INHIBITION OF GROWTH FACTOR-INDUCED PROTEIN-SYNTHESIS BY A SELECTIVE MEK INHIBITOR IN AORTIC SMOOTH-MUSCLE CELLS

A common response of cells to mitogenic and hypertrophic factors is th e activation of high rates of protein synthesis. To investigate the mo lecular basis of this action, we have used the recently developed MAP kinase/extracellular signal-regulated kinase (ERK) kinase (MEK) inhibi tor PD 98059 to examine the involvement of the ERK pathway in the regu lation of global protein synthesis by growth factors in rat aortic smo oth muscle cells (SMC). Incubation with PD 98059 blocked angiotensin I I (AII)-dependent phosphorylation and enzymatic activity of both MEK1 and MEK2 isoforms, leading to inhibition of the phosphorylation and ac tivation of p44(mapk) and p42(mapk). The compound was found to selecti vely inhibit activation of the ERK pathway by AII, but not the stimula tion of p70 S6 kinase, phospholipase C, or tyrosine phosphorylation. M ost importantly, treatment of aortic SMC with PD 98059 potently inhibi ted AII-stimulated protein synthesis with a half-maximal inhibitory co ncentration of 4.3 mu M. The effect of PD 98059 was not restricted to AII, since the compound also blocked to various extent the induction o f protein synthesis by growth factors acting through tyrosine kinase r eceptors, G protein-coupled receptors, or protein kinase C, These resu lts provide strong evidence that activation of ERK isoforms is an obli gatory step for growth factor-induced protein synthesis in aortic SMC.