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Molecular mechanism of response of living body to environmental stress

Research Project

Project/Area Number 10470037
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Pathological medical chemistry
Research InstitutionTohoku University

Principal Investigator

TAMURA Shinri  Tohoku University, Institute of Development, Aging & Cancer, Professor, 加齢医学研究所, 教授 (20124604)

Co-Investigator(Kenkyū-buntansha) KOBAYASHI Takayasu  Tohoku University, Institute of Development, Aging & Cancer, Assistant, 加齢医学研究所, 助手 (10221970)
HIRAGA Akira  Tohoku University, Institute of Development, Aging & Cancer, Assistant Professor, 加齢医学研究所, 助教授 (80134047)
TAKAI Toshiyuki  Tohoku University, Institute of Development, Aging & Cancer, Professor, 加齢医学研究所, 教授 (20187917)
柳川 右千夫  東北大学, 加齢医学研究所, 助手 (90202366)
Project Period (FY) 1998 – 2001
Project Status Completed (Fiscal Year 2001)
Budget Amount *help
¥12,800,000 (Direct Cost: ¥12,800,000)
Fiscal Year 2001: ¥2,700,000 (Direct Cost: ¥2,700,000)
Fiscal Year 2000: ¥2,700,000 (Direct Cost: ¥2,700,000)
Fiscal Year 1999: ¥2,900,000 (Direct Cost: ¥2,900,000)
Fiscal Year 1998: ¥4,500,000 (Direct Cost: ¥4,500,000)
KeywordsSAPK / signaling pathway / IL-1 / TAK1 / PP2C / ストレス応答 / SAPKシグナル伝達路 / プロテインホスファターゼ2C / 環境ストレス / プロテインホスファターゼ / ストレス反応 / SAPKシステム
Research Abstract

Protein phosphatase 2C (PP2C) is implicated in the negative regulation of tress-activated protein kinase (SAPK) cascades in yeast and mammalian cells. In this study, we determined the role of PP2Cβ-1, a major isoform of mammalian PP2C, in the TAK1 signaling pathway, a SAPK cascade that is activated by interleukin-1 (IL-1), transforming growth factor-β or stress. Ectopic expression of PP2Cβ-1 inhibited the TAK1-mediated mitogen-activated protein kinase kinase 4 (MKK4)-c-Jun N-terminal kinase (JNK) and MKK6-p38 signaling pathways. In vitro, PP2Cβ-1 dephosphorylated and inactivated TAK1. Co-immunoprecipitation experiments indicated that PP2Cβ-1 associates with the central region of TAK1. A phosphatase-negative mutant of PP2Cβ-1, PP2Cβ-1(R/G), acted as a dominant negative mutant, inhibiting dephosphorylation of TAK1 by wild-type PP2Cβ-1 in vitro. In addition, ectopic expression of PP2Cβ-1(R/G) enhanced IL-1-induced activation of an AP-1 reporter gene. Collectively, these results indicate that PP2Cβ negatively regulates the TAK1 signaling pathway by direct dephosphorylation of TAK1.

Report

(5 results)
  • 2001 Annual Research Report   Final Research Report Summary
  • 2000 Annual Research Report
  • 1999 Annual Research Report
  • 1998 Annual Research Report
  • Research Products

    (52 results)

All Other

All Publications (52 results)

  • [Publications] Tamura, S.: "Regulation of stress-activated protein kinase signaling pathways by protein phosphatases"Eur. J. Biochem. mini-review series. (in press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Wang H.: "Activation of c-Jun amino-terminal kinase is required for retinoic acid-indused neural differentiation of P19 embryonal carcinoma cells"FEBS Lett.. 503. 91-96 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Higuchi, T.: "Effects of ATP on regulation of galactosyltransferase-I activity responsible for synthesis of the linkage region between the core protein and glycosaminoglycan chains of proteoglycans"Biochem. Cell Biol.. 79. 159-164 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Hanada, M.: "Regulation of the TAK1 signaling pathway by protein phosphatase 2C"J. Biol. Chem.. 276. 5753-5759 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Makinae, K.: "structure of the mouse glutamate decarboxylase 65 gene and its promoter : preferential expression of its promoter in the GAB Aergic neurons transgenic mice"J. Neurochem.. 75. 1429-1437 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Hiraga, A.: "Protein phosphatase 2A is associated in an inactive state with microtubules through 2A1-specific interaction with tubulin"Biochem. J.. 346. 433-439 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Casamayor A, Torrance PD, Kobayashi T, Thorner J, Alessi DR: "Functional counterparts of mammalian protein kinases PDK1 and SGK in budding yeast"Curr. Biol.. 9. 186-197 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Kobayashi T, Cohen P: "Activation of serum-and glucocorticoid-regulated protein kinase by agonists that activate phophatidylinositide 3-kinase is mediated by 3-phosphoinositide-dependent protein kinase-1(PDK-1) and PDk2"Biochem. J.. 339. 319-328 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Kobayashi T, Deak M, Morrice N, Cohen P: "Characterization of the structure and regulation of two novel isoforms of serum and glucocorticoid-induced protein kinase"Biochem. J.. 344. 189-197 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Yamamoto M, Suzuki Y, Kihira H.Miwa H, Kita K, Nagao M, Tamura S, Shiku H, Nishikawa M: "Expressions of four major protein Ser/Thr phosphatases in human primary leukemia cells"Leukemia. 13. 595-600 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Hishiya A, Ohnishi M, Tamura S, Nakamura F: "Protein phosphatase 2C inactivates F-actin binding of human platelet moesin"J. Biol. Chem.. 274. 26705-26712 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Yanagawa Y, Kobayashi T, Ohnishi M, Kobayashi T, Tamura S, Tsuzuki T, Sanbo M, Yagi T, Tashiro F, Miyazaki J: "Enrichment and efficient screening of ES cells containing a targeted mutation : the use of DT-A gene with the polyadenylation signal as a negative selection maker"Transgenic Res.. 8. 215-221 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Ohnishi M, Chida N, Kobayashi T, Wang H, Ikeda S, Hanada M, Yanagawa Y, Katsura K, Hiraga A, Tamura S: "Alternative promoters direct tissue-specific expression of the mouse protein phosphatase 2Cβ gene"Eur. J. Biochem.. 263. 736-745 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Hanada M, Kobayashi T, Ohnishi M, Ikeda S, Wang H, Katsura K, Yanagawa Y, Hiraga A, Kanamaru R, Tamura S: "Selective suppression of stress-activated protein kinase pathways by protein phosphatase 2C in mammalian cells"FEBS Lett.. 437. 172-176 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Kobayashi T, Sadie M, Ohnishi M, Wang H, Ikeda S, Hanada M, Yanagawa Y, Nakajima T, Tamura S: "Isoform specific phosphorylation of fission yeast type 2C protein phosphatase"Biochem. Biophys. Res. Commun.. 251. 296-300 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Kobayashi T, Kusuda K, Ohnishi M, Wang H, Ikeda S, Hanada M, Yanagawa Y, Tamura S: "Isoform specific phosphorylation of protein phosphatase 2C expressed in COS7 cells"FEBS Lett.. 430. 222-226 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Kusuda k, Kobayashi T, Ikeda S, Ohnishi M, Chida N, Yanagawa Y, Shineha R, Nishihira T, Satomi S, Hiraga A, Tamura S: "Mutational analysis of the domain structure of mouse protein phosphatase 2Cβ"Biochem. J.. 332. 243-250 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Tamura S.: "Regulation of stress-activated protein kinase signaling pathways by protein phosphatases."Eur. J. Biochem. mini-review series. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Wang H.: "Activation of c-Jun amino-terminal kinase is required for retinoic acid-induced neural differentiation of P19 embryonal carcinoma cells."FEBS Lett.. 503. 91-96 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Higuchi T.: "Effects of ATP on regulation of galactosyltransferase-I activity responsible for synthesis of the linkage region between the core protein and glycosaminoglycan chains of proteoglycans."Biochem. Cell Biol.. 79. 159-164 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Hanada M.: "Regulation of the TAK1 signaling pathway by protein phosphatase 2C."J. Biol. Chem.. 276. 5753-5759 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Hiraga A.: "Protein phosphatase 2A is associated in an inactive state with microtubules through 2A1-specific interaction with tubulin."Biochem. J.. 346. 433-439 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Makinae K.: "Structure of the mouse glutamate decarboxylase 65 gene and its promoter: preferential expression of its promoter in the GAB Aergic neurons of transgenic mice."J. Neurochem.. 75. 1429-1437 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Casamayor A.: "Functional counterparts of mammalian protein kinases PDK1 and SGK in budding yeast."Curr. Biol.. 9. 186-197 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Kobayashi T.: "Activation of serum- and glucocorticoid-regulated protein kinase by agonists that activate phophatidylinositide 3-kinase is mediated by 3-phosphoinositide-dependent protein kinase-1 (PDK-1) and PDK2."Biochem. J.. 339. 319-328 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Kobayashi T.: "Characterization of the structure and regulation of two novel isoforms of serum and glucocorticoid-induced protein kinase."Biochem. J.. 344. 189-197 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Yamamoto M.: "Expressions of four major protein Ser/Thr phosphatases in human primary leukemic cells."Leukemia. 13. 595-600 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Hishiya A.: "Protein phosphatase 2C inactivates F-actin binding of human platelet moesin."J. Biol. Chem.. 274. 26705-26712 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Yanagawa Y.: "Enrichment and efficient screening of ES cells containing a targeted mutation: the use of DT-A gene with the polyadenylation signal as a negative selection maker."Transgenic Res.. 8. 215-221 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Ohnishi M.: "Alternative promoters direct tissue-specific expression of the mouse protein phosphatase 2Cβ gene."Eur. J. Biochem.. 263. 736-745 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Hanada M.: "Selective suppression of stress-activated protein kinase pathways by protein phosphatase 2C in mammalian cells."FEBS Lett.. 437. 172-176 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Kobayashi T.: "Isoform specific phosphorylation of fission yeast type 2C protein phosphatase. Biochem."Biophys. Res. Commun.. 251. 296-300 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Kobayashi T.: "Isoform specific phosphorylation of protein phosphatase 2C expressed in COS7 cells."FEBS Lett.. 430. 222-226 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Kusuda K.: "Mutational analysis of the domain structure of mouse protein phosphatase 2Cβ."Biochem. J.. 332. 243-250 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Tamura, S.: "Regulation of stress-activated protein kinase signaling pathways by protein phosphatases"Eur. J. Biochem. mini-review series. in press.

    • Related Report
      2001 Annual Research Report
  • [Publications] Wang H.: "Activation of c-Jun amino-terminal kinase is required for retinoic acid induced neural differentiation of P19 embryonal carcinoma cells"FEBS Lett. 503. 91-96 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Higuchi, T.: "Effects of ATP on regulation of galactosyltransferase-I activity responsible for synthesis of the linkage region between the core protein and glycosaminoglycan chains of proteoglycans"Biochem. Cell Biol. 79. 159-164 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Hanada, M.: "Regulation of the TAK1 signaling pathway by protein phosphatase 2C"J. Biol. Chem. 276. 5753-5759 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Hanada,M.: "Regulation of the TAK1 signaling pathway by protein phosphatase 2C."J.Biol.Chem.. (In press).

    • Related Report
      2000 Annual Research Report
  • [Publications] Makinae,K.: "Structure of the mouse glutamate decarboxylase 65 gene and its promoter : preferential expression of its promoter in the GABAergic neurons of transgenic mice."J.Neurochem.. 75. 1429-1437 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Hiraga,A.: "Protein phosphatase 2A is associated in an inactive state with microtubules through 2Al-specific interaction with tubulin."Biochem.J.. 346. 433-439 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Hiraga A.& Tamura S.: "Protein Phosphatase 2A is associated in an inactive state with microtubules through 2A1-specific interaction with tubulin"Biochem. J.. (in press).

    • Related Report
      1999 Annual Research Report
  • [Publications] Hishiya A.,Ohnishi M.,Tamura S.& Nakamura F.: "Protein phosphatase 2C inactivates F-actin binding of human platelet moesin"J. Biol. Chem.. 274. 26705-26712 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Ohnishi M.,Chida N.,Kobayashi T.,Wang H.,Ikeda S.,Hanada Y.,Yanagawa Y.,Katsura K.,Hiraga A. & Tamura S.: "Alternative promoters direct tissue-specitic expression of the mouse protein phosphatase 2C beta gene"Eur. J. Biochem.. 263. 736-745 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Yamamoto M.,Suzuki Y.,Kihira H.,Miwa H.,Kita K.,Nagao M.,Tamura S.,Siku H.& Nishikawa M.: "Expressions of four major protein ser / thr phosphatases in human primary leukemic cells"Leukemia. 13. 565-600 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Yanagawa Y.,Kobayashi T.,Ohnishi M.,Kobayashi T.,Tamura S.,Tsuzuki T.,Sanbo M.,Yagi T.,Tashiro F.& Miyazaki J.: "Enrichment and efficient screening of ES cells containing a targeted mutation: the use of DT-A gene with the polyadenylation signal as a negative selection marker"Transgenic Res.. 8. 215-221 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Kobayashi,T.: "Isoform specific phosphorylation of protein phosphatase 2C expressed in COS7 cells." FEBS Lett.430. 222-226 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Kusuda,K.: "Mutational analysis of the domain structure of mouse protein phosphatase 2Cβ" Biochem.J.332. 243-250 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Kobayashi,T.: "Isoform specific phosphorylation of fission yeast type 2C protein phosphatase." Biochem.Biophys.Res.Commun.251. 296-300 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Hanada,M.: "Selective suppression of stress-activated protein kinase pathway by protein phosphatase 2C in mammalian cells." FEBS Lett.437. 172-176 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Yamamoto,M.: "Expression of four major protein ser/thr phosphatases in human primary leukemic cells." LEUKEMIA. (in press).

    • Related Report
      1998 Annual Research Report
  • [Publications] Kobayashi,T.: "Methods in Molecular Biology(ed,Ludlow,J.W.),Humana Press,Totowa" Expression of mouse protein phosphatase 2C in Eschericha coli and COS7 cells., 5 (1998)

    • Related Report
      1998 Annual Research Report

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

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