the completion of DNA replication, but how the ensuing lethality is regulated or what signals are involved is largely unknown. We demonstrate here the essential role of the ATM/ATR-Chk2-p53 pathway in the mitotic catastrophe observed in Chkl-deficient cells. Chk1 deficiency resulted in a premature onset of mitosis due to abnormal activation of cyclin B-Cdc2, and led to the activation of caspases 3 and 9 through cytoplasmic release of histone H1 and cytochrome c. Chkl-deficient cells were effectively rescued from lethality by the addition of caspase inhibitor. The Chkl deficiency resulted in foci formation of phosphorylated histone H2AX and the activation of Chk2, followed by an increase in the amount of p53 protein. Inhibition of ATM and ATR with caffeine also protected the lethality-prone Chkl-deficient cells. Chk2-deficient and p53-deficient cells were resistant to lethality from Chkl depletion. Our results therefore suggest that ATM/ATR-Chk2-p53 is required for mitotic catastrophe that eliminates cells escaping Chkl-dependent mitotic regulation. Loss of this function might be important in mammalian tumorigenesis.

Research Products

• [Journal Article] Biological Effects and Field Emission-Type X-Rays Generated by Nanotechnology. (2007)
  • Author(s): Nakato, T., Namanishi, M., Kita, S., Okuyama.F., Shibamoto, Y., Otuka, T.
  • Journal Title: Radiat. Res. 48 Pages: 153-161
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] M. Specific role of Chk1 phosphorylation in cell survival and checkpoint activation. (2007)
  • Author(s): Niida, H., Katsuno, Y., Prakash, H.M., Nakanishi
  • Journal Title: Mol Cell Biol. 27 Pages: 2572-2581
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Specific role of Chk1 phosphorylation in cell survival and checkpoint activation. (2007)
  • Author(s): Niida, H., Katsuno, Y., Prakash, H.M., Nakanishi, M.
  • Journal Title: Mol Cell Biol. 27 Pages: 2572-2581
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Biological Effects and Field Emission-Type X-Rays Generated by Nanotechnology. (2007)
  • Author(s): Nakato, T., Namanishi, M., Kita, S., Okuyrama.F., Shibamoto, Y., Otuka, T.
  • Journal Title: Radiat. Res. 48 Pages: 153-161
• [Journal Article] DNA damage checkpoints and cancer. (2006)
  • Author(s): Shimada, M., Nakanishi, M.
  • Journal Title: J. Mol Histol. 37 Pages: 253-260
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Genetic instability in cancer cells by inipaired cell cycle checkpoints. (2006)
  • Author(s): Nakanishi, M., Shimada, M., Niida, H.
  • Journal Title: Cancer Sci. 97 Pages: 984-989
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Regulation of mitotic function of Chk1 through phosphorylation at novel sites by cyclin-dependent kinase 1 (Cdk1). (2006)
  • Author(s): Shiromizu, T., Goto, H., Tomono, Y., Bartek, J., Totsukawa, G., Inoko, A., Nakanishi, M., Matsumura, F., Inagaki, M.
  • Journal Title: Genes Cells. 11 Pages: 477-485
  • Description: 「研究成果報告書概要(和文)」より
• [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] Genetic instability in cancer cells by impaired cell cycle checkpoints. (2006)
  • Author(s): Nakanishi, M., Shimada, M., Niida, H.
  • Journal Title: Cancer Sci. 97 Pages: 984-989
  • NAID: 10019377681
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Regulation of mitotic function of Chk1 through phosphorylation at novel sites by cyclin-dependent kinase 1(Cdk1). (2006)
  • Author(s): Shiromizu, T., Goto, H., Tomono, Y., Bartek, J., Totsukawa, G., Inoko, A., Nakanishi, M., Matsumura, F., Inagaki, M.
  • Journal Title: Genes Cells. 11 Pages: 477-485
• [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. Sei. 102 Pages: 5797-5801
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] A20 is a neeative 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)-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(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: Natl. Acad. Sci. 102 Pages: 5797-5801
  • Description: 「研究成果報告書概要(欧文)」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(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] 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
• [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., onishi, A., Takeda, N., Nakanishi, M.
  • Journal Title: J.Biol.Chem. 280 Pages: 39246-39252
• [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
• [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
• [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 IRF 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