Elucidation of signal transduction systems which are regulated by BHD tumor suppressor protein

• Project/Area Number: 20590316
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Pathological medical chemistry
• Research Institution: Juntendo University
• Principal Investigator: KOBAYASHI Toshiyuki Juntendo University, 大学院・医学研究科, 准教授 (40260070)
• Project Period (FY): 2008 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2010: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2009: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2008: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 家族性腫瘍 / 遺伝性腎癌 / 動物モデル / BHD遺伝子 / TSC2遺伝子 / mTORキナーゼ / AMP依存性キナーゼ / サイクリンD1 / 腎癌 / シグナル伝達 / BHD / 細胞周期 / mTOR / folliculin / AMPK / Tsc2 / mTORC1 / Birt-Hogg-Dube症候群

Research Abstract

It was found that the suppression of BHD (Birt-Hogg-Dube syndrome gene) tumor suppressor protein expression reduced the amount of mTOR complex (mTORC1) and induces cyclin D1 protein level. It is suggested that the BHD mutation induces dysregulation of a signal transduction system regulating cyclin D1 mRNA level and leads to tumorigenesis through aberrant cell cycle. This regulatory system for cyclin D1 expression may be a novel target to develop therapeutic drug for BHD and other tumor predisposing diseases.

Research Products

• [Journal Article] Deficiency of the Erc/mesothelin gene ameliorates renal carcinogenesis in Tsc2 knockout mice. (2011)
  • Author(s): Zhang D, ら
  • Journal Title: Cancer Sci Volume: (印刷中)
  • Peer Reviewed
• [Journal Article] Serine 62 is a phosphorylation site in folliculin, the Birt-Hogg-Dube gene product. (2010)
  • Author(s): Wang L, Kobayashi T, Piao X, Shiono M, Takagi Y, Mineki R, Taka H, Zhang D, Abe M, Sun G, Hagiwara Y, Okimoto K, Matsumoto I, Kouchi M, Hino O
  • Journal Title: FEBS Lett 584 Pages: 39-43
  • Peer Reviewed
• [Journal Article] Clinical and genetic spectrum of Birt-Hogg-Dube syndrome patients in whom pneumothorax and/or multiple lung cysts are the presenting feature. (2010)
  • Author(s): Kunogi M, Kurihara M, Ikegami TS, Kobayashi T, Shindo N, Kumasaka T, Gunji Y, Kikkawa M, Iwakami S, Hino O, Takahashi K, Seyama K
  • Journal Title: J Med Genet 47 Pages: 281-287
  • Peer Reviewed
• [Journal Article] Clinical and genetic spectrum of Birt-Hogg-Dube syndrome patients in whom pneumothorax and/or multiple lung cysts are the predisposing feature. (2010)
  • Author(s): Kunogi M, ら
  • Journal Title: J Med Genet Volume: 47 Pages: 281-287
  • Peer Reviewed
• [Journal Article] Serine 62 is a phosphorylation site in folliculin, the Birt-Hogg-Dube gene product (2010)
  • Author(s): Wang, L, ら
  • Journal Title: FEBS Lett 584 Pages: 39-43
  • Peer Reviewed
• [Journal Article] Phosphorylated hamartin-HSP70 complex regulates apoptosis via mitochondrial localization (2010)
  • Author(s): Inoue H, ら
  • Journal Title: Biochem Biophys Res Commun 391 Pages: 1148-1153
  • Peer Reviewed
• [Journal Article] Regulation of folliculin (the BHD gene product) phosphorylation by Tsc2-mTOR pathway. (2009)
  • Author(s): Piao X, Kobayashi T, Wang L, Shiono M, Takagi Y, Sun G, Abe M, Hagiwara Y, Zhang D, Okimoto K, Kouchi M, Matsumoto I, Hino O
  • Journal Title: Biochem Biophys Res Commun 389 Pages: 16-21
  • Peer Reviewed
• [Journal Article] Regulation of folliculin(the BHD gene product)phosphoiylation by Tsc2-mTOR pathway (2009)
  • Author(s): Piao, X, ら
  • Journal Title: Biochem Biophys Res Commun 389 Pages: 16-21
  • Peer Reviewed
• [Journal Article] Interaction of folliculin (Birt-Hogg-Dube gene product) with a novel Fnip1-like (FnipL/Fnip2) protein. (2008)
  • Author(s): Takagi Y, Kobayashi T, Shiono M, Wang L, Piao X, Sun G, Abe M, Hagiwara Y, Takahashi K, Hino O
  • Journal Title: Oncogene 27 Pages: 5339-5347
  • Peer Reviewed
• [Journal Article] Interaction of folliculin (Birt-Hogg-Dube gene product) with a novel Fnipl-like (Fnip2/FnipL)protein. (2008)
  • Author(s): Takagi, Y., et al.
  • Journal Title: Oncogene 27 Pages: 5339-5347
  • Peer Reviewed
• [Presentation] Functions of mTOR complexes and mTOR-related tumor suppressor proteins (tuberin and folliculin) in differentiation of skeletal muscle cells. (2010)
  • Author(s): 小林敏之, ら
  • Organizer: 第33回日本分子生物学会年会第83回日本生化学会大会 合同大会
  • Place of Presentation: 神戸ポートアイランド(神戸市)
  • Year and Date: 2010-12-10
• [Presentation] TuberinのRac活性促進とRheb-GAP活性の機能連関 (2010)
  • Author(s): 大倉英浩, ら
  • Organizer: 第69回日本癌学会学術総会
  • Place of Presentation: 大阪国際コンベンションセンター(大阪市)
  • Year and Date: 2010-09-22
• [Presentation] Tsc2 KOマウス腎腫瘍増殖におけるErc/mesothelin遺伝子の影響および関わるインテグリン伝達系の解明 (2010)
  • Author(s): 小橋(張)丹青, ら
  • Organizer: 第69回日本癌学会学術総会
  • Place of Presentation: 大阪国際コンベンションセンター(大阪市)
  • Year and Date: 2010-09-22
• [Presentation] 骨格筋細胞分化における腫瘍抑制遺伝子産物(Flcnおよびtuberin)の役割 (2010)
  • Author(s): 小林敏之, ら
  • Organizer: 第16回日本家族性腫瘍学会学術総会
  • Place of Presentation: 朱鷺メッセ(新潟市)
  • Year and Date: 2010-07-09
• [Presentation] Functions of mTOR complexes and mTOR-related tumor suppressor proteins (tuberin and folliculin) in differentiation of skeletal muscle cells (2010)
  • Author(s): 小林敏之、朴香花、正岡亜希子、大倉英浩、大澤麻記、樋野興夫
  • Organizer: 第33日本分子生物学会年会・第83回日本生化学会大会・合同大会
• [Presentation] Tsc2-mTOR axisの異常が関わる病態発生機構 (2010)
  • Author(s): 小林敏之
  • Organizer: 第40回日本腎臓学会東部学術大会
• [Presentation] Regulation of complex formation of FLCN-AMPK by FLCN phosphorylation (2009)
  • Author(s): 朴香花, ら
  • Organizer: 第32回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜(横浜市)
  • Year and Date: 2009-12-11
• [Presentation] Regulation of complex formation of FLCN-AMPK by FLCN phosphorylation (2009)
  • Author(s): 朴香花、王〓、沖本一夫、河内眞美、松本泉美、小林敏之、樋野興夫
  • Organizer: 第32回日本分子生物学会年会
• [Presentation] Bhd蛋白のリン酸化部位の同定とリン酸化酵素の解明 (2008)
  • Author(s): 王 〓 ら
  • Organizer: 第31回日本分子生物学会年会・第81回日本生化学会大会 合同大会
  • Place of Presentation: 神戸
  • Year and Date: 2008-12-12
• [Presentation] Tsc2によるBhdリン酸化の制御 (2008)
  • Author(s): 朴 香花 ら
  • Organizer: 第31回日本分子生物学会年会・第81回日本生化学会大会 合同大会
  • Place of Presentation: 神戸
  • Year and Date: 2008-12-09
• [Presentation] Fnip蛋白によるfolliculinの局在とリン酸化の調節 (2008)
  • Author(s): 小林敏之、高木裕美子、樋野興夫
  • Organizer: 第67回日本癌学会学術総会
• [Presentation] Bhd蛋白のリン酸化部位の同定とリン酸化酵素の解明 (2008)
  • Author(s): 王〓、朴香花、塩野雅俊、高木裕美子、高ひかり、峯木礼子、小林敏之、樋野興夫
  • Organizer: 第31回日本分子生物学会年会・第81回日本生化学会大会・合同大会
• [Remarks] ホームページ等
  • URL: http://www.juntendo.ac.jp/graduate/laboratory/labo/bunshi_byori/k4.html