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Molecular Basis of the nuclear receptor function mediating Inflammation

Research Project

Project/Area Number 20591089
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Endocrinology
Research InstitutionThe University of Tokyo

Principal Investigator

KITAGAWA Hirochika  The University of Tokyo, 生体調節研究所, 教授 (20345234)

Co-Investigator(Kenkyū-buntansha) TAKEYAMA Kenーichi  東京大学, 分子細胞生物学研究所, 講師 (30323570)
TAKADA Ichiro  東京大学, 分子細胞生物学研究所, 助教 (50361655)
Project Period (FY) 2008 – 2010
Project Status Completed (Fiscal Year 2010)
Budget Amount *help
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2010: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2009: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2008: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Keywordsグルココルチコイド / 炎症 / Sumo化 / 炎症制御 / 分解制御 / 炎症反応 / 核内受容体 / クロマチン / マクロファージ / 炎症制御転写因子 / 炎症シグナル / タンパク分解機能制御
Research Abstract

Glucocorticoid is clinically successful in attenuating inflammation caused by diverse diseases, and its anti-inflammatory actions via nuclear glucocorticoid receptor (GR) are known to be mediated by transcriptional repression of inflammatory transcription factors like AP-1 and NF-kB. However, the molecular mechanism underlying hormonal transrepression largely remains to be uncovered at the level of chromatin. Here, we report that glucocorticoid-induced sumoylation of c-Jun via GR triggers transcriptional repression of AP-1 through a histone inactivating methylation (H3K27me3) by recruitment of a polycomb (PRC2) complex. Liganded GR serves as an adaptor for Sumo E3 ligase (PIAS1) to sumoylate c-Jun in the AP-1 unit, but not NF-kB. Sumoylated c-Jun induces association with a PRC2 complex, leading to H3K27 methylation by EZH2 and silencing of AP-1 binding sites on pro-inflammatory cytokine gene promoters. Ablation of EZH2 in mice abrogates glucocorticoid-induced transrepression of the cytokine genes that are induced by activated AP-1. Thus, these findings uncover a molecular mechanism of anti-inflammatory glucocorticoid actions for transrepression of AP-1 through repressive chromatin reorganization, and provide a clue for development of desirable GR synthetic ligands.

Report

(4 results)
  • 2010 Annual Research Report   Final Research Report ( PDF )
  • 2009 Annual Research Report
  • 2008 Annual Research Report
  • Research Products

    (43 results)

All 2011 2010 2009 2008 Other

All Journal Article (26 results) (of which Peer Reviewed: 26 results) Presentation (12 results) Book (2 results) Remarks (3 results)

  • [Journal Article] Williams syndrome is an epigenome-regulator disease.2011

    • Author(s)
      Kitagawa H., Fujiki R., Yoshimura K., Oya H., Kato S.
    • Journal Title

      Endocr J. 8(2)

      Pages: 77-85

    • NAID

      10029587545

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] Williams syndrome is an epigenome-regulator disease2011

    • Author(s)
      Kitagawa H., Fujiki R., Yoshimura K., Oya H., Kato S.
    • Journal Title

      Endocrine J

      Volume: 58 Pages: 77-85

    • NAID

      10029587545

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] TSPY represses the activity of the androgen receptor in androgen-dependent testicular germ cell tumors.2010

    • Author(s)
      Akimoto C., Ueda T., Yamaoka I., Inoue K., Sakari M.,Ohara K., Fujioka T., Nagahara A., Nonomura N., Tsutsumi S., Aburatani H., Miki T., Matsumoto T., Kitagawa H., Kato S.
    • Journal Title

      Proc Natl Acad Sci USA. 107(46)

      Pages: 19891-6

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] Double PHD fingers protein DPF2 recognizes acetylated histones and suppresses the function of ERR{alpha} through histone deacetylase 1.2010

    • Author(s)
      Matsuyama R, Takada I, Yokoyama A, Fujiyama-Nakamura S, Tsuji N, Kitagawa H, Fujiki R, Kim M, Kouzu-Fujita M, Yano T, Kato S.
    • Journal Title

      J Biol Chem. 285(24)

      Pages: 18166-76

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] Purification and identification of estrogen receptor alpha co-regulators in osteoclasts.2010

    • Author(s)
      Takada I, Tsuji N, Youn MY, Fujiyama S, Okada M, Imai Y, Kondo S, Kitagawa H, Yasuda H, Kato S.
    • Journal Title

      Ann N Y Acad Sci. 192(1)

      Pages: 201-7

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] CDP/Cut is an Osteoblastic Co-activator of the Vitamin D receptor (VDR).2010

    • Author(s)
      Ochiai E., Kitagawa H., Takada I., Fujiyama S., Sawatsubashi S., Kim M., Mezaki Y., Tshuushima Y., Takagi K., Yamaoka K., Kato S., Kamimura T.
    • Journal Title

      Bone Miner Res. (in press)

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] NF-YC functions as a corepressor of agonist-bound mineralocorticoid receptor.2010

    • Author(s)
      Murai-Takeda A, Shibata H, Kurihara I, Kobayashi S, Yokota K, Suda N, Mitsuishi Y, Jo R, Kitagawa H, Kato S, Saruta T, Itoh H.
    • Journal Title

      J.Biol.Chem. 285

      Pages: 8084-93

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] NF-YC functions as a corepressor of agonist-bound mineralocorticoid receptor.2010

    • Author(s)
      Murai-Takeda A, Shibata H, Kurihara I, Kobayashi S, Yokota K, Suda N, Mitsuishi Y, Jo R, Kitagawa H, Kato S, Saruta T, Itoh H.
    • Journal Title

      J.Biol.Chem.

      Volume: 285 Pages: 8084-93

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] CDP/Cut is an Osteoblastic Co-activator of the Vitamin D receptor (VDR)2010

    • Author(s)
      Ochiai E., Kitagawa H., Takada I., Fujiyama S., Sawatsubashi S., Kim M., Mezaki Y., Tshuushima Y., Takagi K., Yamaoka K., KatoS., Kamimura T.
    • Journal Title

      J.Bone Miner Res.

      Volume: 25 Pages: 1157-66

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Purification and identification of estrogen receptor alpha co-regulators in osteoclasts.2010

    • Author(s)
      Takada I, Tsuji N, Youn MY, Fujiyama S, Okada M, Imai Y, Kondo S, Kitagawa H, Yasuda H, Kato S.
    • Journal Title

      Ann N Y Acad Sci.

      Volume: 192 Pages: 201-7

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Double PHD fingers protein DPF2 recognizes acetylated histones and suppresses the function of ERR {alpha} through histone deacetylase 12010

    • Author(s)
      Matsuyama R, Takada I, Yokoyama A, Fujiyama-Nakamura S, Tsuji N, Kitagawa H, Fujiki R, Kim M, Kouzu-Fujita M, Yano T, Kato S.
    • Journal Title

      J Biol Chem.

      Volume: 285 Pages: 18166-76

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] TSPY represses the activity of the androgen receptor in androgen-dep endent testicular germ cell tumors.2010

    • Author(s)
      Akimoto C., Ueda T., Yamaoka I., Inoue K., Sakari M., Ohara K., Fujioka T., Nagahara A., Nonomura N., Tsutsumi S., Aburatani H., Miki T., Matsumoto T., Kitagawa H., Kato S.
    • Journal Title

      Proc Natl Acad Sci USA

      Volume: 107 Pages: 19891-6

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] CDP/Cut is an Osteoblastic Co-activator of the Vitamin D receptor(VDR).2010

    • Author(s)
      Ochiai E., et al.
    • Journal Title

      Journal of bone and Mineral Research (In Press)

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Phosphorylation of Williams syndrome transcription factor by MAPK induces a switching between two distinct chromatin remodeling complexes.2009

    • Author(s)
      Oya H., Yokoyama A., Yamaoka I., Fujiki R., Yonezawa M., Youn M., Takada I., Kato S., Kitagawa H.
    • Journal Title

      J.Biol.Chem. 284

      Pages: 32472-32482

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] DNA demethylation in hormone-induced transcriptional derepression.2009

    • Author(s)
      Kim M., Kondo T., Takada I., Youn M., Yamamoto Y., Takahashi S., Matsumoto T., Fujiyama S., Shirode Y., Yamaoka I., Kitagawa H., Takeyama K., Shibuya H., Ohtake F., Kato S.
    • Journal Title

      Nature. 461

      Pages: 1007-1012

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] Distinct function of 2 chromatin remodeling complexes that share a common subunit, Williams syndrome transcription factor (WSTF).2009

    • Author(s)
      Yoshimura K., Kitagawa H., Fujiki R., Tanabe M., Takezawa S., Takada I., Yamaoka I., Yonezawa M., Kondo T., Furutani Y., Yagi H., Yoshinaga S., Masuda T., Fukuda T., Yamamoto Y., Ebihara K., Li D.Y., Matsuoka R., Takeuchi J.K., Matsumoto T., Kato S.
    • Journal Title

      Proc Natl Acad Sci USA. 106

      Pages: 9280-9285

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] GlcNAcylation of a histone methyltransferase in retinoic acid-induced granulopoiesis.2009

    • Author(s)
      Fujiki R., Chikanishi T., Hashiba W., Ito H., Takada I., Roeder R.G., Kitagawa H., Kato S.
    • Journal Title

      Nature. 459

      Pages: 455-459

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] Coactivation of estrogen receptor beta by gonadotropin-induced cofactor GIOT-4.2009

    • Author(s)
      Kouzu-Fujita M., Mezaki Y., Sawatsubashi S., Matsumoto T., Yamaoka I., Yano T., Taketani Y., Kitagawa H., Kato S.
    • Journal Title

      Mol.Cell.Biol. 29

      Pages: 83-92

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] DNA demethylation in hormone-induced transcriptional derepression2009

    • Author(s)
      Kim, M., et al.
    • Journal Title

      Nature 461

      Pages: 1007-1012

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Coactivation of estrogen receptor beta by gonadotropin-induced cofactor GIOT-4.2009

    • Author(s)
      Kouzu-Fujita, M., et al.
    • Journal Title

      Molecular and Cellular Biology 29

      Pages: 83-92

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Co-activation of ERβ by a gonadotropi-induced cofactor GIOT-42009

    • Author(s)
      Kouzu-Fujita M., Mezaki Y., Sawat subashi S., Matsumoto T., Yamaoka I., Yano T., Taketani Y.,Kitagawa H., Kato S.
    • Journal Title

      Molecular and Cellular Biology 29

      Pages: 83-92

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Transrepressive function of TLX requires the histone demethylase LSD1.2008

    • Author(s)
      Yokoyama A., Takezawa S., Schule R., Kitagawa H., Kato S.
    • Journal Title

      Mol.Cell.Biol. 28

      Pages: 3995-4003

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] Spermatogenesis-specific association of SMCY and MSH5.2008

    • Author(s)
      Akimoto C., Kitagawa H., Matsumoto T., Kato S.
    • Journal Title

      Genes Cells 13

      Pages: 623-633

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] Switching of chromatin-remodelling complexes for oestrogen receptor-alpha.2008

    • Author(s)
      Okada M., Takezawa S., Mezaki Y., Yamaoka I., Takada I., Kitagawa H., Kato S.
    • Journal Title

      EMBO Rep. 9

      Pages: 563-568

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] Spermatogenesis-specific association of SMCY and MSH52008

    • Author(s)
      Akimoto C, Kitagawa H., Matsumoto T., Kato S.
    • Journal Title

      Genes to Cells 13

      Pages: 623-633

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Switching of chromatin-remodeling complexes for estrogen receptor α.2008

    • Author(s)
      Okada M., Takezawa S., Mezaki Y., Yamaoka I., Takada I., Kitagawa H., Kato S
    • Journal Title

      EMBO report 9

      Pages: 563-568

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Presentation] Dissection of a Novel Epigenetic Regulatory Mechanism linking Inflammation and Energy Metabolism2010

    • Author(s)
      Hirochika Kitagawa, Shigeaki Kato
    • Organizer
      BMB2010
    • Place of Presentation
      神戸国際会議場
    • Year and Date
      2010-12-10
    • Related Report
      2010 Final Research Report
  • [Presentation] 炎症とエネルギー代謝の接点で機能する新規核内転写制御メカニズムの解明2010

    • Author(s)
      北川浩史、加藤茂明
    • Organizer
      BMS2010
    • Place of Presentation
      神戸ポートピアホテル
    • Year and Date
      2010-12-09
    • Related Report
      2010 Annual Research Report
  • [Presentation] 慢性炎症性疾患の運命決定を担う核内エピゲノム制御メカニズムの解析2010

    • Author(s)
      北川浩史
    • Organizer
      北関東医学会
    • Place of Presentation
      群馬大学
    • Year and Date
      2010-10-07
    • Related Report
      2010 Final Research Report
  • [Presentation] 慢性炎症性疾患の運命決定を担う核内エピゲノム制御メカニズムの解析2010

    • Author(s)
      北川浩史
    • Organizer
      北関東医学会
    • Place of Presentation
      群馬大学刀城会館
    • Year and Date
      2010-10-07
    • Related Report
      2010 Annual Research Report
  • [Presentation] Nuclear Receptors and its frontier': The functional regulation of a chromatin remodeling complex 'WINAC' serving as a co-regulator complex for nuclear receptors2010

    • Author(s)
      Hirochika Kitagawa, Shigeaki Kato
    • Organizer
      14th International Conference of Endocrinology; Satellite Symposium
    • Place of Presentation
      京都国際会議場
    • Year and Date
      2010-03-31
    • Related Report
      2010 Final Research Report
  • [Presentation] The functional regulation of a chromatin remodeling complex'WINAC'serving as a co-regulator complex for nuclear receptors2010

    • Author(s)
      北川浩史
    • Organizer
      第14回国際ステロイドホルモン学会 サテライトシンポジウム
    • Place of Presentation
      京都
    • Year and Date
      2010-03-31
    • Related Report
      2009 Annual Research Report
  • [Presentation] Phosphorylation of WSTF by MAPK is required for the regulation of VDR-mediated transcription by WINAC2010

    • Author(s)
      Hirochika Kitagawa, Shigeaki Kato
    • Organizer
      ICE 2010
    • Place of Presentation
      京都国際会議場
    • Year and Date
      2010-03-27
    • Related Report
      2010 Final Research Report
  • [Presentation] グルココルチコイドレセプター(GR)による炎症制御メカニズムの解析2009

    • Author(s)
      北川浩史、加藤茂明
    • Organizer
      ステロイドホルモン学会
    • Place of Presentation
      九州大学
    • Year and Date
      2009-11-14
    • Related Report
      2010 Final Research Report
  • [Presentation] 核内受容体転写修飾因子として機能するクロマチン構造変換複合体の新規細胞内シグナル依存性機能制御メカニズムの解明2009

    • Author(s)
      北川浩史、加藤茂明
    • Organizer
      日本内分泌学会
    • Place of Presentation
      群馬県民文化会館
    • Year and Date
      2009-04-23
    • Related Report
      2010 Final Research Report
  • [Presentation] ビタミンDレセプターの転写制御におけるクロマチン構造変換の役割2008

    • Author(s)
      北川浩史、藤木亮次、金美善、吉村、公宏、大矢博之、山本陽子、松本高広、高田伊知郎、武山、健一、加藤茂明
    • Organizer
      日本骨代謝学会ミニシンポジウム
    • Place of Presentation
      大阪国際会議場
    • Year and Date
      2008-10-30
    • Related Report
      2010 Final Research Report
  • [Presentation] 炎症制御に関与するグルココルチコイドレセプター(GR)の分解制御メカニズムの解析2008

    • Author(s)
      北川浩史,山岡育子、岡田麻衣子、藤山沙理、加藤茂明
    • Organizer
      日本生化学会
    • Place of Presentation
      神戸国際会議場
    • Year and Date
      2008-10-21
    • Related Report
      2010 Final Research Report
  • [Presentation] グルココルチコイドレセプター(GR)による未知抗炎症作用メカニズムの解析2008

    • Author(s)
      北川浩史,山岡育子、目崎善弘、清水崇史、加藤茂明
    • Organizer
      日本内分泌学会
    • Place of Presentation
      青森
    • Year and Date
      2008-05-18
    • Related Report
      2008 Annual Research Report
  • [Book] 現代栄養学を理解するための分子生物学入門2010

    • Author(s)
      加藤茂明, 他
    • Total Pages
      221
    • Publisher
      光生館
    • Related Report
      2010 Final Research Report
  • [Book] 現代栄養学を理解するための分子生物学入門2010

    • Author(s)
      加藤茂明監修
    • Total Pages
      221
    • Publisher
      光生館
    • Related Report
      2010 Annual Research Report
  • [Remarks] ホームページ等

    • URL

      http://kakunai.dept.showa.gunma-u.ac.jp/kitagawa/

    • Related Report
      2010 Final Research Report
  • [Remarks] 研究室ホームページ

    • URL

      http://kakunai.dept.showa.gunma-u.ac.jp/kitagawa/

    • Related Report
      2010 Annual Research Report
  • [Remarks]

    • URL

      http://www.iam.u-tokyo.ac.jp/bnsikato/syokai.htm

    • Related Report
      2008 Annual Research Report

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Published: 2008-04-01   Modified: 2016-04-21  

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