シグナル伝達機構に基づく細胞の分化と死の制御機構

• Project/Area Number: 12215037
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: The University of Tokyo (2002-2004); Tokyo Medical and Dental University (2000-2001)
• Principal Investigator: 一條 秀憲 東京大学, 大学院・薬学系研究科, 教授 (00242206)
• Co-Investigator(Kenkyū-buntansha): 小川 誠司 東京大学, 大学院・医学系研究科, 寄付講座教員(常勤形態) (60292900) ; 口野 嘉幸 国立がんセンター, 生物物理部, 部長 (60124418)
• Project Period (FY): 2000 – 2004
• Project Status: Completed (Fiscal Year 2004)
• Budget Amount: ¥83,700,000 (Direct Cost: ¥83,700,000); Fiscal Year 2004: ¥27,100,000 (Direct Cost: ¥27,100,000); Fiscal Year 2003: ¥12,600,000 (Direct Cost: ¥12,600,000); Fiscal Year 2002: ¥12,000,000 (Direct Cost: ¥12,000,000); Fiscal Year 2001: ¥13,000,000 (Direct Cost: ¥13,000,000); Fiscal Year 2000: ¥19,000,000 (Direct Cost: ¥19,000,000)
• Keywords: ASK1 / ASKファミリー / MAPキナーゼ / アポトーシス / Blimp1 / ストレス / ASK2 / Nef / c-Myc / TAK1

Research Abstract

本研究計画は、細胞の分化と死のシグナル伝達機構の機能解析に焦点を絞ったものであり、その成果は癌化メカニズムの理解に大きく貢献するものと考えられる。特に細胞の分化ならびに死に関わる細胞内シグナル伝達機構を明らかにすることを目標として設定した。本年度は、ASKファミリー分子群の機能解析を行い、ストレス応答MAPキナーゼ経路と発がんとの関連性の解明を試みた。またB細胞の終末分化に重要な機能を担うと考えられているBlimp1について、造血系におけるBlimp1の条件的欠失マウスの解析、並びにin vitroにおけるBlimp1の細胞周期における機能の解析を行った。ASKファミリー関連としては、新しいメンバーとしてASK3を発見した。ASK2ノックアウトマウスの解析によりASK1に加えてASK2も酸化ストレスならびにカルシウムシグナルによって誘導されるアポトーシスに必要であることが示唆された。さらに、ASKファミリーであるASK1・ASK2ダブルノックアウトマウスの作製、および他のMAPKKK分子とASK1のダブルノックアウトマウスの作製、ASKファミリーノックアウトマウスにおける発がん系の負荷などを行い、他のMAPKKK分子との関係も含めて総合的にASKファミリーの生理的機能ならびに発がん機構との関連性について解析を行った。一方、Blimp1欠失マウスでは約5ヶ月の経過でT細胞の著明な増殖が観察され、Blimp1はp53蛋白の誘導を介した細胞周期の停止に働くこと、また、この際G1停止はRb蛋白に依存性であることが明らかとなった。すなわち、Blimp1は細胞周期の制御を介してT細胞の増殖を制御している可能性が強く示唆された。

Research Products

• [Journal Article] Amyloid β induces neuronal cell death through ROS-mediated ASK1 activation. (2005)
  • Author(s): Kadowaki, H.et al.
  • Journal Title: Cell Death Differ. 12 Pages: 19-24
• [Journal Article] Involvement of ASK1 in Ca^<2+>-induced p38 MAP kinase activation. (2004)
  • Author(s): Takeda, K.et al.
  • Journal Title: EMBO rep. 5 Pages: 161-166
• [Journal Article] Inhibition of Mammalian Target of Rapamycin Activates Apoptosis Signal-Regulating Kinase 1 Signaling by Suppressing Protein Phosphatase 5 Activity. (2004)
  • Author(s): Huang, S.et al.
  • Journal Title: J.Biol.Chem. 279 Pages: 36490-36496
• [Journal Article] Survival and apoptosis signals in ER stress : the role of protein kinases. (2004)
  • Author(s): Kadowaki, H.et al.
  • Journal Title: J.Chem.Neuroanat. 28 Pages: 93-100
• [Journal Article] Possible novel therapy for diabetes with cell-permeable JNK-inhibitory peptide. (2004)
  • Author(s): Kaneto, H.et al.
  • Journal Title: Nat.Med. 10 Pages: 1128-1132
• [Journal Article] Calcium signaling via voltage-dependent L-type Ca^<2+> channels. (2004)
  • Author(s): Naguro, I.et al.
  • Journal Title: Signal Transduction 4 Pages: 195-205
• [Publications] Huang, H.et al.: "Sustained activation of the JNK cascade and rapamycin-induced apoptosis are suppressed by p53/ p21^<Cip1>"Mol.Cell. 11. 1491-1501 (2003)
• [Publications] Takeda, K.et al.: "Roles of MAPKKK ASK1 in Stress-Induced Cell Death"Cell Struct Funct.. 28. 23-29 (2003)
• [Publications] Cho, S.-G.et al.: "Identification of a novel antiapoptotic protein that antagonizes ASK1 and CAD activities"J.Cell Biol.. 163. 71-81 (2003)
• [Publications] Song, S.et al.: "Essential role of E2-25K/Hip-2 in mediating amyloid-beta neurotoxicity"Mol.Cell. 12. 553-563 (2003)
• [Publications] Yamaguchi, O.et al.: "Targeted deletion of apoptosis signal-regulating kinase 1 attenuates left ventricular remodeling"Proc Natl Acad Sci USA.. 100. 15883-15888 (2003)
• [Publications] Takeda, K.et al.: "Involvement of ASK1 in Ca^<2+>-induced p38 MAP kinase activation"EMBO rep.. 5. 161-166 (2004)
• [Publications] Matsuzawa, A.at al.: "Signal Transduction by Reactive Oxygen and Nitrogen Species : Pathways and Chemical Principles"Forman, H.J., Fukuto, J.and Torres, M.(Kluwer Academic Publishers). 411 (2003)
• [Publications] Matsuzawa, A. et al.: "Physiological roles of ASK1-mediated signal transduction in oxidative stress-and endoplasmic reticulum stress-induced apoptosis : advanced findings from ASK1 knockout mice"Antioxidants and Redox Signal. 4. 415-425 (2002)
• [Publications] Nishitoh, H. et al.: "ASK1 is essential for endoplasmic reticulum stress-induced neuronal cell death triggered by expanded polyglutamine repeats"Genes Dev.. 16. 1345-1355 (2002)
• [Publications] Matsuura, H. et al.: "Phoshorylation-dependent scaffolding role of JSAP1/JIP3 in the ASK1-JNK signaling pathway : a new mode of regulation of the MAP kinase cascade"J. Biol. Chem.. 277. 40703-40709 (2002)
• [Publications] Inoshita, S. et al.: "Phosphorylation and Inactivation of Mcl-1 by c-Jun N-terminal Kinase (JNK) in response to oxidative stress"J. Biol. Chem.. 277. 43730-43734 (2002)
• [Publications] Takeda, K. et al.: "Neuronal p38 MAPK signalling : an emerging regulator of cell fate and function in the nervous system"Genes Cells. 7. 1099-1111 (2002)
• [Publications] Kuranaga, E. et al.: "Reaper-mediated inhibition of DIAP1-induced DTRAF1 degradation results in activation of JNK in Drosophila"Nat. Cell Biol.. 4. 705-710 (2002)
• [Publications] Geleziunas, R. et al.: "HIV-1 nef inhibits ASK1-dependent death signalingproviding a potential mechanism for protecting the infected host cell"Nature. 410. 834-838 (2001)
• [Publications] Morita, K. et al.: "Negative feedback regulation of ASK1 by protein phophatase 5 (PP5) in response to oxidative stress"EMBO J.. 20. 6028-6036 (2001)
• [Publications] Tobiume, K. et al.: "ASK1 is required for sustained activations of JNK/p38 MAP kinases and apoptosis"EMBO reports. 2. 222-228 (2001)
• [Publications] Sawada, Y. et al.: "Rap1 is involved in cell stretching modulation of p38 but not ERK or JNK MAP kinase"J.Cell Sci.. 114. 1221-1227 (2001)
• [Publications] Sayama, K. et al.: "Apoptosis signal regulating kinase 1 (ASK1) is an intracellular inducer of keratinocyte differentiation"J.Biol.Chem.. 276. 999-1004 (2001)
• [Publications] Cho, S.-G.et al.: "Glutathione s-transferase mu modulates the stress-activated signals by suppressing apoptosis signal-regulating kinase 1 (ASK1)"J.Blot.Chem.. 276. 12749-12755 (2001)
• [Publications] Mochida,Y.: "ASK1 inhibits IL-1-induced NF-kB activity through disruption of TRAF6- TAK1 interaction."J.Biol.Chem.. 275. 32747-32752 (2000)
• [Publications] Sayama,K.: "Apoptosis signal regulating kinase 1 (ASK1) is an intracellular inducer of keratinocyte differentiation."J.Biol.Chem.. 276. 999-1004 (2001)
• [Publications] Sawada,Y.: "Rap1 is Involved in Cell Stretching Modulation of p38 but not ERK or JNK MAP Kinase."J.Cell Sci. 114. 1221-1227 (2001)
• [Publications] Geleziunas,R.: "HIV-1 nef inhibits ASK1-dependent death signaling : A potential mechanism for protecting the virally infected host cell."Nature. (in press). (2001)
• [Publications] Cho,S.-G.,: "Glutathione s-transferase mu modulates the stress-activated signals by suppressing apoptosis signal-regulating kinase 1 (ASK1)."J.Biol.Chem.. (in press). (2001)
• [Publications] Tobiume,K.: "ASK1 is required for sustained activations of JNK/p38 MAP kinases and apoptosis."EMBO reports. 2. 222-228 (2001)