Identification and analysis of new androgen responsive regulatory genes for development and cancer.

• Project/Area Number: 15H04300
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Tumor biology
• Research Institution: Wakayama Medical University
• Principal Investigator: Yamada Gen 和歌山県立医科大学, 先端医学研究所, 教授 (80174712)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥10,530,000 (Direct Cost: ¥8,100,000、Indirect Cost: ¥2,430,000); Fiscal Year 2017: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000); Fiscal Year 2016: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000); Fiscal Year 2015: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
• Keywords: アンドロゲン / 男性ホルモン / bZipファミリー / 癌関連繊維芽細胞 / MafB / 生殖器間葉細胞 / 外生殖器 / 前立腺 / 癌繊維芽細胞 / 前立腺癌 / エンハンサー / アンドロゲンレセプター / 発生制御 / 発現制御 / 雄性化 / ホルモン

Outline of Final Research Achievements

The current study suggests that the Mafb 3' untranslated region (UTR) is an essential region for its regulation by androgen. We identified 2 functional androgen response elements (AREs) in Mafb 3UTR.
Androgen receptor is bound to such AREs in 3UTR during urethral masculinization. By using such identified UTR-enhancer, we revealed new candidate upstream gene for MafB regulation. Our ongoing study suggests such new transcription factor-AR interaction is essential for regulating MafB enhancer. CAF cells have been also suggested as playing essential role for prostate cancer. The current study gives insight for the regulation of bZip family gene function not only in embryonic mesenchyme cells but also for cancer associated fibroblast (CAF) cells.

Research Products

• [Int'l Joint Research] University of Minnesota、ミネソタ州/NHLBI/NIH、メリーランド州/Cleveland Clinic、オハイオ州(米国)
• [Int'l Joint Research] University of Bonn(ドイツ)
• [Int'l Joint Research] University of Bonn Clinics(ドイツ)
• [Int'l Joint Research] Department of Developmental Biology/Washington University School of Medicine(米国)
• [Int'l Joint Research] Department of Surgery/The university of Hong Kong(中国)
• [Journal Article] Frontiers in the regulation of masculinization; androgen signaling in the developing external genitalia. (2018)
  • Author(s): Shoko Matsushita, Kentaro Suzuki, Aki Murashima, Daiki Kajioka, Alvin Acebedo, Shinichi Miyagawa, Ryuma Haraguchi, Yukiko Ogino, and Yamada G.
  • Journal Title: Nature Reviews Urology Volume: 印刷中
  • Peer Reviewed
• [Journal Article] Functional distinctions associated with the diversity of sex steroid hormone receptors ESR and AR. (2018)
  • Author(s): Yukiko Ogino, Saki Tohyama, Satomi Kohno, Kenji Toyota, Gen Yamada, Ryohei Yatsu, Tohru Kobayashi, Norihisa Tatarazako, Tomomi Sato, Hajime Matsubara, Anke Lange, Charles R. Tyler, Yoshinao Katsu, Taisen Iguchi, Shinichi Miyagawa.
  • Journal Title: Journal of Steroid Biochemistry and Molecular Biology Volume: 印刷中
  • Peer Reviewed
• [Journal Article] 5α-Dihydrotestosterone negatively regulates cell proliferation of the periurethral ventral mesenchyme during urethral tube formation in the murine male genital tubercle (2017)
  • Author(s): Hiroko Suzuki, Shoko Matsushita, Kentaro Suzuki, Gen Yamada
  • Journal Title: Andrology Volume: 5 Issue: 1 Pages: 146-152
  • DOI: 10.1111/andr.12241
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Epispadias and the associated embryopathies; genetic and developmental basis. (2017)
  • Author(s): Kentaro Suzuki, Daisuke Matsumaru, Shoko Matsushita, Aki Murashima, Michael Ludwig, Heiko Reuter, Gen Yamada
  • Journal Title: Clinical Genetics Volume: 91 Issue: 2 Pages: 247-253
  • DOI: 10.1111/cge.12871
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Establishment of estrogen receptor 1 (ESR1)-knockout medaka; ESR1 is dispensable for sexual development and reproduction in medaka, Oryzias latipes. (2017)
  • Author(s): Tohyama S, Ogino Y, Lange A, Myosho T, Kobayashi T, Hirano Y, Yamada G, Sato T, Tatarazako N, Tyler CR, Iguchi T, Miyagawa S.
  • Journal Title: Dev Growth Diff Volume: 59 Issue: 6 Pages: 552-561
  • DOI: 10.1111/dgd.12386
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Developmental Contribution of Wnt-signal-responsive Cells to Mouse Reproductive Tract Formation (2017)
  • Author(s): Haraguchi Ryuma, Kitazawa Riko, Murashima Aki, Yamada Gen, Kitazawa Sohei
  • Journal Title: ACTA HISTOCHEMICA ET CYTOCHEMICA Volume: 50 Issue: 4 Pages: 127-133
  • DOI: 10.1267/ahc.17017
  • NAID: 130006003857
  • ISSN: 0044-5991, 1347-5800
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Androgen Regulates Dimorphic F-Actin Assemblies in the Genital Organogenesis (2017)
  • Author(s): Liu Liqing、Suzuki Kentaro、Chun Eunice、Murashima Aki、Sato Yuki、Nakagata Naomi、Fujimori Toshihiko、Yonemura Shigenobu、He Wanzhong、Yamada Gen
  • Journal Title: Sexual Development Volume: 11 Issue: 4 Pages: 190-202
  • DOI: 10.1159/000477452
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Expression patterns of Fgf8 and Shh in the developing externalgenitalia of Suncus murinus. (2017)
  • Author(s): Miyado M, Miyado K, Nakamura A, Fukami M, Yamada G, Oda SI.
  • Journal Title: Reproduction Volume: 153(2) Pages: 187-195
  • Peer Reviewed
• [Journal Article] Expression patterns of Fgf8 and Shh in the developing external genitalia of Suncus murinus. (2017)
  • Author(s): Miyado M, Miyado K, Nakamura A, Fukami M, Yamada G, Oda SI.
  • Journal Title: Reproduction. Volume: 153(2) Pages: 187-195
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] ISL1 is a major susceptibility gene for classic bladder exstrophy and a regulator of urinary tract development. (2017)
  • Author(s): Zhang R, Knapp M, Suzuki K...Yamada G, Odermatt B, Reutter H.
  • Journal Title: Sci Rep. Volume: 8;7 Issue: 1 Pages: 42170-42170
  • DOI: 10.1038/srep42170
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Genetics of Bladder-Exstrophy-Epispadias Complex (BEEC): Systematic Elucidation of Mendelian and Multifactorial Phenotypes. (2016)
  • Author(s): Reutter H, Keppler-Noreuil K, E Keegan C, Thiele H, Yamada G, Ludwig M.
  • Journal Title: Curr Genomics. Volume: 17(1) Issue: 1 Pages: 4-13
  • DOI: 10.2174/1389202916666151014221806
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Neofunctionalization of androgen receptor by gain-of-function mutations in teleost fish lineage (2016)
  • Author(s): Ogino Y, Kuraku S, Ishibashi H, Miyakawa H, Sumiya E, Miyagawa S, Matsubara H, Yamada G, Baker ME, Iguchi T
  • Journal Title: Mol Biol Evol Volume: 33 Issue: 1 Pages: 228-244
  • DOI: 10.1093/molbev/msv218
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Androgen regulates Mafb expression through its 3’UTR during mouse urethral masculinization (2016)
  • Author(s): Matsushita S, Suzuki K, OginoY, Hino S, Sato T, Suyama M, Matsumoto T, Omori A, Inoue S, Yamada G
  • Journal Title: Endocrinology Volume: 157 Issue: 2 Pages: 844-857
  • DOI: 10.1210/en.2015-1586
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Region-specific regulation of cell proliferation by Fgf receptor signaling during the Wolffian duct development (2015)
  • Author(s): Mika Okazawa, Aki Murashima, Masayo Harada, Naomi Nakagata, Masafumi Noguchi, Mitsuru Morimoto, Tadashi Kimura, David M. Ornitz, Gen Yamada
  • Journal Title: Developmental Biology Volume: 1;400(1) Issue: 1 Pages: 139-147
  • DOI: 10.1016/j.ydbio.2015.01.023
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Systematic stereoscopic analyses for cloacal development: The origin of anorectal malformations. (2015)
  • Author(s): Matsumaru D, Murashima A, Fukushima J, Senda S, Matsushita S, Nakagata N, Miyajima M, Yamada G.
  • Journal Title: Sci Rep. Volume: 10;5 Issue: 1 Pages: 13943-13943
  • DOI: 10.1038/srep13943
  • Peer Reviewed / Open Access
• [Journal Article] Systematic analyses of murine masculinization processes based on genital sex differentiation parameters (2015)
  • Author(s): Suzuki H, Suzuki K, Yamada G
  • Journal Title: Dev Growth Differ. Volume: 57(9) Issue: 9 Pages: 639-647
  • DOI: 10.1111/dgd.12247
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] Frontier of cell migration analysis; androgen development mouse genitalia formation based on the mutant model analysis. (2017)
  • Author(s): 山田 源
  • Organizer: The 25th International syposia on Morphological Sciences (ISMS 2017)、第4軍医大学、中国
  • Int'l Joint Research / Invited
• [Presentation] Molecular mechanisms of external genitalia formation; an emerging model for hormone-induced organogenesis. (2017)
  • Author(s): 山田 源
  • Organizer: Reproduction down under 2017、Mantra on Salt Beach、オーストラリア
  • Int'l Joint Research / Invited
• [Presentation] “Androgen and local signal interaction for mouse sexual differentiation” (2016)
  • Author(s): 山田 源
  • Organizer: 第39回日本分子生物学会
  • Place of Presentation: パシフィコ横浜 （横浜市）
  • Year and Date: 2016-11-30
  • Invited
• [Presentation] “Molecular mechanisms of sexual differentiation; Genetic cascade responsible for sexual reproductive organ formation and diseases, cancer” (2016)
  • Author(s): Gen Yamada
  • Organizer: Philippine society for cell biology (PSCB) meeting (7th Annual and 1st International convention and scientific meeting)
  • Place of Presentation: Institute of Biology, University of the Philippines, Diliman (フィリピン）
  • Year and Date: 2016-10-20
  • Int'l Joint Research / Invited
• [Presentation] 「マウスミュータント系を用いた生殖器形成の解明の最前線：性差は如何に制御されるか」 (2016)
  • Author(s): 山田 源
  • Organizer: 第５３回 北陸実験動物研究会
  • Place of Presentation: 金沢大学 （金沢市）
  • Invited
• [Presentation] Molecular mechanisms of sexual differentiation; recent mouse models (2015)
  • Author(s): Gen Yamada
  • Organizer: Lerner Research Institute Seminar
  • Place of Presentation: Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland Ohio, USA
  • Year and Date: 2015-11-12
  • Invited
• [Presentation] 外生殖器形成機構の最新研究 (2015)
  • Author(s): 山田 源
  • Organizer: 第55回日本先天異常学会学術集会及び第38回日本小児遺伝学会学術集会
  • Place of Presentation: パシフィコ横浜会議センター
  • Year and Date: 2015-07-25
  • Invited
• [Presentation] Development of the external genitalia (2015)
  • Author(s): Gen Yamada
  • Organizer: I-DSD symposium, 5th International DSD symposium
  • Place of Presentation: New Zebra, Ghent, Belsium
  • Year and Date: 2015-06-11
  • Int'l Joint Research / Invited
• [Remarks] Department of Developmental Genetics, WMU
  • URL: http://www.wakayama-med.ac.jp/english/undergraduate/medicine/160904/index.html
• [Remarks] Research Gate, Gen Yamada
  • URL: http://www.researchgate.net/profile/Gen_Yamada
• [Remarks] WMU, Department Of Developmental Genetics
  • URL: http://www.wakayama-med.ac.jp/english/undergraduate/medicine/160904/index.html
• [Remarks] ResearchGate, Gen Yamada
  • URL: https://www.researchgate.net/profile/Gen_Yamada/
• [Remarks] Wakayama Medical University
  • URL: http://www.wakayama-med.ac.jp/english/undergraduate/medicine/genetics.html
• [Remarks] 和歌山県立医科大学 遺伝子制御学研究部
  • URL: http://www.wakayama-med.ac.jp/dept/igakubu/160904/index.html