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Activation of matrix metalloproteinases on cell surface

Research Project

Project/Area Number 10044244
Research Category

Grant-in-Aid for Scientific Research (B).

Allocation TypeSingle-year Grants
Section一般
Research Field Pathological medical chemistry
Research InstitutionThe University of Tokyo

Principal Investigator

SEIKI Motoharu  Inst. Med. Sci., Univ. Tokyo, Prof., 医科学研究所, 教授 (10154634)

Co-Investigator(Kenkyū-buntansha) ITOH Yoshifumi  Inst. Med. Sci., Univ. Tokyo, Assis. Prof., 医科学研究所, 助手 (70292852)
OKADA Akio  Inst. Med. Sci., Univ. Tokyo, Assis. Prof., 医科学研究所, 助手 (00233320)
トンプソン エリク  ビンセント医科学研究所, 室長
ゴールドパーグ グリコリ  ワシントン大学, 医学部, 教授
Project Period (FY) 1998 – 1999
Project Status Completed (Fiscal Year 1999)
Budget Amount *help
¥7,400,000 (Direct Cost: ¥7,400,000)
Fiscal Year 1999: ¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 1998: ¥4,000,000 (Direct Cost: ¥4,000,000)
KeywordsExtracellular matrix / Invasion and metastasis / Matrix metalloproteinase / Gelatinase A / MT-MMP / MMP / MT-1-MMP / ゼラチナーゼA / がんの浸潤・転移
Research Abstract

(1) Malignant melanoma cells degrade gelatin gel beneath the cells by extending protrusions called invadpodia. We foud that MT1-MMP localizes on the invadpodia. To monitor the cell surface. MT1-MMP more easily, we made MT1MMP fused with GFP and expressed it in the melanoma cells. Localization of GFP/MT1-MMP was clearly observed at invade podia where actin bundle can be seen. MT1-MMP was also detected along with actin stress fibers when it is expressed in on invasive CHO-K1 cells. Thus, localization of MT1-nMMP seems to be regulated through actin cytoskelton within the cells.
(2) MT1-MMP activates pro-gelatinase Aby introducing cleavage in the propeptide domain in vitro. Expression of MT1-MMP in cultured cells induce cell-mediated activation of pro-gelatinase A. To confirm whether MT1-MMP can act as the activator of pro-gelatinase A in vivo, we generatedgene knockout mice by substituting the 1st to 4th exons of mouse genome to LacZ and Neo gene. Wild type mouse express MT1-MMP at high levels in various tissue during embryogenesis and activation of pro-gelatinase A in the tissue can be observed. In the knockout mice, however, such actibation of pro-gelatinase A could not be observed anymore. Thus, we conclued that MT1-MMP is the physiological activator of pro-gelatinase A.

Report

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

    (23 results)

All Other

All Publications (23 results)

  • [Publications] Peter, T. J. et al.: "Differentiation-dependent expression of gelatinase B/matrix metalloproteinase-9 in trophoblast cells."Cell Tissue Res. 295. 287-296 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Thant, A. A. et al.: "Ras pathway is required for the activation of MMP-2 secretion and for the invasion of src-transformed 3Y1."Oncogene. 18. 6555-6563 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Sato, T. et al.: "Furin-independent Pathway of Membrane Type 1-Matrix Metalloproteinase Activation in Rabbit Dermal Fibroblasts."J. Biol. Chem.. 274. 37280-37284 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Noritake, H. et al.: "Overexpression of tissue inhibitor of matrix metalloproteinases-1 (TIMP-1) in metastatic MDCK cells transformed by v-src."Clin Exp Metastasis. 17. 105-110 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Konttinen Yrjo. T: "New Collagenolytic Enzymes/Cascade identified at the pannus-hard tissue junction in rheumatoid arthritis."Matrix Biology. 17. 585-601 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Afzal, S: "MT1-MMP and MMP-2 mRNA expression in human ovarian tumors : possible implications for the role of desmoplastic fibroblasts."Human Pathology. 29. 155-165 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Peters, T. J., A. Albieri, E. Bevilacqua, B. M. Chapman, L. H. Crane, G. P. Hamlin, M. Seiki, and M. J. Soares: "Differentiation-dependent expression of gelatinase B/matrix metalloproteinase-9 in trophoblast cells"Cell Tissue Res. 295. 287-296 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Thant, A. A., T. T. Sein, E. Liu, K. Machida, F. Kikkawa, T. Koike, M. Seiki, S. Matsuda, and M. Hamaguchi: "Ras pathway is required for the activation of MMP-2 secretion and for the invasion of src-transformed 3Y1"Oncogene. 18. 6555-6563 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Sato, T., T. Kondo, T. Fujisawa, M. Seiki, and A. Ito.: "Furin-independent Pathway of Membrane Type 1-Matrix Metalloproteinase Activation in Rabbit Dermal Fibroblasts"J Biol Chem. 274. 37280-37284 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Noritake, H., H. Miyamori, C. Goto, M. Seiki, and H. Sato: "Overexpression of tissue inhibitor of matrix metalloproteinases-1 (TMP-1) in metastatic MDCK cells transformed by v-src."Clin Exp Metastasis. 17. 105-110 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Konttinen, Y. T., A. Ceponis, M. Takagi, M. Ainola, T. Sorsa, M. Sutinen, T. Salo. J. Ma, S. Santavirta, and M. Seiki: "New collagenolytic enzymes/cascade identified at the pannus-hard tissue junction in rheumatoid arthritis : destruction from above"Matrix Biol. 17. 585-601 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Afzal, S., E. N. Lalani, R. Poulsom, A. Stubbs, G. Rowlinson, H. Sato, M. Seiki, and G. W. Stamp.: "MT1-MMP, and MMP-2 mRNA expression in human ovarian tumors : possible implications for the role of desmoplastic fibroblasts."Hum Pathol. 29. 155-165 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Peters.T.J.et al.: "Differentiation-dependent expression of gelatinase B/matrix metalloproteinase-9 in trophoblast cells"Cell Tissue Res. 295. 287-296 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Thant,A.A.et al.: "Ras pathway is required for the activation of MMP-2 secretion and for the invasion of src-transformed 3Y1"Oncogene. 18. 6555-6563 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Sato,T.et al.: "Furin-independent pathway of Membrane Type1-Matrix Metalloproteinaze Activation in Rabbit Dermal Fibroblasts"J.Biol.Chem.. 274. 37280-37284 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Akizawa,T.et al.: "Development and application of a microplate assay method for the mass screening of MMP inhibitors"Ann N Y Acad Sci. 878. 622-624 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Noritake,H.et al.: "Overexpression of tissue inhibitor of matrix metalloproteinases-1(TIMP-1) in metastatic MDCK cells transformed by v-src"Clin Exp Metastasis.. 17. 105-110 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Kadono,Y.: "Membrance Type 1-Matrix Metalloprpteinase is involved in the formation of hepatocyte growth factor/scatter factor-induced branching tubules in madin-darby canine kidney epithelial cells." Biochem.Biophys.Res.Commun.251. 681-687 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Yoshiyama,Y.: "Expression of the membrance-type 3 matrix metalloproteinase (MT3-MMP) in human brain tissues." Acta neuropathol.96. 347-350 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Konttinen Yrjo.T: "New Collagenolytic Enzymes/Cascade identified at the pannus-hard tissue junction in rheumatoid arthritis." Matrix Biology. 17. 585-601 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Bando,E.: "Immunohistochemical study of MT-MMP tissue status in gastric carcinoma and correlation with survival analyzed by univariate and multivariate analysis." Oncol.Rep.5. 1485-1488 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Noritake,H.: "Overexpression of tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) in metastatic MDCK cells transformed by v-src." Clin.Exp.Metastasls. (in press). (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] Afzal,S: "MT1-MMP and MMP-2 mRNA expression in human ovarian tumors : possible implications for the role of desmoplastic fibroblasts." Human Pathology. 29. 155-165 (1998)

    • Related Report
      1998 Annual Research Report

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

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