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Analysis of ASK1 and ASK2 as stress signaling intermediates.

Research Project

Project/Area Number 10470396
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Functional basic dentistry
Research InstitutionTokyo Medical and Dental University

Principal Investigator

ICHIJO Hidenori  Tokyo Medical and Dental University Faculty of Dentistry, Professor, 歯学部, 教授 (00242206)

Co-Investigator(Kenkyū-buntansha) SAITOH Masao  Tokyo Medical and Dental University Faculty of Dentistry, Research Fellow of the Japan Society for the Promotion of Science, 歯学部・日本学術振興会, 特別研究員
TAKEDA Kohsuke  Tokyo Medical and Dental University Faculty of Dentistry, Research Associate, 歯学部, 助手 (10313230)
Project Period (FY) 1998 – 1999
Project Status Completed (Fiscal Year 1999)
Budget Amount *help
¥12,500,000 (Direct Cost: ¥12,500,000)
Fiscal Year 1999: ¥5,900,000 (Direct Cost: ¥5,900,000)
Fiscal Year 1998: ¥6,600,000 (Direct Cost: ¥6,600,000)
KeywordsASK1 / JNK / P38 / Apoptosis / p38 / MAPキナーゼ / Traf / Daxx
Research Abstract

Although the molecular mechanisms of execution phase of apoptosis has extensively been studied, very little is known about the induction phase or signal transduction of apoptosis. Here we investigated the molecular mechanisms of apoptosis through identifying the regulatory mechanisms of ASK1. Based on our previous findings that thioredoxin (Trx) and TRAF2 acts on ASK1 as an inhibitor and activator, respectively, we analyzed the relationship of these molecules on the ASK1 molecule. TRAF2 induced the dissociation of Trx from ASK1 in a reactive oxygen species (ROS)-dependent manner. We found that prior dissociation of Trx from ASK1 is required for TRAF2 binding to ASK1 and thereby activation of ASK1, and TRAF2 bound to ASK1 induced oligomerization of ASK1 and autophosphorylation. In addition, phosphorylation of Bcl-2 by JNK was found to be important for the ASK1-induced apoptosis. Moreover, expression of constitutively active ASK1 was found to induce neurite outgrowth in PC12 cells. We found that p38 and to a lesser extent JNK, but not ERK, were activated by the expression of active ASK1. By the treatment with a p38 inhibitor SB203580, ASK1-induced neurite outgrowth was strongly inhibited, suggesting that the activation of p38 is required for the neurite-inducing activity of ASK1. We also observed that ASK1 induced expression of several neuron-specific proteins and phophorylation of neurofilament proteins, confirming that PC12 cells differentiated into mature neuronal cells by ASK1. Moreover, ASK1-expressing PC12 cells could survive in a serum-starved condition. Therefore, ASK1 appears to mediate signals leading to both differentiation and survival in PC12 cells. Together with the previous reports indicating that ASK1 functions as a pro-apoptotic signaling intermediate, these results suggest that ASK1 has much broader range of biological activities in a cell-type specific manner than we expected before.

Report

(3 results)
  • 1999 Annual Research Report   Final Research Report Summary
  • 1998 Annual Research Report
  • Research Products

    (24 results)

All Other

All Publications (24 results)

  • [Publications] Chen Z.: "ASK1 mediates apoptotic cell death induced by genotoxic stress"Oncogene. 18. 173-180 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Ichijo H.: "From receptors to stress-activated MAP kinases (review article)"Oncogene. 18. 6087-6093 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Yamamoto K.: "BCL-2 is phosphorylated and inactivated by an ASK1/JNK pathway normally activated at G2/M"Mol. Cell Biol.. 19. 8469-8478 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Kanamoto T.: "Role of apoptosis signal-regulating kinase in regulation of the Jun N-terminal Kinase pathway and apoptosis in sympathetic neurons"Mol. Cell Biol.. 20. 196-204 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Liu H.: "Activation of apoptosis signal-regulating kinase 1 (ASK1) by TNF receptor- associated factor-2 (TRAF2) requires prior dissociation of the ASK1 inhibitor Thioredoxin"Mol. Cell Biol.. 20. 2198-2208 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Takeda K.: "Apoptosis Signal- regulating Kinase 1 (ASK1) Induces Neuronal Differentiation and Survival of PC12 Cells"J. Biol. Chem.. 275. 9805-9813 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Chen, Z.: "ASK1 mediated apoptotic cell death induced by genotoxic stress."Oncogene. 18. 173-180 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Ichijo, H.: "From receptors to stress-activated MAP kinases."Oncogene. 18, (review article). 6087-6093 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Yamamoto, K.: "BCL-2 is phosphorylated and inactivated by an ASK1/JNK pathway normally activated at G2/M."Mol. Cell Biol.. 19. 8469-8478 (199)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Kanamoto, T.: "Role of apoptosis signal-regulating kinase in regulation of the Jun N-terminal Kinase pathway and apoptosis in sympathetic neurons."Mol. Cell. Biol.. 20. 196-204 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Liu, H.: "Activation of apoptosis signal-regulating kinase 1 (ASK1) by TNF receptor-associated factor-2 (TRAF2) requires prior dissociation of the ASK1 inhibitor Thioredoxin."Mol. Cell. Biol.. 20. 2198-2208 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Takeda, K.: "Apoptosis Signal-regulating Kinase 1 (ASK1) Induces Neuronal Differentiation and Survival of PC12 Cells."J. Biol. Chem.. 275. 9805-9813 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Chen, Z.: "ASK1 mediates apoptotic cell death induced by genotoxic stress."Oncogene. 18. 173-180 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Ichijo, H.: "From receptors to stress-activated MAP kinase.(review article)"Oncogene. 18. 6087-6093 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Yamamoto, K.: "BCL-2 is phosphorylated and inactivated by an ASK1/JNK pathway normally activated at G2/M."Mol. Cell Biol.. 19. 8469-8478 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Kanamoto, T.: "Role of apoptosis signal-regulating kinase in regulation of the Jun N-terminal Kinase pathway and apoptosis in sympathetic neurons."Mol. Cell Biol.. 20. 196-204 (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] Liu, H.: "Activation of apoptosis signal-regulating kinase 1(ASK1) by TNF receptor-associated factor-2 (TRAF2) requires prior dissociation of the ASK1 inhibitor Thioredoxin."Mol. Cell. Biol.. 20. 2198-2208 (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] Takeda, K.: "Apoptosis Signal-regulating Kinase 1(ASK1) Induces Neuronal Differentiation and Survival of PC12 Cells."J. Biol. Chem.. 275. 9805-9813 (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] Funato,N.: "Evidence for apoptosis signal-regulating kinase (ASK)1 in the regenerating palatal epithelium upon acute injury." Lab.Invest.78. 477-483 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Saitoh,M.: "Mammalian thioredoxin is a direct inhibitor of apoptosis signal-regulating kinase (ASK) 1." EMBO J.17. 2596-2606 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Takeda,K.: "Identification of a novel bone morphogenetic protein-responsive gene that may function as a noncoding RNA." J.Biol.Chem.273. 17079-17085 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Nishitoh,H.: "ASK1 is essential for JNK/SAPK activation by TRAF2." Molec.Cell. 2. 389-395 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Berestetskaya,Y.V.: "Regulation of apoptosis by alhpa subunits of G12 and G13 proteins via apoptosis signal-regulating." J.Biol.Chem.273. 27816-27823 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Chang,H.Y.: "Activation of apoptosis signal-regulating kinase 1 (ASK1) by the adapter protein daxx." Science. 281. 1860-1863 (1998)

    • Related Report
      1998 Annual Research Report

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Published: 1998-04-01   Modified: 2016-04-21  

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