TIMP-1 stimulates proliferation of human aortic smooth muscle cells and Ras effector pathways.
Tissue inhibitor of metalloproteinases-1 (TIMP-1) is a multifunctional protein, which is found in most tissues and body fluids. Here, we demonstrated that recombinant TIMP-1 but not the synthetic matrix metalloproteinase inhibitor, GM6001, stimulated proliferation of human aortic smooth muscle cells (AoSMC) in a dose-dependent manner. The mitogenic effect was associated with activation of Ras, increased phosphorylation of ERK, and stimulation of cyclin D1 expression. The phosphatidylinositol 3-kinase (PI3K) signaling pathway was also involved since the PI3K inhibitor, LY294002, abolished the TIMP-1-mediated growth stimulation. These data suggest that TIMP-1 activates Ras, which then turns on the ERK and PI3K signaling pathways to promote cell cycle progression of the AoSMC.
Akahane
Takemi
T
Laboratory of Cellular Carcinogenesis and Tumor Promotion, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4255, USA. akahane@m5.kcn.ne.jp <akahane@m5.kcn.ne.jp>
Akahane
Manabu
M
Shah
Amy
A
Thorgeirsson
Unnur P
UP
D000818:Animals; D001011:Aorta / Q000033:anatomy & histology; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects*; D002867:Chromones / Q000494:pharmacology; D019938:Cyclin D1 / Q000378:metabolism; D004151:Dipeptides / Q000494:pharmacology; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D009025:Morpholines / Q000494:pharmacology; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011480:Protease Inhibitors / Q000494:pharmacology; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000494:pharmacology / Q000502:physiology*; D018631:ras Proteins / Q000378:metabolism*
D002867:Chromones; D019938:Cyclin D1; D004151:Dipeptides; D048049:Extracellular Signal-Regulated MAP Kinases; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011480:Protease Inhibitors; D011994:Recombinant Proteins; D019715:Tissue Inhibitor of Metalloproteinase-1; D018631:ras Proteins; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one