DIFFERENTIAL LONG-TERM REGULATION OF MEK AND OF P42 MAPK IN RAT GLOMERULAR MESANGIAL CELLS

Constitutive stimulation of the mitogen-activated protein kinase (MAPK ) activator MAPK/ERK kinase (MEK) is sufficient to promote long-term e vents such as cell differentiation, proliferation, and transformation. To evaluate a possible mechanism for the chronic regulation of MEK an d p42 MAPK, we studied the long-term effects of fetal bovine serum (FB S), the G protein-coupled receptor agonist endothelin-1 (ET-1), and th e protein tyrosine kinase-coupled receptor agonist platelet-derived gr owth factor BE (PDGF BE) on MEK and p42 MAPK in glomerular mesangial c ells (GMC). FBS, ET-1, and PDGF BB led to a time-dependent increase in MEK-1 mRNA and protein expression without altering p42 MAPK mRNA and protein levels. FBS also induced MEK-1 mRNA expression in diverse cell types, including NIH/3T3 fibroblasts, A7r5 vascular smooth muscle cel ls, and Chinese hamster ovary cells. In GMC, cycloheximide inhibited M EK-1 mRNA induction but stimulated p42 MAPK mRNA expression in the abs ence and presence of FBS, ET-1, or PDGF. The FBS-induced increase in M EK-1 mRNA was accompanied by a sustained enhancement of MEK activity, as assessed by the ability of immunoprecipitated p45 MEK to activate r ecombinant p42 MAPK and hence phosphorylate myelin basic protein, and p42 MAPK activity. We conclude that, in GMC, MEK-1 acts like a delayed -early gene and that it can be chronically induced at the mRNA and pro tein level.