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アポト-シスの分子機構とその生理作用

Research Project

Project/Area Number 06283229
Research Category

Grant-in-Aid for Scientific Research on Priority Areas (A)

Allocation TypeSingle-year Grants
Research InstitutionOsaka University (1995-1999)
Osaka Bioscience Institute (1994)

Principal Investigator

長田 重一  大阪大学, 医学系研究科, 教授 (70114428)

Co-Investigator(Kenkyū-buntansha) 福山 英啓  大阪大学, 医学系研究科, 助手 (70303956)
福永 理己郎  大阪大学, 医学系研究科, 助教授 (40189965)
須田 貴司  金沢大学, がん研究所, 教授 (70250090)
江成 政人  大阪大学, 医学部, 助手 (90294058)
田中 正人  大阪大学, 医学部, 助手 (00294059)
近藤 亨  財団法人大阪バイオサイエンス研究所, 第1研究部, 研究員 (30270573)
渡辺 大介  財団法人大阪バイオサイエンス研究所, 第1研究部, 研究員 (00260175)
Project Period (FY) 1994 – 1999
Project Status Completed (Fiscal Year 1999)
Budget Amount *help
¥142,000,000 (Direct Cost: ¥142,000,000)
Fiscal Year 1999: ¥30,000,000 (Direct Cost: ¥30,000,000)
Fiscal Year 1998: ¥28,000,000 (Direct Cost: ¥28,000,000)
Fiscal Year 1997: ¥25,000,000 (Direct Cost: ¥25,000,000)
Fiscal Year 1996: ¥15,000,000 (Direct Cost: ¥15,000,000)
Fiscal Year 1995: ¥24,000,000 (Direct Cost: ¥24,000,000)
Fiscal Year 1994: ¥20,000,000 (Direct Cost: ¥20,000,000)
Keywordsアポトーシス / カスパーゼ / CAD / ICAD / DNase / Fas / プロテアーゼ / サイトカイン / 劇症肝炎 / Fasリガンド / ジーン・ターゲッティング / TNF / 自己免疫疾患 / シグナル伝達 / CTL / 変異体 / 細胞死
Research Abstract

アポトーシスは動物の発生過程で産生される不要な細胞,害となる細胞を取り除く細胞死の過程であり、細胞・核の凝縮、断片化、染色体DNAのヌクレオソームの単位への切断をともなっている。私達は、昨年、カスパーゼ(システンプロテアーゼ)によって活性化されるDNase(CAD,caspase-activated DNase)とその阻害たんぱく質(ICAD,inhibitor of CAD)を精製、その遺伝子を単離し、アポトーシスにおけるDNA断片化の分子機構を明らかとした。すなわちCADは増殖している細胞中ではICADと複合体を形成しており、アポトーシスの刺激によりカスパーゼが活性化されると、カスパーゼはICADを切断、不活化し自由になったCADが染色体DNAを切断する。本年度、CAD,ICADの組換えたんぱく質を大腸菌や蚕細胞で合成し,CADは高い比活性を持つDNaseであること,ICADはCADの阻害たんぱく質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。すなわち、無細胞系や動物細胞でCADはそれ単独では活性を持つたんぱく質としては合成されず,機能的なたんぱく質が合成されるにはICADの存在が必須であった。また、ICADは塩酸グアニヂンによってdenatureしたCADのrefolding過程を促進した。一方,カスパーゼによって切断される部位に変異を導入したICADを発現するトランスジェニックマウスを樹立した。そのマウスの解析から、アポトーシスの際にはアポトーシスを起こした細胞が自らカスパーゼ・CADの系を用いて自殺するばかりでなく死につつある細胞をマクロファージがとりこみ、そのリソゾームに存在する酵素がDNAを分解することが明らかとなった。

Report

(6 results)
  • 1999 Annual Research Report
  • 1998 Annual Research Report
  • 1997 Annual Research Report
  • 1996 Annual Research Report
  • 1995 Annual Research Report
  • 1994 Annual Research Report
  • Research Products

    (36 results)

All Other

All Publications (36 results)

  • [Publications] Sakahira, H. et al.: "Functional differences of two forms of the inhibitor of ・・・"J. Biol. Chem.. 274. 15740-15744 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] McIlroy, D. et al.: "Involvement of caspase 3-activated D Nase ・・・"Oncogene. 18. 4401-4408 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Nagata, S.: "Fas ligand-induced apoptosis"Annu. Rev. Genetics.. 33. 29-55 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Nagata, S.: "Apoptotic DNA fragmentation"Exp. Cell Res.. (in press).

    • Related Report
      1999 Annual Research Report
  • [Publications] Sakahira, H. et al.: "Specific chaperone-like activity of inhibitor for ・・・"J. Bil Chem.. (in press).

    • Related Report
      1999 Annual Research Report
  • [Publications] Mcilroy, D. et al.: "An auxiliary mode of apoptotic DNA fragmentation ・・・"Genes & Develop.. (in press).

    • Related Report
      1999 Annual Research Report
  • [Publications] Enari,M.et al.: "A caspase-activated DNase that degrades DNA during・・・・" Nature. 391. 43-50 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Sakahira,H.et al.: "Clevage of CAD inhibitor in CAD activation・・・・" Nature. 391. 96-99 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Tanaka,M.et al.: "Down-regulation of Fas ligand by shedding." Nature Med.4. 31-36 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Miwa,K.et al.: "Caspase 1-independent IL-1b release and inflammation・・・・" Nature Med.4. 1287-1291 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Kawahara,A.et al.: "Caspase-independent cell killing by Fas-associated・・・・" J.Cell BIol.143. 1353-1360 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Mukae,N.et al.: "Molecular cloning and characterization of human・・・・" Proc.Natl.Acad.Sci.USA. 95. 9123-9128 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Nagata,S.: "Apoptosis by death factor." Cell. 88. 355-365 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Kondo,T.: "Essential roles of the Fas ligand in the development of・・・" Nature Med.3. 409-413 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Itoh,N.: "Requirement of Fas for the development of autoimmune・・・" J.Exp.Med.186. 613-618 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Enari,M.: "A caspase-activated DNase that degrades DNA during・・・" Nature. 391. 43-50 (1998)

    • Related Report
      1997 Annual Research Report
  • [Publications] Sakahira,H.: "Clevage of CAD inhibitor in CAD activation and DNA・・・" Nature. 391. 96-99 (1998)

    • Related Report
      1997 Annual Research Report
  • [Publications] Tanaka,M.: "Down-regulation of Fas ligand by shedding." Nature Med.4. 31-36 (1998)

    • Related Report
      1997 Annual Research Report
  • [Publications] Enari,M.: "Sequential activation of ICE-like and CPP32-like proteases" Nature. 380. 723-726 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Tanaka,M.: "Fas ligand in human serum" Nature Medicine. 2. 317-322 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Adachi,M.: "Enhanced and accelerated lymphoproliferation in Fas-null mice" Proc.Natl.Acad.Sci.USA. 93. 2137-2142 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Suda,T.: "Apoptosis of mouse naive T cells induced by recombinant" J.Immunol.157. 3918-3924 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Nagata,S.: "Apoptosis by death factor" Cell. 88. 355-365 (1997)

    • Related Report
      1996 Annual Research Report
  • [Publications] Kondo,T.: "Essential roles of the Fas ligand in the development of" Mature Medicine. (in press).

    • Related Report
      1996 Annual Research Report
  • [Publications] Enari,M.et al.: "Involvement of ICE-like protease in Fas-mediated apoptosis." Nature. 375. 78-81 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Nagata,S.et al.: "The Fas death factor." Science. 267. 1449-1456 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Tanaka,M.et al.: "Expression of the functional soluble form of human Fas ligand in activated lymphocytes." EMBO J.14. 1129-1135 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Adachi,M.et al.: "Targeted mutation in the Fas gene causes hyperplasia in the peripheral lymphoid organs liver." Nature Genet.11. 294-299 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Enari,M.et al.: "Apoptosis by a cytosolic extract from Fas-activated cells." EMBO J.14. 5201-5208 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Tanaka,M.et al.: "Fas ligand in human serum." Nature Med.(in press). (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Suda and Nagata: "Purification and characterization of the Fas‐ligand that induces apoptosis." J.Exp.Med.179. 873-878 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Takahashi et al.: "Generalized lymphoproliferative disease in mice,caused by a point mutation in the Fas ligand." Cell. 76. 969-976 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Kagi et al.: "Fas and perforin pathways as major mechanisms of T cell‐mediated cytotoxicity." Science. 265. 528-530 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Watanabe et al.: "Constitutive activation of the Fas ligand gene in mouse lymphoproliferative disorders." EMBO J.14. 12-18 (1995)

    • Related Report
      1994 Annual Research Report
  • [Publications] Tanaka et al.: "Expression of the functional soluble form of human Fas ligand in activated lymphocytes." EMBO J.(in press).

    • Related Report
      1994 Annual Research Report
  • [Publications] Nagata and Golstein: "The Fas death factor" Science. (in press).

    • Related Report
      1994 Annual Research Report

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Published: 1994-04-01   Modified: 2016-04-21  

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