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- W2626379330 abstract "The tissue inhibitor of metalloproteinases (TIMP–1) must be regarded as a multifunctional protein involved in cell growth, fibrosis, angiogenesis, and apoptosis. Recently evidence has been provided that TIMP–1 induces specific signaling pathways. In hu man hepatoma cells we could demonstrate an increased expression of gelatinases (especially MMP–9) as a result of increased TIMP–1 expression. We now show that TIMP–1 overexpressing liver cells exhibit increased migration, which can be reduced further by M MP-inhibition. Wild type HepG2, HepG2 stably transfected with TIMP–1, and HepG2 stably transfected with a TIMP–1-antagonist (MMP–9-H401A, a catalytically inactive MMP which still binds and neutralizes TIMP–1) were incubated in Boyden chambers either wit h or without Galardin (synthetic inhibitor of MMP–1,–2,–3,–8,–9) or a specific inhibitor of gelatinases. After migration (HepG2=100%) 115% of cells overexpressing TIMP–1 were counted and 62% of cells overexpressing MMP–9-H401A. Galardin reduced cell migr ation dose dependently in all cases. The gelatinase inhibitor reduced migration in TIMP–1 overexpressing cells predominantly. Furthermore, we examined intracellular signal transduction pathways of HepG2 cells in dependence on TIMP–1. TIMP–1 deactivates ce ll signaling pathways of MMP–2 and MMP–9 involving p38 MAPK. Specific blockade of the ERK pathway suppressed gelatinase expression either in the presence or absence of TIMP–1. Though overexpressing functional TIMP–1 enhanced migration of HepG2-TIMP–1 c ells depends on enhanced MMP-activity, especially MMP–9. Signal transduction studies revealed differences between wild type and TIMP–1 overexpressing HepG2 concerning the necessity of p38 MAPK. Our data add new insights in the complex function of TIMP–1 a nd control of MMP activity in human hepatoma cells. A" @default.
- W2626379330 created "2017-06-23" @default.
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- W2626379330 date "2004-08-18" @default.
- W2626379330 modified "2023-10-16" @default.
- W2626379330 title "Enhanced migration of TIMP–1 overexpressing hepatoma cells is attributed to gelatinases. Relevance to intracellular signaling pathways" @default.
- W2626379330 doi "https://doi.org/10.1055/s-2004-831815" @default.
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