Inhibitory mechanism of cell proliferation by a novel X-linked tumor suppressor Nrk

• Project/Area Number: 24650610
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Single-year Grants
• Research Field: Carcinogenesis
• Research Institution: Tokyo Institute of Technology
• Principal Investigator: KOMADA Masayuki 東京工業大学, 生命理工学研究科, 准教授 (10225568)
• Co-Investigator(Kenkyū-buntansha): DENDA Kimitoshi 東京工業大学, 大学院生命理工学研究科, 助教 (50212064)
• Project Period (FY): 2012-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2013: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2012: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 癌 / 細胞・組織 / シグナル伝達 / 蛋白質 / 酵素 / 細胞増殖 / 胎盤 / 乳腺 / 腫瘍 / タンパク質

Research Abstract

1) We identified CSIG (cellular senescence-inhibited gene), a protein which inhibits PTEN in the Akt signal transduction pathway, as a Nrk-binding protein in placenta, suggesting that Nrk inhibits the proliferation of spongiotrophoblasts in placenta by inhibiting the Akt signaling pathway. We also found that the level of a cell cycle inhibitor protein p27 is downregulated in Nrk knockout spongiotrophoblasts, suggesting that Nrk increases p27 gene expression or inhibits p27 protein degradation in spongiotrophoblasts.
2) We found that the estrogen level is elevated in the blood and ovary of mammary tumor-harboring Nrk knockout female mice, suggesting that the high estrogen level in the blood causes mammary tumors in Nrk knockout mice. In addition, we found that Nrk is expressed in lactating and old (~12 months) wild-type mice, suggesting that Nrk suppresses the overgrowth of mammary epithelial cells by downregulating estrogen synthesis in the ovary.

Research Products

• [Journal Article] Ubiquitin-interacting motifs confer full catalytic activity, but not ubiquitin chain substrate specificity, to deubiquitinating enzyme USP37 (2014)
  • Author(s): Tanno, H., Shigematsu, T., Nishikawa, S., Hayakawa, A., Denda, K., Tanaka, T., and Komada, M.
  • Journal Title: J. Biol. Chem. Volume: 289 Pages: 2415-2423
  • Peer Reviewed
• [Journal Article] In vivo assembly of the axon initial segment in motor neurons (2013)
  • Author(s): Le Bras, B., Freal, A., Czarnecki, A., Legendre, P., Bullier, E., Komada, M., Brophy, P.J., Davenne, M., and Couraud, F
  • Journal Title: Brain Struct. Funct Volume: 未定 Issue: 4 Pages: 1433-1450
  • DOI: 10.1007/s00429-013-0578-7
  • Peer Reviewed
• [Journal Article] Involvement of Src in the membrane skeletal complex, MPP6-4.1G, in Schmidt-Lanterman incisures of mouse myelinated nerve fibers in PNS (2013)
  • Author(s): Terada, N., Saitoh, Y., Ohno, N., Komada, M., Yamauchi, J., and Ohno S.
  • Journal Title: Histochem. Cell Biol. Volume: 140 Pages: 213-222
  • Peer Reviewed
• [Journal Article] ERK-dependent downregulation of Skp2 reduces Myc activity with HGF, leading to inhibition of cell proliferation through a decrease in Id1 expression (2013)
  • Author(s): Li, X., Bian, Y., Takizawa, Y., Hashimoto, T., Ikoma, T., Tanaka, J., Kitamura, N., Inagaki, Y., Komada, M., and Tanaka, T.
  • Journal Title: Mol. Cancer Res. Volume: 11 Issue: 11 Pages: 1437-1447
  • DOI: 10.1158/1541-7786.mcr-12-0718
  • Peer Reviewed
• [Journal Article] The ubiquitin code and its decoding machinery in the endocytic pathway. (2013)
  • Author(s): Tanno, H.
  • Journal Title: J. Biochem. Volume: 153 Issue: 6 Pages: 497-504
  • DOI: 10.1093/jb/mvt028
  • Peer Reviewed
• [Journal Article] ユビキチン化によるFrizzledのリソソーム分解を介した Wntシグナル強度の制御 (2013)
  • Author(s): Daocharad Burana, 後藤聡, 駒田雅之
  • Journal Title: 細胞工学 Volume: 32 Pages: 396-400
• [Journal Article] Involvement of Src in the membrane skeletal complex, MPP6-4.1G, in Schmidt-Lanterman incisures of mouse myelinated nerve fibers in PNS (2013)
  • Author(s): Terada, N., Saitoh, Y., Ohno, N., Komada, M., Yamauchi, J., and Ohno, S.
  • Journal Title: Histochem. Cell Biol Volume: 139 Issue: 2 Pages: 213-222
  • DOI: 10.1007/s00418-012-1073-6
  • Peer Reviewed
• [Journal Article] ユビキチン化によるFrizzledのリソソーム分解を介したWntシグナル強度の制御 (2013)
  • Author(s): Burana, D.
  • Journal Title: 細胞工学 Volume: 32 Pages: 396-400
• [Journal Article] Essential function of protein 4.1G in targeting of MPP6 into Schmidt-Lanterman incisures in myelinated nerves (2012)
  • Author(s): Terada, N., Saitoh, Y., Ohno, N., Komada, M., Saitoh, S., Peles, E., and Ohno, S.
  • Journal Title: Mol. Cell. Biol. Volume: 32 Pages: 199-205
  • Peer Reviewed
• [Journal Article] The Ankrd 13 family of UIM-bearing proteins regulates EGF receptor endocytosis from the plasma membrane (2012)
  • Author(s): Tanno, H.
  • Journal Title: Mol.Biol.Cell Volume: 23 Issue: 7 Pages: 1343-1353
  • DOI: 10.1091/mbc.e11-09-0817
  • Peer Reviewed
• [Journal Article] Balanced ubiquitination determines cellular responsiveness to extracellular stimuli. (2012)
  • Author(s): Mukai, A.
  • Journal Title: Cell. Mol. Life Sci. Volume: 69 Issue: 23 Pages: 4007-4016
  • DOI: 10.1007/s00018-012-1084-4
  • Peer Reviewed
• [Presentation] Negative regulation of mammary epithelial cell proliferation by protein kinase Nrk (2013)
  • Author(s): 柳川享世、稲谷卓也、伝田公紀、駒田雅之
  • Organizer: 第36回日本分子生物学会大会
  • Place of Presentation: 神戸
  • Year and Date: 2013-12-05
• [Presentation] 分娩発来をもたらす胎盤特異的なプロテインキナーゼNrkが与るシグナル伝達 (2013)
  • Author(s): 伝田公紀、井田加奈子、廣崎賢、岡本直樹、柳川享世、林宣宏、駒田雅之
  • Organizer: 第36回日本分子生物学会大会
  • Place of Presentation: 神戸
  • Year and Date: 2013-12-04
• [Presentation] ユビキチン化と脱ユビキチン化によるストレス顆粒の制御 (2013)
  • Author(s): 松本俊介、解玄、駒田雅之
  • Organizer: 第65回 日本細胞生物学会大会
  • Place of Presentation: ウインクあいち（愛知県）
  • Invited
• [Presentation] Roles of the Ankrd13 family of ubiquitin-binding proteins in the endocytic pathway (2013)
  • Author(s): 駒田雅之、丹野秀崇、Daocharad Burana、奥谷幸平
  • Organizer: 第86回 日本生化学会大会
  • Place of Presentation: パシフィコ横浜（神奈川）
  • Invited
• [Presentation] Endosomal interaction of VCP/p97 with Ankrd13 family of ubiquitin-binding proteins (2013)
  • Author(s): 駒田雅之
  • Organizer: 第36回 日本分子生物学会大会
  • Place of Presentation: 神戸国際会議場（兵庫）
  • Invited
• [Presentation] Interaction of Ankrd13 family of ubiquitin-binding proteins with VCP/p97 is implicated in endosomal sorting of caveolin-1 (2013)
  • Author(s): Daocharad Burana、丹野秀崇、駒田雅之
  • Organizer: 第36回 日本分子生物学会大会
  • Place of Presentation: 神戸国際会議場（兵庫）
• [Presentation] 脱ユビキチン化酵素USP36の核小体局在を阻害する化合物の同定と解析 (2013)
  • Author(s): 齊藤尚吾、川口紘平、本田香織、近藤恭光、斎藤臣雄、長田裕之、駒田雅之
  • Organizer: 第36回 日本分子生物学会大会
  • Place of Presentation: 神戸国際会議場（兵庫）
• [Presentation] 脱ユビキチン化酵素USP37の活性にはたすユビキチン結合モチーフUIMの役割 (2013)
  • Author(s): 重松壮、西川周平、丹野秀崇、駒田雅之
  • Organizer: 第36回 日本分子生物学会大会
  • Place of Presentation: 神戸国際会議場（兵庫）
• [Presentation] Negative regulation of mammary epithelial cell proliferation by protein kinase Nrk (2013)
  • Author(s): 柳川享世、稲谷卓也、伝田公紀、駒田雅之
  • Organizer: 第36回 日本分子生物学会大会
  • Place of Presentation: 神戸国際会議場（兵庫）
• [Presentation] 分娩発来をもたらす胎盤特異的なプロテインキナーゼNrkが与るシグナル伝達 (2013)
  • Author(s): 伝田公紀、井田加奈子、廣崎賢、岡本直樹、柳川享世、林宣宏、駒田雅之
  • Organizer: 第36回 日本分子生物学会大会
  • Place of Presentation: 神戸国際会議場（兵庫）
• [Presentation] ツメガエル初期胚の尾部形成における母性Cyclin Eタンパク質分解とエピジェネティック制御の関係 (2013)
  • Author(s): 田中利明、駒田雅之
  • Organizer: 第36回 日本分子生物学会大会
  • Place of Presentation: 神戸国際会議場（兵庫）
• [Presentation] ユビキチン化と脱ユビキチン化によるストレス顆粒の制御 (2013)
  • Author(s): 駒田 雅之
  • Organizer: 第65回日本細胞生物学会
  • Place of Presentation: ウインク愛知（愛知県）
  • Invited
• [Presentation] Recognition of K63-linked ubiquitin chains by the Ankrd13 family of UIM-bearing proteins regulates endocytosis of plasma membrane proteins. (2013)
  • Author(s): 駒田 雅之
  • Organizer: 第35回内藤コンファレンス
  • Place of Presentation: シャトレーゼ ガトーキングダム サッポロ（北海道）
• [Presentation] タイトル未定 (2013)
  • Author(s): 駒田 雅之
  • Organizer: 第86回日本生化学会
  • Place of Presentation: パシフィコ横浜（神奈川県）
  • Invited
• [Presentation] タイトル未定 (2013)
  • Author(s): 駒田 雅之
  • Organizer: 第36回日本分子生物学会
  • Place of Presentation: 神戸国際会議場（兵庫県）
  • Invited
• [Presentation] The Ankrd 13 family of UIM-bearing proteins regulates endocytosis of ubiquitinated cell surface proteins. (2012)
  • Author(s): 丹野 秀崇
  • Organizer: 第64回日本細胞生物学会
  • Place of Presentation: 神戸国際会議場（兵庫県）
• [Presentation] A deubiquitinating enzyme family protein USP18 is implicated in elimination of misfiled proteins by the proteasome. (2012)
  • Author(s): 小林 倫之
  • Organizer: 第64回日本細胞生物学会
  • Place of Presentation: 神戸国際会議場（兵庫県）
• [Presentation] 脱ユビキチン化酵素による細胞のストレス応答の制御 (2012)
  • Author(s): 駒田 雅之
  • Organizer: 第85回日本生化学会
  • Place of Presentation: 福岡国際会議場（福岡県）
  • Invited
• [Presentation] 脱ユビキチン化酵素USP13によるストレス顆粒の制御 (2012)
  • Author(s): 松本 俊介
  • Organizer: 第85回日本生化学会
  • Place of Presentation: 福岡国際会議場（福岡県）
• [Presentation] 脱ユビキチン化酵素USP18はユビキチン化された変性タンパク質によるアグリソーム形成に関与する (2012)
  • Author(s): Bolotbyek Avliush
  • Organizer: 第85回日本生化学会
  • Place of Presentation: 福岡国際会議場（福岡県）
• [Remarks]
  • URL: http://www.komada-lab.bio.titech.ac.jp
• [Remarks] 東京工業大学 大学院生命理工学研究科 駒田研究室 ホームページ
  • URL: http://www.komada-lab.bio.titech.ac.jp
• [Remarks] 東京工業大学 大学院生命理工学研究科 駒田研究室
  • URL: http://www.komada-lab.bio.titech.ac.jp