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Alternations of the Transcriptional Co-activator p300 in Oral Cancers and Its Novel Role in Tumor Suppression

Research Project

Project/Area Number 10470400
Research Category

Grant-in-Aid for Scientific Research (B).

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

IKEDA Masa-aki  Tokyo Med.& Dent.Univ., Graduate School, Associate Professor, 大学院・医歯学総合研究科, 助教授 (20193211)

Co-Investigator(Kenkyū-buntansha) IKEDA Yayoi  Univ.of Tsukuba, Inst.Basic Med.Sci., Lecturer, 基礎医学系, 講師 (00202903)
ADACHI Mimi  Tokyo Med.& Dent.Univ., Med.Res.Inst., Research Associate, 難治疾患研究所, 助手 (10323693)
Project Period (FY) 1998 – 2000
Project Status Completed (Fiscal Year 2000)
Budget Amount *help
¥13,600,000 (Direct Cost: ¥13,600,000)
Fiscal Year 2000: ¥2,800,000 (Direct Cost: ¥2,800,000)
Fiscal Year 1999: ¥2,900,000 (Direct Cost: ¥2,900,000)
Fiscal Year 1998: ¥7,900,000 (Direct Cost: ¥7,900,000)
Keywordsp300 / oral cancer / transcriptional coactivator / tumor suppressor gene / bromodomain / histone acetyltransferase / TGFβ / cell growth
Research Abstract

The p300 acetyltransferase and transcriptional coactivator plays key roles in the regulation of cell proliferation and differentiation. p300 is targeted by viral oncoproteins, and mutations of p300, accompanied by inactivation of the second allele, have been reported in certain types of cancers, carcinomas. Nevertheless, a role for p300/CBP in human tumorigenesis is still remains poorly understood.
In this study, We have identified p300 mutations associated with the inactivation of the second allele in two lines of human carcinoma cells. First, we identified a homozygous p300 deletion of exons 15-18 in the SiHa cervical carcinoma cell line, which results in an in-frame deletion that causes specific loss of the bromodomaimt, a conserved domain implicated in the regulation of HAT activity (Ohshima et al. 2001). In addition, we found two point mutations in the human oral squamouse cell carcinoma HOC313 ; a missence mutation within the E1A binding region, and a nonsense mutation leading to … More a loss of the C-terminal Q-rich and SRC/p160 binding domains (Suganuma et al. submitted).
Next, we investigated the ability of p30O to suppress the growth of cells lacking normal counterparts and the effects of p300 mutations on cell growth control and transcriptional regulation. We demonstrate that reintroduction of wild-type p300 suppressed growth of human carcinoma cells lacking normal p300 and the tumor-derived mutants lost suppressive activity. Furthermore, responses to TGFβ signaling, which is important for the negative regulation of epithelial cell growth, were severely impaired in the p300-deficient cells and wild-type expression restored responsiveness (Suganuma et al. submitted). We also show that multiple, distinct functions of p300 important for its chromatin remodeling and coactivator activities play critical roles in both the suppression of tumor cell growth and transcriptional regulation involved in negative regulation of cell growth. These results provide the first experimental evidence that p30O acts as a suppressor of carcinoma cell growth, and shed light on a role for p30O in epithelial malignancies. Less

Report

(4 results)
  • 2000 Annual Research Report   Final Research Report Summary
  • 1999 Annual Research Report
  • 1998 Annual Research Report
  • Research Products

    (38 results)

All Other

All Publications (38 results)

  • [Publications] Ohshima,T., et al.: "A novel mutation lacking the bromodomain of the transcriptional co-activator p300 in the SiHa cervical carcinoma cell line."Biochemical and Biophysical Research Communications. 281. 569-575 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Adachi,S. et al.: "Cyclin A/cdk2 activation is involved in hypoxia-induced apoptosis in cardiomyocytes."Circulation Research. (印刷中). (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Matsui,M., et al.: "High Expression of HLA-A2 on an Oral Squamous Cell Carcinoma with Down-Regulated Transporter for Antigen Presentation."Biochemical and Biophysical Research Communications. (印刷中). (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Nonomura,Y., et al.: "Suppression of Arthritis by Forced Expression of Cyclin-Dependent Ki-nase Inhibitor p21Cip1 Gene into the Joints."International Immunology. (印刷中). (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Ohtani,K., et al.: "Cell Growth-Regulated Expression of mammalian MCM5 and MCM6 Genes Mediated by the Transcription Factor E2F"Oncogene. 18. 2299-2309 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Ota,M., et al.: "Accumulation of p300 mediates transcriptional repression of simian virus 40 enhancer in undifferentiated F9 embryonal carcinoma cells."Cell Growth & Differentiation. 9. 989-997 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Tamamori M., et al.: "Essential roles for G1 cyclin-dependent kinase activity in development of cardiomyocyte hypertrophy."American Journal of Physiology. 275. H2036-H2040 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Ohtani,K., et al.: "Regulation of cell growth-dependent expression of mammalian CDC6 gene by the cell cycle transcription factor E2F."Oncogene. 17. 1777-1785 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Nakajima,Y: "Interaction of E2F/Rb Family members with Factor Binding to Co-repressor Element on B-myb and E2F1 Promoters"The Journal of The Stomatological Society, Japan. 65. 172-173 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Natsunaga,Y.: "Expression of Cyclin E in Postmitotic Cells in the Central Nervous System"The Journal of The Stomatological Society, Japan. 67. 169-181 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Ohshima, T., et al.: "A novel mutation lacking the bromodomain of the transcription co-activator p300 in the SiHa cervical carcinoma cell line."Biochemical and Biophysical Research Communications. 281. 569-575 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Adachi, S., et al.: "Cyclin A/cdk2 activation is involved in hypoxia-induced apoptosis in cardiomyocytes."Circulation Research. (in press). (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Matsui, M., et al.: "High Expression on HLA-A2 on an Oral Squamous Cell Carcinoma with Down-Regulated Transporter for Antigen Presentation."Biochemical and Biophysical Research Communications. (in press). (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Nonomura, Y., et al.: "Suppression of Arthritis by Forced Expression of Cyclin-Dependent Kinase Inhibitor p21^<Cip1> Gene into the Joints."International Immunology. (in press). (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Ohtani, K., et al.: "Cell Growth-Regulated Expression of mammalian MCM5 and MCM6 Genes Mediated by the Transcription Factor E2F"Oncogene. 18. 2299-2309 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Ota, M., et al.: "Accumulation of p300 mediates transcriptional repression of simian virus 40 enhancer in undifferentiated F9 embryonal carcinoma cells."Cell Growth & Differentiation. 9. 989-997 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Tamamori M., et al.: "Essential roles for G1 cyclin-dependent kinase activity in development of cardiomyocyte hypertrophy."American Journal of Physiology. 275. H2036-H2040 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Ohtani, K., et al.: "Regulation of cell growth-dependent expression of mammalian CDC6 gene by the cell cycle transcription factor E2F."Oncogene. 17. 1777-1785 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Nakajima, Y: "Interaction of E2F/Rb Family Members with Factor Binding to Co-repressor Element on B-myb and E2F1 Promoters"The Journal of The Stomatological Society, Japan. 65. 172-173 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Natsunaga, Y.: "Expression of Cyclin E in Postmitotic Cells in the Central Nervous System"The Journal of The Stomatological Society, Japan. 67. 169-181 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Ohshima, T., et al.: "A novel mutation lacking the bromodomain of the transcriptional co-activator p300 in the SiHa cervical carcinoma cell line."Biochemical and Biophysical Research Communications. 281. 569-575 (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] Adachi, S. et al.: "Cyclin A/cdk2 activation is involved in hypoxia-induced apoptosis in cardiomyocytes."Circulation Research. (印刷中). (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] Matsui,M., et al.: "High Expression of HLA-A2 on an Oral Squamous Cell Carcinoma with Down-Regulated Transporter for Antigen Presentation."Biochemical and Biophysical Research Communications. (印刷中). (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] Nonomura,Y., et al.: "Suppression of Arthritis by Forced Expression of Cyclin-Dependent Kinase Inhibitor p21Cip1 Gene into the Joints."International Immunology. (印刷中). (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] Ohtani,K., et al.: "Cell Growth-Regulated Expression of mammalian MCM5 and MCM6 Genes Mediated by the Transcription Factor E2F"Oncogene. 18. 2299-2309 (1999)

    • Related Report
      2000 Annual Research Report
  • [Publications] Ota,M., et al.: "Accumulation of p300 mediates transcriptional repression of simian virus 40 enhancer in undifferentiated F9 embryonal carcinoma cells."Cell Growth & Differentiation. 9. 989-997 (1998)

    • Related Report
      2000 Annual Research Report
  • [Publications] Tamamori M., et al.: "Essential roles for G1 cyclin-dependent kinase activity in development of cardiomyocyte hypertrophy."American Journal of Physiology. 275. H2036-H2040 (1998)

    • Related Report
      2000 Annual Research Report
  • [Publications] Ohtani,K., et al.: "Regulation of cell growth-dependent expression of mammalian CDC6 gene by the cell cycle transcription factor E2F."Oncogene. 17. 1777-1785 (1998)

    • Related Report
      2000 Annual Research Report
  • [Publications] Nakajima, Y: "Interaction of E2F/Rb Family Members with Factor Binding to Co-repressor Element on B-myb and E2F1 Promoters"The Journal of The Stomatological Society, Japan. 65. 172-173 (1998)

    • Related Report
      2000 Annual Research Report
  • [Publications] Narsunaga, Y.: "Expression of Cyclin E in Postmitotic Cells in the Central Nervous System"The Journal of The Stomatological Society, Japan. 67. 169-181 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Ohtani, K.: "Cell Growth-Regulated Expression of mammalian MCM5 and MCM6 Genes Mediated by the Transcription Factor E2F."Oncogene. 18. 2299-2309 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Ota, M.: "Accumulation of p300 mediates transcriptional repression of simian virus 40 enhancer in undifferentiated F9 embryonal carcinoma cells."Cell Growth & Differentiation. 9. 989-997 (1998)

    • Related Report
      1999 Annual Research Report
  • [Publications] Tamamori M.: "Essential roles for G1 cyclin-dependent kinase activity in development of cardiomyocyte hypertrophy."Am. J. Physiol.. 275. H2036-H2040 (1998)

    • Related Report
      1999 Annual Research Report
  • [Publications] Ohtani, K.: "Regulation of cell growth-dependent expression of mammalian CDC6 gene by the cell cycle transcription factor E2F."Oncogene. 17. 1777-1785 (1998)

    • Related Report
      1999 Annual Research Report
  • [Publications] Tamamori M.,et al.: "Essential roles for G1 cyclin-dependent kinase activity in development of cardiomyocyte hypertrophy." Am.J.Physiol.275. H2036-H2040 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Ota,M. et al: "Accumulation of p300 mediates transcriptional repression of simian virus 40 enhancer in undifferentiated F9 embryonal carcinoma cells" Cell Growth & Differentiation. 9. 989-997 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Ohtani,K.et al: "Cell Growth-Regulated Expression of mammalian MCM5 and MCM6 Genes Mediated by the Transcription Factor E2F" Oncogene. (発表予定). (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] Ohtani,K.et al: "Regulation of cell growth-dependent expression of mammalian CDC6 gene by the cell cycle transcription factor E2F" Oncogene. 17. 1777-1785 (1998)

    • Related Report
      1998 Annual Research Report

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Published: 1998-04-01   Modified: 2016-04-21  

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