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Establishment of the concept of androgen insensitivity syndrome due to the abnormality of transcriptional cofactor and analysis of the responsible cofactor.

Research Project

Project/Area Number 10671037
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Endocrinology
Research InstitutionKyushu University

Principal Investigator

TAKAYANAGI Ryoichi  Graduate School of Medical Sciences, Kyushu University Prof., 大学院・医学研究院, 教授 (30154917)

Co-Investigator(Kenkyū-buntansha) NAWATA Hajime  Graduate School of Medical Sciences, Kyushu University, Prof., 大学院・医学研究院, 教授 (10038820)
Project Period (FY) 1998 – 2000
Project Status Completed (Fiscal Year 2001)
Budget Amount *help
¥3,800,000 (Direct Cost: ¥3,800,000)
Fiscal Year 2000: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 1999: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 1998: ¥1,600,000 (Direct Cost: ¥1,600,000)
Keywordsandrogen / cofactor / testicular feminization / receptor / insensitivity / transcription / steroid hormone / 転写因子 / アンドロゲン不応症 / アンドロゲン受容体 / 核内受容体
Research Abstract

We found a patient who was diagnosed phenotypically and endocrinologically as having complete androgen insensitivity syndrome (AIS), but who had no abnormality in the androgen receptor (AR) gene. Transactivation by the normal entire AR in the patient fibroblasts was markedly low compared with that in the controls, strongly suggesting that this patient manifests AIS due to the abnormality of coactivator. The aims of the present study were the establishment of the concept of a coactivator disease and the isolation of its coactivator, and the following results were obtained. Investigation of the transactivation by the AR, glucocorticoid receptor (GR), their AF-1- or AF-2-truncated receptors and their chimeric receptors in primary-cultured genital skin fibroblasts from the patient revealed that transmission of the activation signal from AF-1 of the AR was disrupted. Co-transfection of known transcriptional cofactors did not restore the impaired AR-dependent transactivation in the patient. The binding of a protein with an apparent Mr of about 90 kDa to GST-fused AF-1 of the AR was lost in the patient fibroblasts. A cDNA which enhances the AR-dependent transactivation was isolated by yeast two hybrid system using as AR-AF-1 as a bait.
In conclusion, we have established a new form of steroid hormone insensitivity, a coactivator disease, and also isolated one of the AR-AF-1-specific coactivators.

Report

(4 results)
  • 2001 Final Research Report Summary
  • 2000 Annual Research Report
  • 1999 Annual Research Report
  • 1998 Annual Research Report
  • Research Products

    (51 results)

All Other

All Publications (51 results)

  • [Publications] Ikuyama S et al.: "Expression of an orphan nuclear receptor DAX-1 in human pituitary adenomas"Clin Endocrinol. 48. 647-654 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Takayanagi R et al.: "Big endothelin analogues with inhibitory activity on endothelin-converting enzyme-1"J Cardivasc Pharmacol. 31(Suppl 1). S62-S63 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Okabe T et al.: "Nur77, a member of the steroid receptor superfamily, antagonizes negative feedback of ACTH synthesis and secretion by glucocorticoid in ptuitary corticotrope cells"J Endocrinol. 156. 169-175 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Shimoike T et al.: "Subcutaneous or visceral adipose tissue expression of the PPAR g gene is not altered in the fatty (fa/fa) Zucker Rat"Metabolism. 47. 1494-1498 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Natori S et al.: "Chromogranin B (secretogranin I), a neuroendocrine-regulated secretory protein, is sorted to exocrine secretory granules in transgenic mice"EMBO J. 17. 3277-3289 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Hamaguchi K et al.: "Novel germline mutations of the MEN1 gene in Japanese patients with multiple endocrine neoplasia type 1"J Hum Genet. 44. 43-47 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Ohe K et al.: "Nicotinamide potentiates TSHR and MHC class II promoter activity in FRTL-5 cells"Mol Cell Endocrinol. 149. 141-151 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Nawata H et al.: "Human Ad4BP/SF-1 and its related nuclear receptor"J Steroid Biochem Molec Biol. 69. 323-328 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Hirase N et al.: "Thioazolidinedione induces apoptosis and monocytic differentiation in the promyelocytic leukemia cell line HL6O"Oncology. 57(suppl 2). 17-26 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Adachi M et al.: "Androgen-insensitivity syndrome as a possible coactivator disease"N Engl J Med. 343. 856-862 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Takayanagi R et al.: "Epidemiologic study of adrenal disorders in Japan"Biomed & Pharmacother. 54 Suppl 1. 164-168 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Mu Yi-M, et al.: "Insulin sensitizer, troglitazone, directly inhibits aromatase activity in human ovarian granulosa cells"Biochem Biophys Res Commun. 271. 710-713 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Hirase N et al.: "Thiazolidinedione suppresses the expression of erythroid phenotype in erythroleukemia cell line K562"Leukemia Res. 24. 393-400 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Mu Yi-M, et al.: "A nuclear receptor system constituted by PAR and RXR induces aromatase activity in MCF-7 human breast cancer cells"Mol Cell Endocrinol. 166. 137-145 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Oba K et al.: "Transcriptional regulation of the human FTZ-F1 gene encoding Ad4BP/SF-1"J Biochem. 128. 517-528 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Mu Yi-M, et al.: "Combined treatment with specific ligands for PPARg : RXR nuclear receptor system markedly inhibits the expression of cytochrome P45Oarom in human granulosa cancer cells"Mol Cell Endcrinol. 181. 239-248 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Tomura, A et al.: "The subnuclear three-dimensional image analysis of androgen receptor fused to green fluorescence protein"J Biol Chem. 276. 28395-28401 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Nishi, Y et al.: "Establishment and characterization of a steroidogenic human granulosa-like tumor cell line KGN, that expresses functional follicle-stimulating hormone receptor"Endocrinology. 142. 437-445 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Ikuyama S et al.: "Expression of an orphan nuclear receptor DAX-1 in human pituitary adenomas"Clin Endocrinol.. 48. 647-654 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Takayanagi R et al.: "Big endothelin analogues with inhibitory activity on endothelin-converting enzyme-1"J Cardivasc Pharmacol.. 31(Suppl 1). S62-S63 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Okabe T et al.: "Nur77, a member of the steroid receptor superfamily, antagonizes negative feedback of ACTH synthesisand secretion by glucocorticoid in ptuitary corticotrope cells"J Endocrinol.. 156. 169-175 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Shimoike T et al.: "Subcutaneous or visceral adipose tissue expression of the PPAR g gene is not altered in the fatty (fa/fa) Zucker Rat"Metabolism. 47. 1494-1498 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Natori S et al.: "Chromogranin B (secretogranin I), a neuroendocrine-regulated secretory protein, is sorted to exocrine secretory granules in transgenic mice"EMBO J. 17. 3277-3289 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Hamaguchi K et al.: "Novel germline mutations of the MEN1 gene in Japanese patients with multiple endocrine neoplasia type 1"J Hum Genet. 44. 43-47 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Ohe K et al.: "Nicotinamide potentiates TSHR and MHC class II promoter activity in FRTL-5 cells"Mol Cell Endocrinol.. 149. 141-151 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Nawata H et al.: "Human Ad4BP/SF-1 and its related nuclear receptor"J Steroid Biochem Molec Biol.. 69. 323-328 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Hirase N et al.: "Thioazolidinedione induces apoptosis and monocytic differentiation in the promyelocytic leukemia cell line HL60"Oncology. 57(Suppl 12). 17-26 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Adachi M et al.: "Androgen-insensitivity syndrome as a possible coactivator disease"N Engl J Med.. 343. 856-862 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Takayanagi R et al.: "Epidemiologic study of adrenal disorders in Japan"Biomed & Pharmacother.. 54Suppl 1. 164-168 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Mu Yi-M et al.: "Insulin sensitizer, troglitazone, directly inhibits aromatase activity in human ovarian granulosa cells"Biochem Biophys RES Commun. 271. 710-713 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Hirase N et al.: "Thiazolidinedione suppresses the expression of erythroid phenotype in erythroleukemia cell line K562"Leukemia Res.. 24. 393-400 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Mu Yi-M et al.: "A nuclear receptor system constituted by RAR and RXR induces aromatase activity in MCF-7 human breast cancer cells"Mol Cell Endocrinol. 166. 137-145 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Oba K et al.: "Transcriptional regulation of the human FTZ-F1 gene encoding Ad4BP/SF-1"J Biochem. 128. 517-528 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Mu Yi-M et al.: "Combined treatment with specfic ligands for PPARγ. RXR nuclear receptor system markedly inhibits the expression of cytochrome P450arom in human granulosa cancer cells"Mol Cell Endocrinol. 181. 239-248 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Tomura A et al.: "The subnuclear three-dimensional image analysis of androgen receptor fused to green fluorescence protein"J Biol Chem. 276. 28395-28401 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Nishi Y et al.: "Establishment and characterization of a steroidogenic human granulosa-like tumor cell line, KGN, that expresses functional follicle-stimulating hormone receptor"Endocrinology. 142. 437-445 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Adachi M et al.: "Androgen-insensitivity syndrome as a possible coactivator disease."N Engl J Med. 343. 856-862 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Takayanagi R et al.: "Epidemiologic study of adrenal disorders in Japan."Biomed & Pharmacother. 54Suppl1. 164-168 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Mu Yi-M et al.: "Insulin sensitizer, troglitazone, directly inhibits aromatase activity in human ovarian granulosa cells."Biochem Biophys Res Commun. 271. 710-713 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Mu Yi-M et al.: "A nuclear receptor system constituted by RAR and RXR induces aromatase activity in MCF-7 human breast cancer cells."Mol Cell Endoerinol. 166. 137-145 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Oba K et al.: "Transcriptional regulation of the human FTZ-F1 gene encoding Ad4BP/SF-1."J Biochem. 128. 517-528 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] 高柳涼一 他: "アンドロゲンレセプター共役因子異常症 新しい疾患概念."月刊薬事. 42. 1141-1146 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Ohe K.: "Nicotinamide potentiates TSHR and MHC classII promoter activity in FRTL-5 cells"Mol. Cell. Endocrinol.. 149. 141-151 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Nawata H.: "Human Ad4BP/SF-1 and its related nuclear receptor"J. Steroid Biochem. Molec. Biol.. 69. 323-328 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] 後藤 公宣: "前立腺癌治療に用いられる抗アンドロゲン剤のアンドロゲンレセプターに対する作用"Pharma Medica. 17. 97 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Shoichi Natori: "Chromogranin B(secretogranin I), a neuroendocrine regulated secretory protein, is steroid to exocrine secretory granules in transgenic mice" EMBO J.17巻・12号. 3277-3289 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] 足立雅広: "AR遺伝子に異常を認めず転写共役因子病と推測された完全型睾丸性女性化症の1例" 日本内分泌学会雑誌. 74巻(1号). 70 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] 高柳涼一: "アンドロゲン受容体遺伝子" 小児内科. 3巻(8号). 1033-1037 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] 後藤公宣: "核内レセプターと遺伝性疾患" 実験医学. 16巻(19号). 2454-2458 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] 高柳涼一: "核内受容体nur77/NGFI-βファミリーの生理機能" 遺伝子医学. 2巻(4号). 621-623 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Tomoko Shimoike: "Subcutaneous of visceral adipose tissue expression of the PPARγ gene is not altered in the fatty(fa/fa) zucker rat" Metabolism. 47巻(12号). 1494-1498 (1998)

    • Related Report
      1998 Annual Research Report

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

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