細胞の増殖・分化・死のシグナル伝達機構

• Project/Area Number: 07CE2006
• Research Category: Grant-in-Aid for COE Research
• Allocation Type: Single-year Grants
• Research Institution: Osaka University
• Principal Investigator: 祖父江 憲治 大阪大学, 医学系研究科, 教授 (20112047)
• Co-Investigator(Kenkyū-buntansha): 長田 重一 大阪大学, 医学系研究科, 教授 (70114428) ; 中村 敏一 大阪大学, 医学系研究科, 教授 (00049397) ; 平野 俊夫 大阪大学, 医学系研究科, 教授 (40136718) ; 米田 悦啓 大阪大学, 医学系研究科, 教授 (80191667) ; 辻本 賀英 大阪大学, 医学系研究科, 教授 (70132735)
• Project Period (FY): 1995 – 1999
• Project Status: Completed (Fiscal Year 1999)
• Budget Amount: ¥1,070,000,000 (Direct Cost: ¥1,070,000,000); Fiscal Year 1999: ¥380,000,000 (Direct Cost: ¥380,000,000); Fiscal Year 1998: ¥360,000,000 (Direct Cost: ¥360,000,000); Fiscal Year 1997: ¥330,000,000 (Direct Cost: ¥330,000,000)
• Keywords: カルデスモン / インターロイキン-6(IL-6) / 肝細胞増殖因子(HGF) / Fas因子 / bc1-2 / 核輸送 / 低分子暈型G蛋白質 / 細胞死 / 低分子量型G蛋白質

Research Abstract

祖父江は、平滑筋細胞形質がPI3キナーゼ/PKB(Akt)系とERKおよびp38MAPキナーゼ系の力のバランスにより決定されることを明らかにしたが、さらにこれらシグナル伝達系支配下にNkx-3.2,SRF,GATA6の3転写因子によるα1インテグリン遺伝子の平滑筋細胞特異的転写制御機構を解明した。また、mGluR1のシナプスへのターゲッティングに、シナプス後肥厚部に局在するPSD-Zip45が関与していることを証明した。
平野は、サイトカイン受容体gp130を介する細胞の増殖、生存シグナルにはSTAT3が重要な役割を果たしていることを昨年までに明らかにしたが、今年度はSTAT3の標的遺伝子として、c-myc,pim1/2を同定しこれらが協調して作用していることを示した。またpimの標的遺伝子としてVCPをみつけた。さらにgp130のシグナル特異的変異gp130発現マウスを作製し、STAT3とSHP2を介するシグナルが生体内で正と負に作用していることを証明した。
アポトーシスは染色体DNAの切断をともなっている。この過程にはカスパーゼによって活性化されるDNase(CAD)とその阻害たんぱく質(ICAD)が関与している。長田は、CAD,ICADの組換え蛋白質を合成し,CADは高い比活性を持つDNaseであること,ICADはCADの阻害因子としてばかりでなく、CADが合成される際,シャペロンとして作用することを示した。一方,カスパーゼ切断部位に変異を持つICADのトランスジェニクマウスの解析から、アポトーシスをおこした細胞をマクロファージが取り込み、そのDNAを分解しうることも示した。
米田は、Wnt/Winglessのシグナル伝達に重要な役割を果たす分子であるβ-cateninが、それ自身が持つ核膜孔複合体への結合能によって核へ移行し、その移行はRanに依存しない、新たな輸送経路であることを明らかにした。また、小胞体膜から核への情報伝達に関わる分子である SREBPが、アダプター分子を介することなく、importin-βに直接結合して輸送されることを証明した。さらに、importin-βのN末端側約半分の単独の結晶構造解析に初めて成功した。
倉智は、細胞生理に密接に連関するKチャネル(Kir)の局在について、Kir3.2は黒質ドーパミン神経樹状突起の後シナプス膜に局在すること、PDZ蛋白質がその局在に関与し得ること、さらにPDZ蛋白質はチャネルの活性制御も行うこと、脳下垂体で分泌小胞上のKir3.1/Kir3.4は分泌時に細胞膜へ移行し、機能すること、上皮細胞に発現するKir4.1は細胞により異なる極性に分布することを明らかにした。
辻本は、Bcl-2ファミリーたんぱくのミトコンドリアにおける機能ターゲットとして、外膜チャネルであるVDACを同定し、細胞死促進因子Bax/BakはVDACの開孔を通しシトクロムc遊離を誘導し、細胞死抑制因子Bcl-xLはVDACを閉孔することを示した。また、アポトーシスの実行過程の解析から、アポトーシスを特徴づける核クロマチン凝縮を誘導する新規因子Acinusを単離同定し、その機能解析を行った。
高井は、Rhoファミリー低分子量G蛋白質(Cdc42、Rac、Rho)の活性化機構と作用機構を明らかにすると共に、RhoファミリーとRabファミリー低分子量G蛋白質が協調的に作用して、細胞の運動と接着を制御することを見出した。また、Racによって制御されている新しい細胞間接着系NAP系が、カドヘリン.カテニン系の局在を制御し、上皮細胞の接着装置複合体の形成や維持に必須であることを明らかにした。
宮坂は、リンパ節へのリンパ球ホーミングを媒介する血管 HEVに特異的に発現する遺伝子の同定に成功した。また、リンパ球ホーミングを媒介する接着分子L-セレクチン、CD44の新規リガンドとして特殊なプロテオグリカン、バースカンを同定し、この分子間相互作用がL-セレクチン、CD44の糖鎖認識ドメインとバーシカン上のグリコサミノグリカン鎖を介するものであることを初めて明らかにした。
中村は、HGF gene therapyによりHGFが肝線維症/肝硬変の治療に有効であることを確認した。HGFが心筋の急性傷害に対する保護・修復因子であることを明らかにした。HGFは糖尿病ならびに糖尿病性腎症に対してもその発症・進行を抑制する効果をもつことを示した。また、HGFアンタゴニスト活性と血管新生阻害活性を合わせ持つHGF断片NK4はin vivoにおけるヒト膵癌の増殖・転移能を著名に抑制することを明らかにした。

Research Products

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• [Publications] Ishiwatari-Hayasaka,H.et al.: "Induction of cell death by chimeric L-selectin-Fas receptors." Int.Immunol.9. 627-635 (1997)
• [Publications] Koyanagi Y.et al.: "Primary human immunodeficiency virus type 1 viremia and central nervous system invasion in a novel hu-PBL-immunodeficient mouse strain." J.Virol.71. 2417-2424 (1997)
• [Publications] Yamada M.et al.: "Sulfonylurea receptor 2B and Kir6.1 form a sulfonilurea-sensitive but ATP-insensitive K+channel." J.Physiol.499. 715-720 (1997)
• [Publications] O Horio Y.et al.: "Clustering and enhanced activity of an inwardly rectifying potassium channel,Kir4.1,by an anchoring protein,PSD-95/SAP90 family." J.Biol.Chem.272. 12885-12888 (1997)
• [Publications] Hibino H.et al.: "An ATP-dependent inwardly rectifying potassium channel,KAB-2(Kir4.1),in cochlear stria vascularis of inner ear : its specific subcellular localization and correlation with the formation of endocochlear potential." J.Neurosci.17. 4711-4721 (1997)
• [Publications] Ishii M.et al.: "Expression and clustered distribution of an inwardly rectifying potassium channel,KAB-2/Kir4.1,on mammalian retinal muller cell membrane ; Their regulation by insulin and laminin signals." J.Neurosci.17. 7725-7735 (1997)