Mj. Servant et al., INHIBITION OF GROWTH FACTOR-INDUCED PROTEIN-SYNTHESIS BY A SELECTIVE MEK INHIBITOR IN AORTIC SMOOTH-MUSCLE CELLS, The Journal of biological chemistry, 271(27), 1996, pp. 16047-16052
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.