Molecular Basis of the nuclear receptor function mediating Inflammation

• Project/Area Number: 20591089
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Endocrinology
• Research Institution: The 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: ¥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.

Research Products

• [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
  • Peer Reviewed
• [Journal Article] Williams syndrome is an epigenome-regulator disease (2011)
  • Author(s): Kitagawa H., Fujiki R., Yoshimura K., Oya H., Kato S.
  • Journal Title: Endocrine J Volume: 58 Pages: 77-85
  • NAID: 10029587545
  • 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
  • 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
  • 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
  • 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)
  • 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
  • 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
  • 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
  • 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
  • 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. Volume: 285 Pages: 18166-76
  • 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
  • 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)
  • 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
  • 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
  • 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
  • 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
  • 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
  • Peer Reviewed
• [Journal Article] DNA demethylation in hormone-induced transcriptional derepression (2009)
  • Author(s): Kim, M., et al.
  • Journal Title: Nature 461 Pages: 1007-1012
  • 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
  • Peer Reviewed
• [Journal Article] Co-activation of ERβ by a gonadotropi-induced cofactor GIOT-4 (2009)
  • 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
  • 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
  • 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
  • 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
  • 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 to Cells 13 Pages: 623-633
  • 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
  • Peer Reviewed
• [Presentation] Dissection of a Novel Epigenetic Regulatory Mechanism linking Inflammation and Energy Metabolism (2010)
  • Author(s): Hirochika Kitagawa, Shigeaki Kato
  • Organizer: BMB2010
  • Place of Presentation: 神戸国際会議場
  • Year and Date: 2010-12-10
• [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
• [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
• [Presentation] Nuclear Receptors and its frontier': The functional regulation of a chromatin remodeling complex 'WINAC' serving as a co-regulator complex for nuclear receptors (2010)
  • 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
• [Presentation] The functional regulation of a chromatin remodeling complex'WINAC'serving as a co-regulator complex for nuclear receptors (2010)
  • 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
• [Presentation] Phosphorylation of WSTF by MAPK is required for the regulation of VDR-mediated transcription by WINAC (2010)
  • 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
• [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
• [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
• [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
• [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
• [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
• [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
• [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
• [Remarks] ホームページ等
  • URL: http://kakunai.dept.showa.gunma-u.ac.jp/kitagawa/
• [Remarks] 研究室ホームページ
  • URL: http://kakunai.dept.showa.gunma-u.ac.jp/kitagawa/
• [Remarks]
  • URL: http://www.iam.u-tokyo.ac.jp/bnsikato/syokai.htm