Abstract
[3H]Thymidine (TdR) incorporation by human osteosarcoma cell line MG-63 was significantly stimulated at as early as 3 h after the addition of either TIMP-1 or TIMP-2 alone. Maximum stimulation was attained at a concentration of either 20 ng/ml (0.71 nM) TIMP-1 or 1.0 ng/ml (46 pM) TIMP-2. Tyrosine kinase inhibitors such as genistein, erbstatin, and herbimycin A almost completely inhibited the [3H]TdR incorporation stimulated by either of the TIMPs. However, essentially no effect was observed with H-89, H-7, bisindolylmaleimide and K-252a. These inhibition studies suggest a crucial role for tyrosine kinase in the signal transduction of TIMPs. Phosphotyrosine-containing proteins were significantly elevated by the treatment with both TIMPs. We also found that either TIMP stimulated an increase in mitogen-activated protein (MAP) kinase activity, suggesting that MAP kinase plays a role in TIMP-dependent growth signaling.
MeSH terms
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Benzoquinones
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Calcium-Calmodulin-Dependent Protein Kinases / metabolism
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DNA / biosynthesis
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DNA / drug effects
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Enzyme Activation
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Genistein
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Glycoproteins / antagonists & inhibitors
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Glycoproteins / metabolism*
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Humans
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Hydroquinones / metabolism
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Hydroquinones / pharmacology
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Isoflavones / metabolism
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Isoflavones / pharmacology
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Lactams, Macrocyclic
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Mitogen-Activated Protein Kinase 1
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Osteosarcoma / genetics
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Osteosarcoma / metabolism
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Osteosarcoma / pathology
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Phosphorylation
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Protease Inhibitors / metabolism
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Protease Inhibitors / pharmacology*
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Protein-Tyrosine Kinases / metabolism
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Proteins / antagonists & inhibitors
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Proteins / metabolism*
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Quinones / metabolism
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Quinones / pharmacology
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Rifabutin / analogs & derivatives
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Signal Transduction*
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Thymidine / metabolism
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Thymidine / pharmacokinetics
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Time Factors
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Tissue Inhibitor of Metalloproteinase-2
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Tissue Inhibitor of Metalloproteinases
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Tritium
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Tumor Cells, Cultured
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Tyrosine / metabolism*
Substances
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Benzoquinones
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Glycoproteins
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Hydroquinones
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Isoflavones
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Lactams, Macrocyclic
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Protease Inhibitors
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Proteins
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Quinones
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Tissue Inhibitor of Metalloproteinases
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Tritium
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Tissue Inhibitor of Metalloproteinase-2
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Rifabutin
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Tyrosine
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herbimycin
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DNA
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Genistein
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Protein-Tyrosine Kinases
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Calcium-Calmodulin-Dependent Protein Kinases
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Mitogen-Activated Protein Kinase 1
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Thymidine
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erbstatin