神経突起伸長に関与する分子の探索と機能解析

• Project/Area Number: 12053234
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Kyoto University
• Principal Investigator: 野田 亮 京都大学, 医学研究科, 教授 (30146708)
• Co-Investigator(Kenkyū-buntansha): 北山 仁志 京都大学, 医学研究科, 助教授 (30231286) ; 近藤 科江 京都大学, 医学研究科, 研究員(COE) (40314182)
• Project Period (FY): 2000 – 2004
• Project Status: Completed (Fiscal Year 2004)
• Budget Amount: ¥121,600,000 (Direct Cost: ¥121,600,000); Fiscal Year 2004: ¥25,000,000 (Direct Cost: ¥25,000,000); Fiscal Year 2003: ¥25,900,000 (Direct Cost: ¥25,900,000); Fiscal Year 2002: ¥23,700,000 (Direct Cost: ¥23,700,000); Fiscal Year 2001: ¥23,500,000 (Direct Cost: ¥23,500,000); Fiscal Year 2000: ¥23,500,000 (Direct Cost: ¥23,500,000)
• Keywords: Rap1 / C3G / Ras / MMP-2 / MT1-MMP / RECK / septin / endomucin / コロイドプレキサス / セプチン / パーキンソン病 / シンドビズ・ウイルス / 海馬 / グルタミン酸受容体 / RGL3 / Lewy小体 / sindbis virus / 神経突起 / ニューロトロフィン / RAP1 / エンハンサー・トラップ / TMX / c-IAP2 / MMP / エンハンサートラップ / TGF-beta / チオレドキシン / NGFI-A / PC12

Research Abstract

Rap1に関する成果
(1)神経分化したNG108-15細胞にシンドビス・ウイルス・ベクターを用いて遺伝子導入し、whole cells patch法によって電気興奮性を記録するという実験系において、活性化型Rap1が活動電位を抑制し、活性化型Rasが活動電位を増強することを見出した(今村ら)。
(2)random mutagenesisおよび酵母two-hybrid法を用いて、Rap1の活性化因子の一つであるC3Gの機能をdominant negativeに抑制するRap1変異体を取得した(施ら)。
細胞外マトリックス関連の成果
(1)遺伝子欠損マウスの交配によって分泌型MMPであるMMP-2と膜型MMPであるMT1-MMPの2重変異体を作成したところ、出生直後に無呼吸のまま死亡することが分かった。これらのマウス新生仔では、血管径が著しく小さく、筋肉も未発達であった(呉ら)。
(2)肺非小細胞癌(竹中ら)および大腸癌(武内ら)において、RECKの発現と良好な予後との間に相関性が見られることが示された。
(3)TIMP-2による血管内皮細胞の運動抑制に際して、Rap1を介したRECKの発現誘導が関与する可能性が示された(呉ら)。
(4)L-selectinを介したリンパ球のローリングに静脈内皮に発現しているendomucinが関与することが見出された.(神田ら)。
その他
Sept4欠損マウスにおいて精子形成に異常が生ずることを見出した(猪原ら)。

Research Products

• [Journal Article] Effects of Rap1 and Ras on voltage-gated sodium current in cultured neuronal cells. (2004)
  • Author(s): Y.Imamura
  • Journal Title: Neuroscience 127 Pages: 973-981
• [Journal Article] Rap1 mutants with increased affinity for the guanine-nucleotide exchange factor C3G. (2004)
  • Author(s): S.Shi
  • Journal Title: Oncogene 23 Pages: 8711-8719
• [Journal Article] Overlapping functions between two distinct matrix metalloproteinases, MMP-2 and MT1-MMP, in mouse (2004)
  • Author(s): J Oh
  • Journal Title: Oncogene 23 Pages: 5041-5048
• [Journal Article] The Membrane-anchored matrix metalloproteinase (MMP) regulator RECK in combination with MMP-9 serves as an informative prognostic indicator for colorectal cancer (2004)
  • Author(s): K.Takeuchi
  • Journal Title: Clin Cancer Res. 10 Pages: 5572-5579
• [Journal Article] TIMP-2 inhibits endothelial Cell migration through increased expression of RECK (2004)
  • Author(s): J.Oh
  • Journal Title: Cancer Res. 64 Pages: 9062-9069
• [Journal Article] Expression of a novel MMP regulator, RECK, and its clinical significance in resected non-small cell lung cancer (2004)
  • Author(s): K.Takenaka
  • Journal Title: Eur.J.Cancer 40 Pages: 1617-1623
• [Journal Article] Cortical organization by the septin cytoskeleton is essential for structural and mechanical integrity of mammalian spermatozoa.
  • Author(s): M.Ihara
  • Journal Title: Developmental Cell (印刷中)
• [Publications] N.Matsumotoら: "Isolation of a set of genes expressed in the choroid plexus of the mouse using suppression subtractive hybridization"Neuroscience. 117. 405-415 (2003)
• [Publications] T.Masuiら: "Imamura : RECK expression in pancreatic cancer : Its correlation with lower invasiveness and better prognosis."Clin.Cancer Res.. 9. 1779-1784 (2003)
• [Publications] M.Iharaら: "Association of the cytoskeletal GTP-binding protein Sept4/H5 with cytoplasmic inclusions found in Parkinson's disease and other synucleinopathies"J.Biol.Chem.. 278. 24095-24102 (2003)
• [Publications] C.Takahashiら: "Rb and N-ras function together to control differentiation in the mouse"Mol.Cell.Biol.. 23. 1203-1207 (2003)
• [Publications] Y.Imamuraら: "Possible involvement of Rap1 and Ras in the regulation of glutamatergic synaptic transmission"NeuroReport. 14. 1203-1207 (2003)
• [Publications] J.Ohら: "Overlapping functions between two distinct matrix metalloproteinases, MMP-2 and MT1-MMp, in mouse"Oncogene. (印刷).
• [Publications] M.Nodaら: "RECK : A novel suppressor of malignancy linking oncogenic signaling to extracellular matrix remodeling(総説)"Cancer Metastasis Rev.. 22. 167-175 (2003)
• [Publications] H.Kitasato: "Activated Ras modifies the proliferative response of rheumatoid synovial cells to TNF-α and TGF-α"Inflamm.Res.. 50. 592-597 (2002)
• [Publications] N.Matsumoto: "Isolation of a set of genes expressed in the choroid plexus of the mouse using suppression subtractive hybridization"Neuroscience. 117. 405-415 (2003)
• [Publications] T.Masui: "RECK expression in pancreatic cancer : Its correlation with lower invasiveness and better prognosis"Clin. Cancer Res.. (in press).
• [Publications] M.Ihara: "Association of the cytoskeletal GTP-binding protein Sept4/H5 with cytoplasmic inclusions found in Parkinson's disease and other synucleinopathies"J.Biol.Chem.. (in press).
• [Publications] M.Kinoshita: "Roles of septins in the mammalian cytokinesis machinery"Cell Struct. Funct. 26. 667-670 (2002)
• [Publications] I.G.Macara: "Mammalian septins nomenclature"Mol.Biol.Cell. 13. 4111-4113 (2002)
• [Publications] R.M.Sasahara: "Transcriptional control of the RECK metastasis/angiogenesis suppressor gene"Cancer Det. Prev.. 26. 435-443 (2002)
• [Publications] M.Noda: "RECK : a novel suppressor of malignancy linking oncogenic signaling to extracellular matrix remodeling"Cancer Metastasis Rev.. (in press).
• [Publications] K.Furumoto: "RECK gene expression in hepatocellular carcinoma : Correlation with invasion-related clinicopathological factors and its clinical significance"Hepatology. 33. 189-195 (2001)
• [Publications] T.Ueda: "c-IAP2 is induced by ionizing radiation through NF-kB binidng sites"FEBS Lett.. 491. 40-44 (2001)
• [Publications] Y.Matsuo: "Identifiaction of a novel thioredoxin-related transmembrane protein"J.Biol.Chem.. 276. 10032-10038 (2001)
• [Publications] M.Kinoshita: "Identification of human endomucin-1 and -2 as membrane-bound O-sialoglycoproteins with anti-adhesive"FEBS Lett.. 499. 121-126 (2001)
• [Publications] M.Ihara: "Chronic cerebral hypoperfusion induces MMP-2 but not MMP-9 expression in the microglia and vascular endothelium or white matter"J.Cereb.Blood Fl.Met.. 21. 828-834 (2001)
• [Publications] G.Joberty: "Septin organisation is controlled by Borgs and negatively regulated by Cdc42"Nature Cell Biol. 3. 861-866 (2001)
• [Publications] J Oh: "The Membrane-Anchored MMP-Inhibitor RECK is a Key Regulator of Extracellular Matrix Integrity and Angiogenesis"Cell. 107. 789-800 (2001)
• [Publications] 松尾禎之 ら: "Identifiaction of a novel thioredoxin-related transmembrane protein"J.Biol.Chem.. (in press).
• [Publications] 上田俊彦 ら: "c-IAP2 is induced by ionizing radiation through NF-kB binidng sites"FEBS Lett.. 491. 40-44 (2001)
• [Publications] 今村行雄 ら: "Roles of GABAergic inhibition and NMDA receptor subunits in the spatio-temporal integration in the cerebellar cortex of mice"Neurosci.Res.. 38. 289-301 (2000)
• [Publications] 木下彩栄 ら: "Differential localization of septins in the mouse brain"J.Comp.Neurol.. 428. 223-239 (2000)
• [Publications] 秋山暢丈 ら: "Identification of a series of TGF-beta-responsive genes by retrovirus-mediated gene trap screening"Mol.Cell.Biol.. 20. 3266-3273 (2000)
• [Publications] 松本貴子 ら: "Transient overexpression of NGFI-A gene suppresses NGF-induced neurite outgrowth in PC12 cells"NeuroReport. 11. 1001-1005 (2000)