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Transcriptional regulation of arylhydrocarbon receptor (AhR), Arnt and E2F genes on proliferation process in A549 cells by dioxin and its mechanism.

Research Project

Project/Area Number 17590109
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Environmental pharmacy
Research InstitutionNihon University

Principal Investigator

TEZUKA Masakatsu  Nihon University, College of Pharmacy, Professor, 薬学部, 教授 (00046294)

Project Period (FY) 2005 – 2006
Project Status Completed (Fiscal Year 2006)
Budget Amount *help
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2006: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2005: ¥1,800,000 (Direct Cost: ¥1,800,000)
Keywordsdioxin / AhR / Arnt / E2F / transcription factor / A549 cells / 薬学 / 環境 / 癌 / 遺伝子
Research Abstract

Arylhydrocarbon receptor (AhR) is a ligand-activated transcription factor that mediates a spectrum of toxicological and bio-logical effects of 2,3,7,8-tetrachlorodiben.zo-p-dioxine (TCDD) and related compounds. AhR is included in a family of basic-helix-loop-helix/PAS domain-containing transcription factors. AhR expression is associated with the development of human lung carcinoma. In fact, we found that the overexpression of AhR accelerated the cell proliferation of A549 cells, established from a human alveolar cell carcinoma. We also demonstrated that the increased cell proliferations in A549 cells were associated with the activation of E2F gene expression, a transcription factor related in carcinogenesis, by the expression of heterodimer complex of AhR and AhR nuclear translocator (Arnt). In this study, we investigated the mechanisms of relationship of E2F gene activation and expression of AhR/Arnt complex.
We obtained the deleted cell lines of AhR, Arnt and E2F genes expression by s … More iRNA transfection technique in A549 cells. E2F-dependent transcription activity was decreased by the suppression of AhR, Arnt and E2F expression. To identify the domains of AhR and Arnt genes responsible for E2F-dependent transcription activity, a series of deletion constructs linked the luciferase activity were transfected into A549 cells. The PAS regions of AhR and Arnt sequences were required for the activation of E2F transcription. Next, an effect of E2F expression to the transcription activity of AhR and Arnt was determined by using of reporter assay contained XRE sequences, as AhR/Arnt-binding regions. The AhR/Arnt complex-dependent transcription activity on XRE sequences was increased by the suppression of E2F expression. The Rb protein-binding regions in E2F sequences were required on the interaction of AhR/Arnt complex. Rb protein is a repressive factor of carcinogenesis. Furthermore, we demonstrated that AhR/Arnt complex was complexed with E2F protein using a immuno-precipitation assay. These results suggested that AhR/Arnt and E2F complex binding on E2F-binding sequences was accelerated the cell proliferation, while the complex binding on XRE sequences was affected as a repressor in gene transcription. Less

Report

(3 results)
  • 2006 Annual Research Report   Final Research Report Summary
  • 2005 Annual Research Report
  • Research Products

    (6 results)

All 2006 2005

All Journal Article (6 results)

  • [Journal Article] Transcriptional regulation of the hypoxia inducible factor-2 α (HIF-2 α) gene during adipose differentiation in 3T3-L1 cells.2006

    • Author(s)
      T.Wada, S.Shimba, M.Tezuka
    • Journal Title

      Biological & Pharmaceutical Bulletin 29(1)

      Pages: 49-54

    • NAID

      110005602081

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Transcriptional regulation of the hypoxia inducible factor-2 α (HIF-2 α) gene during adipose differentiation in 3T3-L1 cells2006

    • Author(s)
      T.Wada, S.Shimba, M.Tezuka
    • Journal Title

      Biol. Pharm. Bull. 29(1)

      Pages: 49-54

    • NAID

      110005602081

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Transcriptional regulation of the hypoxia inducible factor-2alpha (HIF-2alpha) gene during adipose differentiation in 3T3-L1 cells.2006

    • Author(s)
      Wada, T., Shimba, S., Tezuka, M.
    • Journal Title

      Biol.Pharm.Bull. 29

      Pages: 49-54

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Brain and muscle Arnt-like protein- 1(BMAL1), a component of the molecular clock, regulates adipogenesis.2005

    • Author(s)
      S.Shimba, M.Tezuka et al.
    • Journal Title

      Proceedings of the National Academy of Sciences of U.S.A. 102(34)

      Pages: 12071-12076

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Brain muscle Arnt-like protein-1 (BMAL1), a component of the molecular clock regulates adipogenesis2005

    • Author(s)
      S.Shimba, M.Tezuka et al.
    • Journal Title

      Proc. Natl. Acad. Sci. USA 102(34)

      Pages: 12071-12076

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] BMAL1,a component of the molecular clock, regulates adipogenesis.2005

    • Author(s)
      Shimba, S., Ishii, N., Ohta, Y., Ohno, T., Watabe, Y., Hayashi, M., Wada, T., Aoyagi, T., Tezuka, M.
    • Journal Title

      Proc.Natl.Acad.Sci.U.S.A. 102

      Pages: 12071-12076

    • Related Report
      2005 Annual Research Report

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Published: 2005-04-01   Modified: 2016-04-21  

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