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Role of the NO-activated MAP kinase pathways in carcinogenesis

Research Project

Project/Area Number 13470400
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field 病態科学系歯学(含放射線系歯学)
Research InstitutionTokyo Medical and Dental University

Principal Investigator

TAKEDA Kohsuke  Tokyo Medical and Dental University Graduate School, Research Associate, 大学院・医歯学総合研究科, 助手 (10313230)

Co-Investigator(Kenkyū-buntansha) ICHIJO Hidenori  The University of Tokyo Graduate School of Pharmaceutical Sciences, Professor, 大学院・薬学系研究科, 教授 (00242206)
Project Period (FY) 2001 – 2002
Project Status Completed (Fiscal Year 2002)
Budget Amount *help
¥13,700,000 (Direct Cost: ¥13,700,000)
Fiscal Year 2002: ¥6,600,000 (Direct Cost: ¥6,600,000)
Fiscal Year 2001: ¥7,100,000 (Direct Cost: ¥7,100,000)
KeywordsNitric oxide(NO) / Signal transduction / MAP kinase / Apoptosis / stress
Research Abstract

In this research project, we have shown the following two results.
1. We have shown that nitric oxide (NO) strongly activated apoptosis signal-regulating kinase 1(ASK1), which is known to regulate the JNK and p38 MAP kinase pathways, and that NO-induced early activation of p38 was impaired in mouse embryonic fibroblasts obtained from ASK 1-deficient mice. These results strongly suggest that ASK1 is a pivotal regulator of NO-induced activation of the MAP kinase pathways.
2. Recently, we have found that calcium influx activates ASK1. It has been reported that the calcium influx triggers the NO production and that, conversely, NO regulates the calcium homeostasis, suggesting the intimate relationship between NO and calcium signaling. To know how calcium signal affects NO-medicated activation of the ASK1-MAP kinase pathways in calcium signaling, we investigated the activation mechanism of ASK1 by calcium signal. We have shown that a kinase cascade composed of calcium/calmodulin-dependent protein kinase type II (CaMKII)-ASK1-MKK3/MKK6-p38 constituted a novel calcium-signaling pathway. Calcium influx activated CaMKII, and activated CaMKII recruited and activated ASK1 by phosphorylation. Moreover, calcium influx evoked by membrane depolarization in primary neurons and synaptosomes induced strong activation of p38, which was impaired in those derived from ASK 1-deficient mice. Thus, ASK1 appears to be a critical intermediate of calcium signaling between CaMKII and p38.

Report

(3 results)
  • 2002 Annual Research Report   Final Research Report Summary
  • 2001 Annual Research Report
  • Research Products

    (35 results)

All Other

All Publications (35 results)

  • [Publications] Tobiume, K., et al.: "ASK1 is required for sustained activations of JNK/p38 MAP kinases and apoptosis"EMBO reports. 2. 222-228 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [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)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [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)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Yanagisawa, M., et al.: "Inhibition of BMP2-induced, TAK1 kinase-mediated neurite outgrowth by Smad6 and Smad7"Genes Cells. 6. 1091-1099 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [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)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [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)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Inoshita, S., et al.: "Phosphorylation and Inactivation of Mc1-1 by c-Jun N-terminal Kinase (JNK) in response to oxidative stress"J. BioI. Chem.. 277. 43730-43734 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Matsuura, H., et al.: "Phosphorylation-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)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [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"Antioxid. Redox Signal. 4. 415-425 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Takeda, K., Ichijo, H: "Neuronal p38 MAPK signalling : an emerging regulator of cell fate and function in the nervous system"Genes Cells. 7. 1099-1111 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Tobiume, K., et al.: "Activation of apoptosis signal-regulating kinase 1 by the stress-induced activating phosphorylation of pre-formed oligomer"J. Cell. Physiol.. 191. 1091-1099 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [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)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Tobiume, K.,. Et al.,: "ASK1 is required for sustained activations of JNK/p38 MAP kineses and apoptosis."EMBO reports. 2. 222-228 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Geleziunas, R., et al.,: "HIV-1 nef inhibits ASKl-dependent death signalingproviding a potential mechanism for protecting the infected host cell"Nature. 410. 834-838 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Sawada, Y., et al.,: "Rapl is involved in cell stretching modulation of p38 but not ERK or JNK MAP kinase"J.Cell Sci.. 114. 1221-1227 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Yanagisawa, M., et al.,: "Inhibition of BMP24nduced, TAK1 kinase-mediated neurite outgrowth by Smad6 and Smad7"Genes Cells. 6. 1091-1099 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [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)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Nishitoh, H., et al.,: "ASK1 is essential for endoplasmic reticulum stress-induced neuronal cell death triggered by expanded polyglutamine"Genes Dev.. 16. 1345-1355 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [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)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Matsuura, H., et al.,: "Phosphorylation-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)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [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"Antioxid. Redox Signal.. 4. 415-425 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [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)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Tobiume, K., et al.,: "Activation of apoptosis signal-regulating kinase 1 by the stress-induced activating phosphorylation of pre-formed oligomer"J. Cell. Physiol.. 191. 95-104 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Kuranaga, E., et al.,: "Reaper-mediated inhibition of DIAPl-induced DTRAF1 degradation results in activation of JNK in Drosophila"Nat. Cell Biol.. 4. 705-710 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Matsuzawa, A. et al.: "Physiological roles of ASK1-mediated signal transduction in oxidative stress-and endopasmic reticulum stress-induced apoptosis : advanced findings from ASK1 knockout mice"Antioxidants and Redox Signal. 4. 415-425 (2002)

    • Related Report
      2002 Annual Research Report
  • [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)

    • Related Report
      2002 Annual Research Report
  • [Publications] Matsuura, H. et al.: "Phosphorylation-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)

    • Related Report
      2002 Annual Research Report
  • [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)

    • Related Report
      2002 Annual Research Report
  • [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)

    • Related Report
      2002 Annual Research Report
  • [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)

    • Related Report
      2002 Annual Research Report
  • [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)

    • Related Report
      2001 Annual Research Report
  • [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)

    • Related Report
      2001 Annual Research Report
  • [Publications] Tobiume, K. et al.: "ASK1 is required for sustained activations of JNK/p38 MAP kinases and apoptosis."EMBO reports. 2. 222-228 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Yanagisawa, M. et al.: "Inhibition of BMP2-induced, TAK1 kinase-mediated neurite outgrowth by Smad6 and Smad7."Genes Cells. 6. 1091-1099 (2001)

    • Related Report
      2001 Annual Research Report
  • [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. (in press). (2002)

    • Related Report
      2001 Annual Research Report

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Published: 2001-04-01   Modified: 2016-04-21  

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