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Concentration-dependent switch-on and -off mechanism of cell-growth promoting activity of TIMP-1

Research Project

Project/Area Number 14571783
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Functional basic dentistry
Research InstitutionSchool of Dentistry, Aichi-Gakuin University

Principal Investigator

HAYAKAWA Taro  Aichi-Gakuin University, Department of Biochemistry School of Dentistry, Professor, 歯学部・生化学, 教授 (80064822)

Co-Investigator(Kenkyū-buntansha) YAMASHITA Kyoko  Aichi-Gakuin University, Department of Biochemistry School of Dentistry, Lecturer, 歯学部・生化学, 講師 (40231659)
Project Period (FY) 2002 – 2003
Project Status Completed (Fiscal Year 2003)
Budget Amount *help
¥2,300,000 (Direct Cost: ¥2,300,000)
Fiscal Year 2003: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 2002: ¥1,200,000 (Direct Cost: ¥1,200,000)
Keywordstissue inhibitor of metalloproteinases-1 (TIMP-1) / gene transfection / cell proliferation / TIMP-1 secretion / cell-growth regulation / mitogen-activated protein kinase (MAPK) / MAPK kinas (MEK) / p38 MAPK / p38 / HT1O80細胞 / オートクリン機構
Research Abstract

It has been already reported that TIMP-1 shows a typical bell-shaped dose curve on its cell-growth promoting activity, suggesting the presence of some concentration-dependent regulation of the cell-growth promoting activity of TIMP-1(Hayakawa et al., J. Cell Sci. 107, 2373-2379, 1994; Yamashita et al., FEBS Lett. 396, 103-107, 1996). To confirm this point, human TIMP-1 gene-transfected [CGEMT1] and empty vector-transfected [CGEMEV] HTlO8O cells were first prepared, and compared their proliferation and TIMP-1 expression/secretion in fetal calf serum-free Dulbecco's modified Eagle's minimal essential medium(DMEM) were examined. CGEMT1 cells secreted TIMP-1 and proliferated after 2 days lag period. CGEMEV cells, however, neither secreted TIMP-1 nor proliferated at all. Proliferation of CGEMT1 cells were completely suppressed by the addition of a minute amount of anti-TIMP-t monoclonal antibody, clearly indicating that the proliferation is totally depend on the TIMP-1 produced by cells the … More mselves, that is, an autocrine mechanism of the cell-growth promoting activity of TIMP-1. Furthermore, cell proliferation leveled off at around 4 culture day, and TIMP-1 secretion ceased and got a plateau. TIMP-1 concentration in the culture medium was around 100ng/ml. Then, we kept CGEMT1 cells in D-MEM supplemented with 〜160 ng/ml human recombinant TIMP-1. The cells neither proliferated nor secreted TIMP-1, but started to secrete TIMP-1 and proliferate from 1 day after replacing the culture medium with DMEM alone. Concerning to the intracellular signal transduction in HT1080 cells, TIMP-1 activated both MEK and p238 MAPK maximally at the low concentration (〜25 ng/ml), but not activated at the higher concentration (>100 ng/ml). ERK1/2, however, were activated constantly by TIMP-1 at all the concentrations examined (25〜150 ng/ml). These results strongly support our hypothesis, i.e., the presence of a concentration-dependent switch-on and -off mechanism for the control of cell-growth promoting activity of TIMP-1. Less

Report

(3 results)
  • 2003 Annual Research Report   Final Research Report Summary
  • 2002 Annual Research Report

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Published: 2002-04-01   Modified: 2016-04-21  

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