Exploration of novel glucocorticoid action via genome-wide approach

2011 Fiscal Year Final Research Report

• 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
• Keywords: 内分泌学 / 代謝学 / 副腎皮質 / 遺伝子発現

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] 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
• [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] (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
• [Remarks]
  • URL: http://www.h.ims.u-tokyo.ac.jp/gairai/depts-03.html