p38 MAP kinase negatively regulates cyclin D1 expression in airway smooth muscle cells.
We have demonstrated that platelet-derived growth factor (PDGF) stimulates p38 mitogen-activated protein (MAP) kinase activation in bovine tracheal myocytes, suggesting that p38 is involved in growth regulation. We therefore examined whether p38 regulates expression of cyclin D1, a G(1) cyclin required for cell cycle traversal. The chemical p38 inhibitors SB-202190 and SB-203580 each increased basal and PDGF-induced cyclin D1 promoter activity and protein abundance. Overexpression of a dominant negative allele of MAP kinase kinase-3 (MKK3), an upstream activator of p38alpha, had similar effects. Conversely, active MKK3 and MKK6, both of which increase p38alpha activity, each decreased transcription from the cyclin D1 promoter. Together, these data demonstrate that p38 negatively regulates cyclin D1 expression. We tested whether p38 regulates cyclin D1 expression via inhibition of extracellular signal-regulated kinase (ERK) activation. Chemical inhibitors of p38 induced modest ERK phosphorylation and activation. However, dominant negative MKK3 was insufficient to activate ERK, and active MKK3 and MKK6 did not attenuate platelet-derived growth factor-mediated ERK activation. These data are consistent with the notion that p38alpha negatively regulates cyclin D1 expression via an ERK-independent pathway.
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Department of Pediatrics, University of Chicago, Chicago, Illinois 60637-1470, USA.
Li
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J
Hershenson
M B
MB
D000818:Animals; D019556:COS Cells; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000096:biosynthesis / Q000235:genetics; D002417:Cattle; D002478:Cells, Cultured; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology; D048371:MAP Kinase Kinase 3; D048669:MAP Kinase Kinase 6; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases / Q000096:biosynthesis / Q000235:genetics; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D009130:Muscle, Smooth / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009154:Mutation; D010766:Phosphorylation / Q000187:drug effects; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D011233:Precipitin Tests; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D014132:Trachea; D014158:Transcription, Genetic; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases
D004791:Enzyme Inhibitors; D007093:Imidazoles; D010982:Platelet-Derived Growth Factor; D011725:Pyridines; D011993:Recombinant Fusion Proteins; D019938:Cyclin D1; D011505:Protein-Tyrosine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048371:MAP Kinase Kinase 3; D048669:MAP Kinase Kinase 6; D020929:Mitogen-Activated Protein Kinase Kinases; C093642:SB 203580; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole