Exploration of novel glucocorticoid action via genome-wide approach

• Project/Area Number: 21390285
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Endocrinology
• Research Institution: The University of Tokyo
• Principal Investigator: TANAKA Hirotoshi 東京大学, 医科学研究所, 准教授 (00171794)
• Co-Investigator(Kenkyū-buntansha): SHIMIZU Noriaki 東京大学, 医科学研究所, 特任研究員 (30396890) ; YOSHIKAWA Noritada 東京大学, 医科学研究所, 助教 (70396878)
• Project Period (FY): 2009 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥17,940,000 (Direct Cost: ¥13,800,000、Indirect Cost: ¥4,140,000); Fiscal Year 2011: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2010: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000); Fiscal Year 2009: ¥7,800,000 (Direct Cost: ¥6,000,000、Indirect Cost: ¥1,800,000)
• Keywords: 内分泌学 / 代謝学 / 副腎皮質 / 遺伝子発現 / 生理学

Research Abstract

Adrenal glucocorticoids produce their hormone actions via a signal pathway involving ubiquitously expressed glucocorticoid receptor(GR), a prototypic member of the nuclear receptor superfamily, which acts as a ligand-dependent transcription factor. Upon binding glucocorticoids, GR translocates into the nucleus and binds the glucocorticoid response element(GRE) on the target gene promoters. Binding of liganded receptors with target DNA is followed by recruitment of mediators and coactivators to the proximity of the target DNA, resulting in RNA polymerase II(RNAPII) recruitment nearby transcription start sites and activation of transcription. In skeletal muscle, glucocorticoids elicit a variety of biological actions in metabolism of glucose, lipids, and proteins and contribute to metabolic homeostasis. On the other hand, glucocorticoids are used as a key drug for treatment of, for example, inflammatory disorders, hematologic malignancies, and allergic diseases, and prolonged oversecretion or exogenous administration of glucocorticoid drug gives rise to undesirable effects including muscle atrophy. given this, we decided to explore GR target gene via genome wide approach, especially in skeletal and cardiac muscles
In skeletal muscle, we confirmed that KLF15 and REDD1 are direct target genes of GR, playing important roles in mTOR inhibition and muscle atrophy via distinct pathways. Together with the results with cardiac muscles, we think that our genome wide approach will clarify the biological significance of GC-GR system and contribute to further understanding of human physiology and development of GC therapy.

Research Products

• [Journal Article] Crosstalk between Glucocorticoid Receptor and Nutritional Sensor mTOR in Skeletal Muscle (2011)
  • Author(s): Shimizu N, Yoshikawa N, Ito N, Maruyama T, Suzuki Y, Takeda S, Nakae J, Tagata Y, Nishitani S, Takehana K, Sano M, Fukuda K, Suematsu M, Morimoto C, Tanaka H
  • Journal Title: Cell Metab Volume: 13(2) Pages: 170-182
• [Journal Article] Epigenetic modulation of the renalβ-adrenergic. WNK4 pathway in salt-sensitive hypertension (2011)
  • Author(s): Mu SY, Shimosawa T, Ogura S, Wang H, Uetake Y, Kawakami-Mori F, Marumo T, Yatomi Y, Geller DS, Tanaka H, Fujita T
  • Journal Title: Nat. Med Volume: 17(5) Pages: 573-580
• [Journal Article] The histone demethylase JMJD2B plays an essential role in human carcinogenesis through positive regulation of cyclin-dependent kinase 6 (2011)
  • Author(s): Toyokawa G, Cho H-S, Iwai Y, Yoshimatsu M, Takawa M, Hayami S, Maejima K, Shimizu N, Tanaka H, Tsunoda T, Field H, Kelly J, Neal D, Ponder B, Maehara Y, Nakamura Y, and Hamamoto R
  • Journal Title: Cancer Prev. Res Volume: 4(12) Pages: 2051-2061
• [Journal Article] Epigenetic modulation of the renal β-adrenergic-WNK4 pathway in salt-sensitive hypertension (2011)
  • Author(s): Mu SY, Shimosawa T, Ogura S, Wang H, Uetake Y, Kawakami-Mori F, Marumo T, Yatomi Y, Geller DS, Tanaka H, Fujita T
  • Journal Title: Nat.Med. Volume: 17 Issue: 4 Pages: 573-580
  • DOI: 10.1038/nm0412-630b
  • Peer Reviewed
• [Journal Article] The histone demethylase JMJD2B plays an essential role in human carcinogenesis through positive regulation of cyclin-dependent kinase 6 (2011)
  • Author(s): Toyokawa G, Cho H-S, Iwai Y, Yoshimatsu M, Takawa M, Hayami S, Maejima K, Shimizu N, Tanaka H, Tsunoda T, Field H, Kelly J, Neal D, Ponder B, Maehara Y, Nakamura Y, Hamamoto R
  • Journal Title: Cancer Prev.Res. Volume: 4 Issue: 12 Pages: 2051-2061
  • DOI: 10.1158/1940-6207.capr-11-0290
  • Peer Reviewed
• [Journal Article] Crosstalk between Glucocorticoid Receptor and Nutritional Sensor mTOR in Skeletal Muscle. (2011)
  • Author(s): Shimizu N, Yoshikawa N, Ito N, Maruyama T, Suzuki Y, Takeda S, Nakae J, Tagata Y, Nishitani S, Takehana K, Sano M, Fukuda K, Suematsu M, Morimoto C, Tanaka H.
  • Journal Title: Cell Metab. Volume: 13(2) Pages: 170-182
  • Peer Reviewed
• [Journal Article] Targeting KRAS mutation-bearing lung cancer in vivo by pulmonary surfactant-adenovirus-mediated gene transfer (2010)
  • Author(s): Fukazawa T, Maeda Y, Matsuoka J, Ono T, Mominoki K, Yamatsuji T, Shigemitsu K, Morita I, Murakami I, Tanaka H, Durbin ML, Naomoto Y
  • Journal Title: Anticancer Res Volume: 30(12) Pages: 4925-4935
• [Journal Article] Targeting KRAS mutation-bearing lung cancer in vivo by pulmonary surfactant-adenovirus-mediated gene transfer. (2010)
  • Author(s): Fukazawa T, Maeda Y, Matsuoka J, Ono T, Mominoki K, Yamatsuji T, Shigemitsu K, Morita I, Murakami I, Tanaka H, Durbin ML, Naomoto Y
  • Journal Title: Anticancer Res. Volume: 30(12) Pages: 4925-4935
  • Peer Reviewed
• [Journal Article] Glucocorticoid protects rodent hearts from ischemia/reperfusion injury by activating lipocalin-type prostaglandin D synthase-derived PGD_2 biosynthesis. (2009)
  • Author(s): Tokudome S, et al.
  • Journal Title: J Clin Invest 119(6) Pages: 1477-1488
  • Peer Reviewed
• [Journal Article] SHP-2 inhibits tyrosine phosphorylation of Cas-L and regulates cell migration. (2009)
  • Author(s): Yo, K., et al.
  • Journal Title: Biochem Biophys Res Commun. 382(1) Pages: 210-214
  • Peer Reviewed
• [Journal Article] Ligand-based gene expression profiling identifies critical role of glucocorticoid receptor in rat neonatal cardiomyocytes. (2009)
  • Author(s): Yoshikawa N, et at
  • Journal Title: Am J Physiol Endocrinol Metab 296(6)
  • Peer Reviewed
• [Presentation] 骨格筋萎縮研究の新展開 (2011)
  • Author(s): 田中廣壽
  • Organizer: リウマチ膠原病よつやセミナー
  • Place of Presentation: 東京、ベルサール八重洲(招待講演)
  • Year and Date: 2011-08-27
• [Presentation] ゲノムワイドアプローチによるグルココルチコイド作用の解析 (2011)
  • Author(s): 田中廣壽
  • Organizer: CKDと心血管イベントExpert Meeting VI
  • Place of Presentation: 東京、東京ドームホテル(招待講演)
  • Year and Date: 2011-07-08
• [Presentation] 骨格筋量調節の分子基盤 (2011)
  • Author(s): 田中廣壽
  • Organizer: 第7回核内レセプター創薬研究会
  • Place of Presentation: 東京、霞ヶ関ナレッジスクエア(招待講演)
  • Year and Date: 2011-06-16
• [Presentation] ステロイド2010-新薬開発と副作用克服に向けて (2010)
  • Author(s): 田中廣壽
  • Organizer: 中部リウマチ学会総会
  • Place of Presentation: ANAクラウンプラザホテル新潟
  • Year and Date: 2010-09-04
• [Presentation] 特別講演:ステロイド2010-新薬開発と副作用克服に向けて (2010)
  • Author(s): 田中廣壽
  • Organizer: 中部リウマチ学会総会
  • Place of Presentation: ANAクラウンプラザホテル新潟
  • Year and Date: 2010-09-04
• [Presentation] (2009)
  • Author(s): 田中廣壽
  • Organizer: 第28回関東腎研究会
  • Place of Presentation: 関東倶楽部、東京
  • Year and Date: 2009-07-04
• [Presentation] グルココルチコイドの新しい役割 (2009)
  • Author(s): 田中廣壽
  • Organizer: 第28回関東腎研究会
  • Place of Presentation: 東京
  • Year and Date: 2009-07-04
• [Remarks]
  • URL: http://www.h.ims.u-tokyo.ac.jp/gairai/depts-03.html
• [Remarks]
  • URL: http://www.u-tokyo.ac.jp/public/public01_230202_j.html
• [Remarks]
  • URL: http://www.ims.u-tokyo.ac.jp/imsut/jp/research/papers/post_27.php