Molecular Mechanism for Nuclear Receptor Degradation

• Project/Area Number: 17390014
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Biological pharmacy
• Research Institution: University of Tsukuba
• Principal Investigator: YANAGISAWA Jun University of Tsukuba, Graduate School of Life and Environmental Sciences, professor, 大学院生命環境科学研究科, 教授 (50301114)
• Project Period (FY): 2005 – 2006
• Project Status: Completed (Fiscal Year 2006)
• Budget Amount: ¥14,700,000 (Direct Cost: ¥14,700,000); Fiscal Year 2006: ¥7,100,000 (Direct Cost: ¥7,100,000); Fiscal Year 2005: ¥7,600,000 (Direct Cost: ¥7,600,000)
• Keywords: genome / protein / gene regulation / proteome / transcription / 核内受容体 / 蛋白質分解 / ユビキチン化 / プロテアソーム

Research Abstract

Estrogen receptor alpha (ERα) is a valuable prognostic factor in early-stage breast cancer, however, ERα-negative cancers typically exhibit higher histological grades than ERα-positive cancers during the progressive stages. In contrast, TGF-β acts as a tumor suppressor early in tumor development, but promotes invasion and metastasis at later stages. We found that exogenous expression of ERα in ERα-negative breast cancer cells abrogated TGF-β-mediated signaling pathways, reducing the invasive and metastatic potential of these cells. ERα formed a protein complex with Smad, a signal transducer in the TGF-β pathway, and Smurfs, ubiquitin ligases, to induce their ubiquitination and subsequent degradation. In human breast tumor tissues, an anticorrelation between ERα and Smad protein levels was observed. These findings suggest that ERα, opposes the effects of TGF-13 on cancer progression via a novel non-genomic mechanism. Several other nuclear receptors (NRs) tested also possessed the ability to induce Smad degradation. These observations provide new insight into non-genomic functions of NRs and the mechanisms underlying NR-mediated suppression of tumor invasion.

Research Products

• [Journal Article] Analysis of the role of Aurora B on the chromosomal targeting of condensing I. (2007)
  • Author(s): Murayama A, Katano M, Urano T, Furukawa K, Yokoyama S, Yanagisawa J, Hanaoka F, Kimura K
  • Journal Title: Nucleic Acids Res. 35 Pages: 2403-2412
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Analysis of the role of Aurora B on the chromosomal targeting of condensing I. (2007)
  • Author(s): Murayama A, Katano M, Urano T, Furukawa K, Yokoyama S, Yanagisawa J, Hanaoka F, Kimura K.
  • Journal Title: Nucleic Acids Res 35 Pages: 2403-2412
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Negative regulation of condensing I by CK2-mediated phosphorylation. (2006)
  • Author(s): Takemoto A, Kimura K, Yanagisawa J, Yokoyama S, Hanaoka F
  • Journal Title: EMBO J 25 Pages: 5339-5348
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Turning Off Estrogen Receptor β-Mediated Transcription Requires Estrogen-Dependent Receptor Proteolysis. (2006)
  • Author(s): Tateishi Y, Sonoo R, Sekiya Y, Sunahara N, Kawano M, Wayama M, Hirota R, Kawabe Y, Murayama A, Kato S, Kimura K, Yanagisawa J
  • Journal Title: Molecular and Cellular Biology 26.21 Pages: 7966-7976
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] A specific CpG site demethylation in the human interleukin 2 gene promoter is an epigenetic memory. (2006)
  • Author(s): Murayama A, Sakura K, Nakama M, Yasuzawa-Tanaka K, Fujita E, Tateishi Y, Wang Y, Ushijima T, Shibuya K, Kawabe Y, Yanagisawa J
  • Journal Title: EMBO J. 25 Pages: 1081-1092
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] An hGCN5/TRRAP histone acetyltransferase complex co-activates BRCA1 transactivation function through histone modification (2006)
  • Author(s): Oishi H, Kitagawa H, Wada O, Takezawa S, Tora L, Kouzu-Fujita M, Takada I, Yano T, Yanagisawa J, Kato S
  • Journal Title: J Biol Chem 281(1) Pages: 20-26
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Negative regulation of condensing I by CK2-mediated phosphorylation. (2006)
  • Author(s): Takemoto A, Kimura K, Yanagisawa J, Yokoyama S, Hanaoka F.
  • Journal Title: EMBO J. 25 Pages: 5339-5348
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Turning Off Estrogen Receptor 13-Mediated Transcription Requires Estrogen-Dependent Receptor Proteolysis. (2006)
  • Author(s): Tateishi Y, Sonoo R, Sekiya Y, Sunahara N, Kawano M, Wayama M, Hirota R, Kawabe Y, Murayama A, Kato S, Kimura K, Yanagisawa J.
  • Journal Title: Molecular and Cellular Biology 26.21 Pages: 7966-7976
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] A specific CpG site demethylation in the human interleukin 2 gene promoter is an epigenetic memory. (2006)
  • Author(s): Murayama A, Sakura K, Nakama M, Yasuzawa-Tanaka K, Fujita E, Tateishi Y, Wang Y, Ushijima T, Shibuya K, Kawabe Y, Yanagisawa J.
  • Journal Title: EMBO J 25 Pages: 1081-1092
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] An hGCN5/TRRAP histone acetyltransferase complex co-activates BRCA1 transactivation function through histone modification. (2006)
  • Author(s): Oishi H, Kitagawa H, Wada 0, Takezawa S, Tora L, Kouzu-Fujita M, Takada I, Yano T, Yanagisawa J, Kato S.
  • Journal Title: J Biol Chem 281 (1) Pages: 20-26
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Negative regulation of condensing 1 by CK2-mediated phosphorylation. (2006)
  • Author(s): Takemoto A, Kimura K, Yanagisawa J, Yokoyama S, Hanaoka F
  • Journal Title: EMBO J 25 Pages: 5339-5348
• [Journal Article] Turning Off Estrogen Receptor β-Mediated Transcription Requires Estrogen-Dependent Receptor Proteolysis. (2006)
  • Author(s): Tateishi Y, Sonoo R, Sekiya Y, Sunahara N, Kawano M, Wayama M, Hirota R, Kawabe Y, Murayama A, Kato S, Kimura K, Yanagisawa J.
  • Journal Title: Molecular and Cellular Biology 26.21 Pages: 7966-7976
• [Journal Article] A specific CpG site demethylation in the human interleukin 2 gene promoter is an epigenetic memory. (2006)
  • Author(s): Murayama A, Sakura K, Nakama M, Yasuzawa-Tanaka K, Fujita E, Tateishi Y, Wang Y, Ushijima T, Shibuya K, Kawabe Y, Yanagisawa J.
  • Journal Title: EMBO J. 25 Pages: 1081-1092
• [Journal Article] A specific CpG site demethylation in the human interleukin 2 gene promoter is an epigenetic memory. (2006)
  • Author(s): Murayama A, Sakura K, Nakama M, Yasuzawa-Tanaka K, Fujita E, Tateishi Y, Wang Y, Ushijima T, Shibuya K, Kawabe Y, Yanagisawa J.
  • Journal Title: EMBO J. (in press)
• [Journal Article] An hGCN5/TRRAP histone acetyltransferase complex co-activates BRCA1 transactivation function through histone modification (2006)
  • Author(s): Oishi H, Kitagawa H, Wada O, Takezawa S, Tora L, Kouzu-Fujita M, Takada I, Yano T, Yanagisawa J, Kato S
  • Journal Title: J Biol Chem. 281・1 Pages: 20-26
• [Journal Article] Repressive domain of unliganded human estrogen receptor alpha associates with Hsc70. (2005)
  • Author(s): Ogawa S, Oishi H, Mezaki Y, Kouzu-Fujita M, Matsuyama R, Nakagomi M, Mori E, Murayama E, Nagasawa H, Kitagawa H, Yanagisawa J, Yano T, Kato S
  • Journal Title: Genes Cells. 10・12 Pages: 1095-1102
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Splicing potentiation by growth factor signals via estrogen receptor phosphorylation. (2005)
  • Author(s): Masuhiro Y, Mezaki Y, Sakari M, Takeyama K, Yoshida T, Inoue K, Yanagisawa J, Hanazawa S, O'malley BW, Kato S
  • Journal Title: Proc Natl Acad Sci USA. 102・23 Pages: 8126-8131
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Repressive domain of unliganded human estrogen receptor alpha associates with Hsc70. (2005)
  • Author(s): Ogawa S, Oishi H, Mezaki Y, Kouzu-Fujita M, Matsuyama R, Nakagomi M, Mori E, Murayama E, Nagasawa H, Kitagawa H, Yanagisawa J, Yano T, Kato S.
  • Journal Title: Genes Cells. Dec 10(12) Pages: 1095-1102
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Splicing potentiation by growth factor signals via estrogen receptor phosphorylation. (2005)
  • Author(s): Masuhiro Y, Mezaki Y, Sakari M, Takeyama K, Yoshida T, Inoue K, Yanagisawa J, Hanazawa S, O'malley BW, Kato S.
  • Journal Title: Proc Natl Acad Sci USA. 102(23) Pages: 8126-8131
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Repressive domain of unliganded human estrogen receptor alpha associates with Hsc70. (2005)
  • Author(s): Ogawa S, Oishi H, Mezaki Y, Kouzu-Fujita M, Matsuyama R, Nakagomi M, Mori E, Murayama E, Nagasawa H, Kitagawa H, Yanagisawa J, Yano T, Kato S.
  • Journal Title: Genes Cells 10・12 Pages: 1095-1102
• [Journal Article] Splicing potentiation by growth factor signals via estrogen receptor phosphorylation. (2005)
  • Author(s): Masuhiro Y, Mezaki Y, Sakari M, Takeyama K, Yoshida T, Inoue K, Yanagisawa J, Hanazawa S, O'malley BW, Kato S.
  • Journal Title: Proc Natl Acad Sci USA. 102・23 Pages: 8126-8131