Activation of big mitogen-activated protein kinase-1 regulates smooth muscle cell replication.
This study examined the activation of big mitogen-activated protein (MAP) kinase-1 (BMK1) in rat carotid smooth muscle cells (SMCs). Platelet-derived growth factor, fibroblast growth factor-2, sorbitol, and serum all increased the activation of BMK1 in rat carotid SMCs, whereas angiotensin II, phorbol esters, and tumor necrosis factor-alpha had only slight effects. With the exception of tumor necrosis factor-alpha, all these factors phosphorylated extracellular signal-regulated kinase (ERK)1/2. The MAPK kinase inhibitor (MEKI), U0126 (1 micromol/L), blocked ERK1/2 phosphorylation and at higher doses (5 micromol/L) blocked BMK1 phosphorylation. This inhibitor also blocked SMC DNA synthesis in a dose-dependent manner. When SMCs were transfected with an adenoviral construct expressing dominant mutant BMK1 and stimulated with fibroblast growth factor-2, a significantly smaller increase in cyclin D1 and cyclin A expression and in retinoblastoma factor phosphorylation was detected compared with the increase in cells transfected with an adenoviral construct expressing green fluorescent protein (GFP). SMC DNA synthesis was significantly blocked in the cells transfected with the dominant mutant BMK1. These data support the suggestion that BMK1 is important and necessary for mitogen-induced SMC proliferation.
Luo
Honglin
H
McDonald Research Laboratories/The iCAPTURE Centre, Department of Pathology and Laboratory Medicine, St. Paul's Hospital/Providence Health Care, University of British Columbia, Vancouver, Canada.
Reidy
Michael A
MA
D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000378:metabolism; D002478:Cells, Cultured; D004261:DNA Replication / Q000187:drug effects; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006133:Growth Substances / Q000494:pharmacology; D048369:MAP Kinase Kinase 1; D048054:Mitogen-Activated Protein Kinase 7; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D009154:Mutation; D009570:Nitriles / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D051381:Rats
D002070:Butadienes; D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; D006133:Growth Substances; D009570:Nitriles; C113580:U 0126; D017346:Protein Serine-Threonine Kinases; D048054:Mitogen-Activated Protein Kinase 7; D020928:Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; D020929:Mitogen-Activated Protein Kinase Kinases