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FUNCTION OF COFACTORS MODIFYING THYROID HORMONE RECEPTOR FUNCTION

Research Project

Project/Area Number 09671223
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field General surgery
Research InstitutionNagoya University

Principal Investigator

FUNAHASHI Hiroomi  School of Medicine, Nagoya University, Assistant Professor, 医学部, 講師 (50135357)

Co-Investigator(Kenkyū-buntansha) IMAI Tsuneo  School of Medicine, Nagoya University, Assistant Professor, 医学部, 講師 (80252245)
MURATA Yoshiharu  Res.Inst.Environ.Med., Nagoya University, Professor, 環境医学研究所, 教授 (80174308)
高木 弘  名古屋大学, 医学部, 教授 (70154755)
Project Period (FY) 1997 – 2000
Project Status Completed (Fiscal Year 2000)
Budget Amount *help
¥3,200,000 (Direct Cost: ¥3,200,000)
Fiscal Year 2000: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 1999: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 1998: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 1997: ¥1,000,000 (Direct Cost: ¥1,000,000)
KeywordsCushing's syndrome / cortisol-producing adenoma / ACTH receptor gene / SF-1 (Ad4-BP) / glutathione-S-transferase A-1 / SF-1(Ad4-BP) / グルタチオン-S-トランスフェラーゼ) / 転写調節 / 転写因子SF-1(Ad4-BP) / コルチゾル産生副賢皮質腺腫
Research Abstract

1. ANALYSIS OP MUTATIONS IN p53 AND ACTH RECEPTOR (ACTH-R) GENES IN CORTISOL-PRODUCING ADENOMAS (CPA)
Possible mutations in p53 and ACTH-R genes were screened in benign adrenocortical adenomas producing cortisol. In eleven CPA samples obtained at surgery, no mutation was detected either in p53 and ACTH-R genes. It was thus suggested that mutations in these genes are rare cause of CPA.
2. ANALYSIS OF ACTH RECEPTOR (ACTH-R) EXPRESSION IN CORTISOL-PRODUCING ADENOMAS (CPA)
We and others demonstrated that expression of ACTH-R gene is upregulated by its own ligand ACTH.If the same regulation applies to CPA, expression of ACTH-R should be suppressed because of the lack of endogenous ACTH secretion. However, clinical evidence that ACTH administration to the patients with Cushing's syndrome resulted in further increase in cortisol production, suggesting the expression of functional ACTH-R.Northem blot analysis demonstrated that CPA expresses ACTH-R mRNA more abundantly than the adjacent non-neopla … More stic adrenal gland. It was thus suggested that regulation of ACTH-R gene expression is different from that of normal adrenal gland. To gain more insight how ACTH-R expression is regulated, we cloned the promoter region of ACTH-R gene. To assess the function of the promoter, reporter genes were constructed by placing the promoter region or its deletion mutants to the upstream of the firefly luciferase gene. By transfecting the reporter gene constructs, it was demonstrated that SF-1 is responsible for adrenal specific expression. Furthermore, both AP-1 and SF-1 are shown to be involved in ACTH-dependent upregulation of its receptor gene.
3. SEARCH FOR GENES SPECIFICALLY EXPRESSED IN CORTISOL-PRODUCING ADENOMAS (CPA)
To gain insight for the pathogenesis of CPA, mRNAs were separated from 10 CPA samples and adjacent atrophic normal tissues. After the synthesis of corresponding double stranded cDNA, they were restricted with DpnII and adaptors were ligated, resulting in the construction of each amplicon representing CPA or normal cDNAs. PCR-based subtraction revealed that several clones were identified to be preferentially expressed in CPA.Among them, glutathione-S-transferase A-1 (GST-A1) was marked upregulated in all the CPA samples when the expression was compared with that in corresponding normal tissues. Inhibition of this enzyme by ethacrinic acid caused severe reduction of the proliferation of the cell line derived from adrenocortical cancer. It was thus suggested GST-A1 plays an important role for the tumorigenesis of CPA. Less

Report

(5 results)
  • 2000 Annual Research Report   Final Research Report Summary
  • 1999 Annual Research Report
  • 1998 Annual Research Report
  • 1997 Annual Research Report
  • Research Products

    (23 results)

All Other

All Publications (23 results)

  • [Publications] Imai T,Sarkar D,Shibata A,Eunahashi H, et al.: "Overexpression of glutathione S-transferase A1 (GSTA1) in benign adrenocortical adenomas from patients with Cushing's syndrome"Journal Clnical Endocrinology and Metabolism. (印刷中).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Sarkar D,Imai T,Kambe F, et al. Funahashi H,Seo H.: "Expression of adrenocorticotropin receptor gene in adrenocortical adenomas from patients with Cushing's syndrome : Possible contribution for the autonomous production of cortisol."Annals of Surgery. (印刷中).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Imai T,Kikumori T,Funahashi H,Nakao A: "Surgical management of Cushing's syndrome."Biomedical Pharmacotherapy. 54 Suppl 1. 140-145 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Sarkar D,Kambe F,Hayashi Y,Ohmori S,Funahashi H,Seo H: "Involvement of AP-1 and steroidogenic factor (SF)-1 in the cAMP-dependent induction of human adrenocorticotropic hormone receptor (ACTHR) promoter."Endocrine Journal. 47(1). 63-75 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Imai T,Tobinaga J, et al., Seo H,Funahashi H: "Virilizing adrenocortical adenoma : In vitro steroidogenesis, immunohistochemical studies of steroidogenic enzymes, and gene expression of corticotropin recepttor."Surgery. 125(4). 396-402 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Imai T,Kikumori T,Ohiwa M,Mase T,Funahashi H: "A case-controlled study of laparoscopic compared with open lateral adrenalectomy."American Journal of Surgery. 178(1). 50-53 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Imai T, Sarkar D, Shibata A, Eunahashi H, et al.: "Overexpression of glutathione S-transferase A1 (GSTA1) in benign adrenocortical adenomas from patients with Cushing's syndrome"Journal Clnical Endocrinology and Metabolism. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Sarkar D, Imai T, Kambe F, et al.Funahashi H, Seo H.: "Expression of adrenocortico-tropin receptor gene in adrenocortical adenomas from patients with Cushing's syndrome : Possible contribution for the autonomous production of cortisol"Annals of Surgery. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Imai T, Kikumori T, Funahashi H, Nakao A.: "Surgical management of Cushing's syndrome."Biomedical Pharmacotherapy. 54 Suppl 1. 140-145 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Sarkar D, Kambe F, Hayashi Y, Ohmori S, Funahashi H, Seo H.: "Involvement of AP-1 and steroidogenic factor (SF)-1 in the cAMP-dependent induction of human adrenocorticotropic hormone receptor (ACTHR) promoter."Endocrine Journal. 47(1). 63-75 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Imai T, Tobinaga J, et al., Seo H, Funahashi H.: "A case-controlled study of laparoscopic compared with open lateral adrenalectomy."American Journal of Surgery. 178(1). 50-53 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Imai T, Tobinaga J, Seo H, Funahashi H et al.: "Virilizing adrenocortical adenoma : In vitro steroidogenesis immunohistochemical studies of steroidogenic enzymes and gene expression of corticotropin receptter."Surgery. 125(4). 396-402 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Imai T,Sarkar D,Shibata A,Funahashi H, et al.: "Overexpression of glutathione S-transferase A1 (GSTA1) in benign adrenocortical adenomas from patients with Cushing's syndrome"Journal Clnical Endocrinology and Metabolism. (印刷中).

    • Related Report
      2000 Annual Research Report
  • [Publications] Sarkar D,Imai T,Kambe F, et al.Funahashi H,Seo H.: "Expression of adrenocorticotropin receptor gene in adrenocortical adenomas from patients with Cushing's syndrome : Possible contribution for the autonomous production of cortisol"Annals of Surgery. (印刷中).

    • Related Report
      2000 Annual Research Report
  • [Publications] Imai T,Kikumori T,Funahashi H,Nakao A: "Surgical management of Cushing's syndrome. Biomed Pharmacother."Biomedical Pharmacotherapy. 54 Suppl 1. 140-145 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Sarkar D,Kambe F,Hayashi Y,Ohmori S,Funahashi H,Seo H: "Involvement of AP-1 and steroidogenic factor (SF)-1 in the cAMP-dependent induction of human adrenocorticotropic hormone receptor (ACTHR) promoter."Endocrine Journal. 47・1. 63-75 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Sarkar D,Kambe F,et al.,Funahashi H,Seo H: "Involvement of AP-1 and steroidogenic factor(SF)-1 in the cAMP dependent induction of human adrenocorticotropic hormone receptor promoter."Endocrine Journal. (印刷中).

    • Related Report
      1999 Annual Research Report
  • [Publications] Hayashi Y,Ohmori S,et al.,Funahashi H,Seo H: "Polymorphism of homopolymeric gluamine in coactivators for nuclear hormone receptors"Endocrine Journal. 46(2). 279-284 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Shibata A,Hayashi Y,Imai T,Funahashi H,Seo H: "Polymorphism of AIB1 in patients with breast cancer"Envriron Med. 43(2). 103-104 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Kikumori T, Kambe F, Nagaya T, Imai T, Funahashi H, Seo H.: "Activation of transcriptionally active nuclear factor-kapa B by tumor necrosis factor-a and its inhibition by antioxidants in rat thyroid FRTL-5 cells." Endocrinology. 139. 1715-1722 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Sarkar D, Kambe F, Hayashi Y, Ohmori S, Funahashi H, Seo H.: "Characterization of 5'-regulatory region of human ACTH receptor gene." Environ Med. 42. 23-25 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Kikumori T: "Antioxidants inhibits TNA-a induced activation of transcriptionally active NF-kB in rat thyroid FRTL-5 cells." Environmental Medicine. 41. 31-33 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Kikumori T: "Activation of transcriptionally active nuclear factor-kapa B by tumor necrosis factor-a and its inhibition by antioxidants in rat thyroid FRTL-5 cells." Endocrinology. (印刷中). (1998)

    • Related Report
      1997 Annual Research Report

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Published: 1997-04-01   Modified: 2016-04-21  

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