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Inductioin and activation of p53 tumor suppressor protein by Cdt in HPV-related cancer cells

Research Project

Project/Area Number 13671962
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field 病態科学系歯学(含放射線系歯学)
Research InstitutionTokyo Medical and Dental University

Principal Investigator

YAMATO Kenji  Tokyo Medical and Dental University, Graduate School, Division of Oral Health Science, Lecturer, 大学院・医歯学総合研究科, 講師 (50174751)

Co-Investigator(Kenkyū-buntansha) NISHIHARA Tatsuji  Kyushu Dental College, Professor, 歯学部, 教授 (80192251)
Project Period (FY) 2001 – 2002
Project Status Completed (Fiscal Year 2002)
Budget Amount *help
¥2,600,000 (Direct Cost: ¥2,600,000)
Fiscal Year 2002: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2001: ¥1,600,000 (Direct Cost: ¥1,600,000)
KeywordsBPV / p53 / E6 / siRNA / Cdt / P / p21
Research Abstract

The cytolethal distending toxin (Cdt) from Actinobacillus actinomycetemcomitans has been shown to induce cell cycle arrest in the G2 phase as well as cell death in mammalian cells. However, the precise mechanism by which the toxin induces these effects remains unknown. Human papillomavirus-16 (HPV-16) and HPV-18 are considered as causative agents of most human rectogenital cancers and part of oropharyngeal cancers. The E7 viral oncoprotein inactivates the retinoblastoma-related gene-product (Rb) and the E6 oncoprotein inhibits the p53 tumor suppressor protein by promoting its degradation.
We have found that Cdt caused accumulation of p53 during the induction of G2 arrest and cell death in HPV-18 positive HeLa cells. HS-72 mouse hybridoma cells expressing wild-type p53 were stably transfected with HPV-16 E6/E7. Using E6/E7-expressing HS-72 cells, we demonstrated that these cells were also sensitive to Cdt-mediated G2 arrst and cell death. To explore the molecular mechanism of p53 accumulation, we established the the siRNA system in HPV-positive cancer cell lines (HeLa, SiHa).Using lamin A/C siRNA which had been reported to exhibit a strong RNAi activity, we maximize the induction rate of siRHA into these cells. He found that HeLa cells and SiHa cells can be introduced with siRNA with a extremely high efficiency (more than 90%). We also found synthesized HPV-16 E6 and E7 siRNAs down-regulated the expression E6 and E7 mRHA by 70% and 80%, respectively. These results showed that SiHa cells were highly susceptible to siRNA. We are now planning to study if either ATM, ATR, Chkl, Chk2, DNA-PK or ARF is involved in the Cdt-induced p53 accumulation using the siRNA method.

Report

(3 results)
  • 2002 Annual Research Report   Final Research Report Summary
  • 2001 Annual Research Report
  • Research Products

    (23 results)

All Other

All Publications (23 results)

  • [Publications] Sato, T., et al.: "p53-independent expression of p21CIP1/WAF1 in plasmacytic cells during G2 cell cycle arrest induced by Actinobacillus actinomycetemcomitans cytolethal distending toxin"Infect. Immun.. 70. 528-534 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Yamato, K., et al.: "Activation of the p21^<CIP1/WAF1> promoter by bone morphogenetic protein-2 in mouse B lineage cells"Oncogene. 20. 4383-4392 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Koseki, T., et al.: "Role of TGF-β family in osteoclastogenesis induced by RANKL"Cell Signal.. 14. 31-36 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Muto, A., et al.: "A novel differentiation-inducing therapy for acute promyelocytic leukemia with a combination of arsenic trioxide and GM-CSF"Leukemia. 15. 528-534 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Okahashi, N., et al.: "Osteoclast differentiation is associated with transient upregulation of cyclin-dependent kinase inhibitors p21^<WAF1/CIP1> and p27^<KIP1>"J. Cell. Biochem.. 80. 339-345 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Nakahara, T., et al.: "Growth/differentiation factor-5 induces growth arrest and apoptosis in mouse B lineage cells with modulation by Smad"Cell. Signal. 15. 181-187 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Ito, K., et al.: "Caffeine induces G2/M arrest and apoptosis via novel p53-dependent pathway in NB4 promyelocytic leukemia cells"J. Cell Physiol. (in press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Sato, T., Koseki, T., Yamato, K., Saiki, K., Kosishi, K., Yoshikawa, M., ishikawa, I., Nishihara, T.: "p53-independent expression of p21^<CIP1/WAP1> in plasmacytic ceils during G2 cell cycle arrest induced by Actinobacillus actinomycetemcomitans cytolethal distending toxin"Infect. Immun.. 70. 528-534 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Yamato, K., Hashimoto, s., Imamura, T., Uchida, H., Okahashi, N., Koseki, T., Ishisaki, A., Kizaki, M., Miyazono, K., Ikeda, Y., Nishihara, T.: "Activation of the p21^<CIP1/WAP1> promoter by bone morphogenetic protein-2 in mouse B lineage cells"Oncogene. 20. 4383-4392 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Koseki, T., Gao, Y., Okahashi, N., Murase, Y., Tsujisawa, T., Sato, T., Yamato, K., Nishihara, T.: "Role of TGF-b family in osteoclastogenesis induced by RANKL"Cell Signal. 14. 31-36 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Muto, A., Kizaki, M., Kawamura, C., Matsushita, H., Fukuchi, Y., Umezawa, A., Yamada, T., Hata, J., Hozumi, N., Yamato, K., Ito, M., ueyama, Y., Ikeda, Y.: "A novel differentiation-inducing therapy for acute promyelocytic leukemia with a combination of arsenic trioxide and GM-CSF"Leukemia. 15. 528-534 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Okahashi, N., Murase, Y., Koseki, T., Sato, T., Yamato, K., Nishihara, T.: "steoclast differentiation is associated with transient upregulation of cyclin-dependent kinase inhibitors"J. Cell. Biochem.. 80. 339-345 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Nakahara, T., Tominaga, K., Koseki, T, Yamamoto, M., Yamato, K., and Nishihara, T.: "Growth/differentiation factor-5 induces growth arrest and apoptosis in mouse B lineage cells with"Cell. Signal.. 15. 181-187 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Ito, K., Nakazota, T., Miyakawa, Y., Yamato, K., Ikeda, Y., and Kizaki, M.: "Caffeine induces G2/M arrest and apoptosis via novel p53-dependent pathway in NB4 prdmonocytic leukemia cells"J. Cell Physiol.. in press.

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Nakahara, T., et al.: "Growth/differentiation factor-5 induces growth arrest and apoptosis in mouse B lineage cells with modulation by Smad"Cell. Signal. 15. 181-187 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Ito, K., et al.: "Caffeine induces G2/M arrest and apoptosis via novel p53-dependent pathway in NB4 promyelocytic leukemia cells"J. Cell Physiol.. (in press).

    • Related Report
      2002 Annual Research Report
  • [Publications] Sato, T. et al.: "p53-independent exprossion of p21^<CIPI/WAF1> in plasmacytic cells during G2 cell cycle arrest induced by Actinobacillus actinomy cetemcomitans cytolethal distending toxin"Infect, Immun.. 70. 528-534 (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Yamato, K. et al.: "Activation of the p21^<CIP1/WAF1> promoter by bone morphogenetic protein-2 in mouse B lineage cells"Oncogene. 20. 4383-4392 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Koseki, T. et al.: "Role of TGF-β family in ostepclatogencsis induced by RANKL"Cell Signal.. 14. 31-36 (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Muto, A. et al.: "A novel differentiation-inducing therapy for acute promyelocytic liukemia with a combination of arsenic trioxide and GM-CSF"Leukemia. 15. 528-534 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Fukuchi, Y. et al.: "Mcl-1, an early-induction molecule, modulates activin A-induced apoptosis and differentiation of CML"Oncogene. 20. 704-713 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Okahashi, N. et al.: "Osteoclast differentiation is associated with transient upregulation of cyclin-dependent kinase inhibitors p21^<WAF1/CIP1> and p27^<KIP1>"J.Cell.Biochem.. 80. 339-345 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Hashimoto, S. et al.: "Intracellular apoptosis-inducing factor is induced by a type H^+-ATP ase inhibitor in B lineago cells"J.Cell.Physionl.. 186. 65-72 (2001)

    • Related Report
      2001 Annual Research Report

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Published: 2001-04-01   Modified: 2016-04-21  

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