Basic and clinical research on abnormalities of sexual differentiation associated with synthesis and action of sex steroids

2008 Fiscal Year Final Research Report

• Project/Area Number: 16086207
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Kyushu University
• Principal Investigator: YANASE Toshihiko Kyushu University, 大学院・医学研究院, 准教授 (30239818)
• Co-Investigator(Renkei-kenkyūsha): OKABE Taijiro 九州大学, 大学院・医学研究院, 講師 (40264030) ; NOMURA Masatoshi 九州大学, 大学病院, 講師 (30315080)
• Project Period (FY): 2004 – 2008
• Keywords: アンドロゲン / Ad4BP / SF-1 / アロマターゼ / ステロイド産生細胞

Research Abstract

(1)アンドロゲン過敏性としての低濃度アンドロゲンによるアンドロゲン受容体(AR)転写活性化亢進機序としてのIGF-1の関与を解析した。下流のFox01がAR転写活性を抑制性に調節し、IGF-1-PI3K-Akt活性によるリン酸化で不活性化され、結果的にAR転写活性を増強する機構を明らかにした。
(2)トリアジン系除草剤のアトラジンが単独でSF-1依存性にアロマターゼ転写活性を増強することを見出し、その機序の一端として、SF-1の弱いリガンドとして作用する可能性を見出した。
(3)マウスあるいはヒトの骨髄由来あるいは脂肪組織由来の間葉系幹細胞にAd4BP/SF-1を遺伝子導入することによりACTH,LH反応性のステロイド産生細胞の創出に成功した。上記二つの組織ソースの違いによって、副腎系あるいは性腺系ステロイドの産生リネージを示した。(4)ARによるエネルギー産生亢進機序として、ARはレプチンシグナルの下流分子であるSTAT3の核内移行を促進する結果、レプチンシグナルを増強する機序を明らかにした。

Research Products

• [Journal Article] Characterizaton of human growth differntiation factor-9 signaling in ovarian granulose cells (2008)
  • Author(s): Mottershead, D.G., Pulkko, M., Muggalla, P., Pastemach, A., Tolone, M., Myllymaa, S., Korchynskyi, O., Nishi, Y., Yanase, T., Lun, S., Juengel, J., Laitinen, M., Rivos, O
  • Journal Title: Mol Cell Endocrinol 283 Pages: 58-67
  • Peer Reviewed
• [Journal Article] Inhibition of proteasome activity sensitizes human granulosa tumor cells to TRAIL-induced cell death (2008)
  • Author(s): Woods, D.C., Liu, H.K., Nishi, Y., Yanase, T., Johnson, A.L.
  • Journal Title: Cancer Lett 260 Pages: 20-27
  • Peer Reviewed
• [Journal Article] Methylation of a conserved intronic CpG island of mouse SF-1 is associated with cell-specific expression of SF-1 in a culture system but not with tissue-specific expression (2008)
  • Author(s): Shiirohzu, H., Okabe, T., Gondo, S., Tanaka, T., Ohe, K., Morinaga, H., Kawate, H., Nomura, M., Takayanagi, R., Nawata, H., Yanase, T
  • Journal Title: Biochem Biophys Res Commun 369 Pages: 862-867
  • Peer Reviewed
• [Journal Article] Glutathione S-transferase theta 1 expressed in granulosa cells as a biomarker for oocyte quality in age-related infertility (2008)
  • Author(s): Ito, M., Muraki, M., Takahashi, Y., Imai, M., Tsukui, T., Yamakawa, N., Nakagawa, K., Ohgi, S., Horikawa, T., Iwasaki, W., Iida, A., Nishi, Y., Yanase, T., Nawata, H., Miyado, K., Kono, T., Hosoi, Y., Saito, H
  • Journal Title: Fertil Steril 90 Pages: 1026-1035
  • Peer Reviewed
• [Journal Article] Adipose tissue-derived and bone marrow-derived mesenchymal cells develop into different lineage of steroidogenic cells by forced expression of steroidogenic factor 1 (2008)
  • Author(s): Gondo, S., Okabe, T., Tanaka, T., Morinaga, H., Nomura, M., Takayanagi, R., Nawata, H., Yanase T
  • Journal Title: Endocrinology 149(9) Pages: 4717-25
  • Peer Reviewed
• [Journal Article] Functional potentiation of leptin-STAT3 signaling by the androgen receptor (2008)
  • Author(s): Fan, W., Yanase, T., Nishi, Y., Chiba, S., Okabe, T., Nomura, M., Yoshimatsu, H., Kato, S., Takayanagi, R., Nawata, H
  • Journal Title: Endocrinology 149(12) Pages: 6028-6036
  • Peer Reviewed
• [Journal Article] IGF1/insulin signaling activates androgen signaling through direct interactions of Foxo1 with androgen receptor (2007)
  • Author(s): Fan, W., Yanase, T., Morinaga, H., Okabe, T., Nomura, M., Daitoku, H, Fukamizu, A., Kato, S., Takayanagi, R., Nawata, H
  • Journal Title: J. Biol. Chem 282 Pages: 7329-38
  • Peer Reviewed
• [Journal Article] The pituitary function of androgen receptor constitutes a glucocorticoid production circuit.Mol (2007)
  • Author(s): Miyamoto, J., Matsumoto, T., Shiina, H., Inoue, K., Takada, I., Ito, S., Itoh, J., Minematsu, T., Sato, T., Yanase, T., Nawata, H., Osamura, Y.R., Kato, S
  • Journal Title: Cell Biol 27 Pages: 4807-14
  • Peer Reviewed
• [Journal Article] Atrazine-induced aromatase expression is SF-1- dependent: implications for endocrine disruption in wildlife and reproductive cancers in humans (2007)
  • Author(s): Fan, W., Yanase, T., Morinaga, H., Gondo, S., Okabe, T., Nomura, M., Komatsu, T., Morohashi, K., Hayes, T.B., Takayanagi, R., Nawata, H
  • Journal Title: Enviromental Health Perspectives 117 Pages: 720-727
  • Peer Reviewed
• [Journal Article] Herbicide atrazine activates SF-1direct affinity and concomitant aoactivators recruitments to induces aromatase expression via promoter II (2007)
  • Author(s): Fan, W., Yanase, T., Morinaga, H., Gondo, S., Okabe, T., Nomura, M., Hayes, T.B., Takayanagi, R., Nawata, H
  • Journal Title: Biochem Biores Res Commun 355 Pages: 012-1018
  • Peer Reviewed
• [Journal Article] Steroidogenic factor 1/adrenal 4 binding protein transforms human bone marrow mesenchymal cells into steroidogenic cells (2007)
  • Author(s): Tanaka, T., Gondo, S., Okabe, T., Ohe, K., Shirohzu, H., Morinaga, H., Nomura, M., Tani, K., Takayanagi, R., Nawata, H., Yanase, T
  • Journal Title: J Mol Endocrinol 39 Pages: 343-350
  • Peer Reviewed
• [Journal Article] Identification of the functional domains of ANT-1, a novel coactivator of the androgen receptor (2006)
  • Author(s): Fan, S., Goto, K., Chen, G., Morinaga, H., Nomura, M., Okabe, T., Nawata, H., Yanase, T
  • Journal Title: Biochem Biophys Res Commum 341 Pages: 192-201
  • Peer Reviewed
• [Journal Article] The Gly 146Ala variation in human SF-1 gene:Its association with insulin resistance and type 2 diabetes in Chinese (2006)
  • Author(s): Liu, W., Liu, M., Fan, W., Nawata, H., Yanase, T
  • Journal Title: Diabetes Research Clinical Practice 73 Pages: 322-328
  • Peer Reviewed
• [Journal Article] Modification of glucocorticoid-sensitivity by MAP kinase signaling pathways in glucocorticoid-induced T-cell apoptosis (2006)
  • Author(s): Tanaka, T., Okabe, T., Gondo, S., Fukuda, M., Yamamoto, M., Umemura, T., Tani, K., Nomura, M., Goto, K., Yanase, T., Nawata, H
  • Journal Title: Experimental Hematology 34 Pages: 1542-52
  • Peer Reviewed
• [Journal Article] Activation of peroxisome proliferator activated receptor γand retinoid X receptor inhibits CYP19 transcription through NF-κB in ovarian granulosa cells (2005)
  • Author(s): Fan, W., Yanase, T., Wei L, Nomura, M., Okabe, T., Goto, K., Harada, N., Nawata, H
  • Journal Title: Endocrinology 146 Pages: 85-92
  • Peer Reviewed
• [Journal Article] Androgen receptor null male mice develop late-onset obesity due to decreased energy expenditure and lypolytic activity but show normal insulin sensitivity with high adiponectin secretion (2005)
  • Author(s): Fan, W., Yanase, T., Nomura, M., Okabe, T., Goto, K., Sato T, Kawano, H., Kato, S., Nawata, H
  • Journal Title: Diabetes 54 Pages: 1000-1008
  • Peer Reviewed
• [Journal Article] Dehydroepiandrosterone negatively regulates the p38 mitogen-activated protein kinase pathway by a novel PTPN7 locus-derived transcript (2005)
  • Author(s): Ashida, K., Goto, K., Zhao, Y., Okabe, T., Yanase, T., Takayanagi, R., Nomura, M., Nawata, H
  • Journal Title: Biochim.Biophys. Acta 1728 Pages: 84-94
  • Peer Reviewed
• [Journal Article] Subtle 17α-hydroxylase/17, 20-lyase deficiency with homozygous Y201N mutation in an infertile women (2005)
  • Author(s): Taniyama, M., Tanabe, M., Saito,H., Ban, Y., Nawata, H., Yanase, T
  • Journal Title: J. Clin. Endocrinol. Metab 90 Pages: 2508-2511
  • Peer Reviewed
• [Journal Article] INHA promoter polymorphisms are associated with premature ovarian failure (2005)
  • Author(s): Harris, S.E., Chand, A.L., Winship, I.M., Gersak, K., Nishi, Y., Yanase, T., Nawata, H., Shelling, A
  • Journal Title: Molecular Human Reproduction 11 Pages: 779-784
  • Peer Reviewed
• [Journal Article] Modulation of androgen receptor transactivation by FoxH1: A newly identified androgen receptor corepressor (2005)
  • Author(s): Chen, G., Nomura, M., Morinaga, H., Matsubara, E., Okabe, T., Goto, K., Yanase, T., Zheng, H., Lu, J., Nawata, H
  • Journal Title: J. Biol. Chem 280 Pages: 36355-63
  • Peer Reviewed
• [Journal Article] Impaired nuclear translocation, nuclear matrix targeting and intranuclear mobility of mutant androgen receptors carring amino acid substitutions in the deoxyribonucleic acid-binding domain derived from androen insensitivity syndrome (2005)
  • Author(s): Kawate, H., Wu, Y., Ohnaka, K., Tao, R.-H., Nakamura, K., Okabe, T., Yanase, T., Nawata, H., Takayanagi, R
  • Journal Title: Patients. J. Clin. Endocrinol. Metab 90 Pages: 6162-6169
  • Peer Reviewed
• [Journal Article] The orphan nuclear receptor NURR1 and NGFI-B modulate aromatase gene expression in ovarian granulose cells : A possible mechanism for repression of aromatase expression upon luteinizing hormone surge (2005)
  • Author(s): Wu, Y., Ghosh, S., Nishi, Y., Yanase, T., Nawata, H., Hu, Y
  • Journal Title: Endocrinology 146 Pages: 237-46
  • Peer Reviewed
• [Journal Article] Protein kinase A potentiates Ad4BP/SF-1 transactivation by re-integrating the subcellular dynamic interactions of the nuclear receptor with its cofactors (2004)
  • Author(s): Fan, W., Yanase, T., Yin, W., Kawate, H., Saitoh, M., Oba, K., Nomura, M., Okabe, T., Goto, K., Yanagisawa, J., Kato, S., Takayanagi, R., Nawata, H
  • Journal Title: GCN5/TRRAP and suppressor, DAX-1: alaser confocal imaging study in living KGN cells. Mol. Endocrinol 18 Pages: 127-141
  • Peer Reviewed
• [Journal Article] A benzimidazole fungicide, benomyl and its metabolite carbendazim induce aromatase activity in human ovarian granulose-like tumor cell line(KGN) (2004)
  • Author(s): Morinaga, H., Yanase, T., Nomura, M., Okabe, T., Goto, K., Harada, N., Nawata,H
  • Journal Title: Endocrinology 145 Pages: 1860-1869
  • Peer Reviewed
• [Journal Article] Transrepression of estrogen receptor {beta} signaling by nuclear factor-{kappa}B in ovarian granulosa cells (2004)
  • Author(s): Chu, S., Nishi, Y., Yanase, T., Nawata,H., Fuller, .PJ
  • Journal Title: Mol. Endocrinol 18 Pages: 1919-1928
  • Peer Reviewed
• [Journal Article] SF-1/Ad4BP transforms primary long-term cultured bone marrow cells into ACTH-responsive steroidogenic cells (2004)
  • Author(s): Gondo, S., Yanase, T., Okabe, T., Tanaka, T., Morinaga, H., Nomura, M., Goto, K., Nawata, H
  • Journal Title: Genes to Cells 9 Pages: 1239-1247
  • Peer Reviewed
• [Presentation] Symposium "Androgen Receptor regulated transcription"Modulation of androgen receptor transactivation by Foxo1 (2008)
  • Author(s): Yanase, T
  • Organizer: 13th Internatinal Congress of Endocrinology
  • Place of Presentation: Brazil(Symposium)
  • Year and Date: 20081109-12
• [Presentation] エビデンスに基づいたステロイドホルモン補充療法「副腎皮質機能不全症患者における副腎ステロイド補充療法の現状と問題点」 (2008)
  • Author(s): 柳瀬敏彦、高柳涼一、大関武彦、佐藤文三、碓井 亞
  • Organizer: 第81回日本内分泌学会学術総会
  • Place of Presentation: 青森(クリニカルアワー)
  • Year and Date: 20080516-18
• [Presentation] シンポジウムI「ステロイドホルモンからみたメタボリックシンドロームの成因と治療の展望」アンドロゲンとメタボリックシンドローム (2008)
  • Author(s): 柳瀬敏彦、范呉強、西芳寛、加藤茂明、名和田新、高柳涼一
  • Organizer: 第16回日本ステロイドホルモン学会
  • Place of Presentation: 福井(シンポジウム)
  • Year and Date: 2008-11-22
• [Presentation] 生活習慣病研究からアンドロゲン産生細胞再生まで (2008)
  • Author(s): 柳瀬敏彦:アンドロゲン
  • Organizer: 第27回日本アンドロロジー学会
  • Place of Presentation: 京都(特別講演)
  • Year and Date: 2008-07-04
• [Presentation] シンポジウム10「核内レセプターと糖脂質代謝代謝の最前線」アンドロゲン-アンドロゲン受容体作用系とメタボリックシンドローム (2007)
  • Author(s): 柳瀬敏彦、范呉強、京屋香奈子、高柳涼一、名和田新
  • Organizer: 第80回日本内分泌学会学術総会
  • Place of Presentation: 東京(シンポジウム)
  • Year and Date: 20070614-16
• [Presentation] IGF-1/insulin signaling activates andorgen signaling throughout direct interactions of Foxo1 with andorgen receptor (2007)
  • Author(s): Yanase, T., Fan, W., Takayanagi, R., Nawata, H
  • Organizer: 4th International Nuclear Receptor Meeting
  • Place of Presentation: saka(Symposium)
  • Year and Date: 20070201-20
• [Presentation] Approach to managing metabolic syndrome in Japan (2007)
  • Author(s): Yanase T
  • Organizer: 第7回日本Men's Healt 医学会&ASEAN交流シンポジウム「Metabolic syndrome」
  • Place of Presentation: 金沢(シンポジウム)
  • Year and Date: 2007-11-17
• [Presentation] Symposium 17 "Steroids and Metabolic Syndrome" Androgens and Metabolic Syndrome : Lessons From Androgen Receptor (ARKO) Mice (2006)
  • Author(s): Yanase, T, Fan, W., Nawata, H
  • Organizer: International Congress on Hormonal Steroids and Hormones and Cancer
  • Place of Presentation: Greece(Symposium)
  • Year and Date: 20060913-16
• [Presentation] Androgen receptor and metabolic syndrome (2006)
  • Author(s): Yanase, T
  • Organizer: 3rd Meeting of Bone Biology Forum
  • Place of Presentation: Shizuoka(Symposium)
  • Year and Date: 20060827-28
• [Presentation] シンポジウム「内・外環境と生物応答」アンドロゲン受容体の機能的意義 (2006)
  • Author(s): 柳瀬敏彦
  • Organizer: 日本生化学会九州支部開催特別シンポジウム
  • Place of Presentation: 福岡(シンポジウム)
  • Year and Date: 20060727-28
• [Presentation] シンポジウム「性とステロイド」生活習慣病背景因子としての性ステロイドの意義 (2006)
  • Author(s): 柳瀬敏彦
  • Organizer: 第14回日本ステロイドホルモン学会
  • Place of Presentation: 大阪(シンポジウム)
  • Year and Date: 2006-12-09
• [Presentation] シンポジウム5『メタボリックシンドロームと動脈硬化』 性ステロイドとメタボリックシンドローム (2006)
  • Author(s): 柳瀬敏彦
  • Organizer: 第44回日本糖尿病学会九州地方会
  • Place of Presentation: 福岡(シンポジウム)
  • Year and Date: 2006-10-13
• [Presentation] 教育セミナー3「アンドロゲンとメタボリックシンドローム」 (2006)
  • Author(s): 柳瀬敏彦
  • Organizer: 第25回日本アンドロロジ-学会
  • Place of Presentation: 金沢(教育講演)
  • Year and Date: 2006-07-16
• [Presentation] シンポジウム「核内受容体と代謝・機能調節」アンドロゲン受容体とメタボリックシンドローム (2006)
  • Author(s): 柳瀬敏彦
  • Organizer: 第38回日本動脈硬化学会
  • Place of Presentation: 東京(シンポジウム)
  • Year and Date: 2006-07-14
• [Presentation] 「内分泌代謝学におけるシグナル伝達と臨床応用」共焦点顕微鏡画像を駆使した核内受容体作用機構研究とその応用展開 (2005)
  • Author(s): 柳瀬敏彦、范呉強、野村政壽、名和田新
  • Organizer: 第77回日本内分泌学会学術総会
  • Place of Presentation: 京都(シンポジウム)
  • Year and Date: 20050624-26
• [Presentation] 性ステロイドとメタボリックシンドローム (2005)
  • Author(s): 柳瀬敏彦
  • Organizer: 第5回日本内分泌学会九州地方会イブニングセミナー
  • Place of Presentation: 福岡(特別講演)
  • Year and Date: 2005-10-01