Inhibition of Growth Factor-induced Protein Synthesis by a Selective MEK Inhibitor in Aortic Smooth Muscle Cells*

  1. Sylvain Meloche§
  1. From the Centre de Recherche, Hôtel-Dieu de Montréal and Department of Pharmacology, University of Montreal, Montreal, Quebec, H2W 1T8 Canada
  1. § Scholar of the Medical Research Council of Canada. To whom correspondence should be addressed: Centre de Recherche, Hôtel-Dieu de Montréal, 3850 St. Urbain St., Montreal, Quebec, H2W 1T8 Canada. Tel.: 514-843-2733; Fax: 514-843-2715.

Abstract

A common response of cells to mitogenic and hypertrophic factors is the activation of high rates of protein synthesis. To investigate the molecular basis of this action, we have used the recently developed MAP kinase/extracellular signal-regulated kinase (ERK) kinase (MEK) inhibitor PD 98059 to examine the involvement of the ERK pathway in the regulation of global protein synthesis by growth factors in rat aortic smooth muscle cells (SMC). Incubation with PD 98059 blocked angiotensin II (AII)-dependent phosphorylation and enzymatic activity of both MEK1 and MEK2 isoforms, leading to inhibition of the phosphorylation and activation of p44mapk and p42mapk. The compound was found to selectively inhibit activation of the ERK pathway by AII, but not the stimulation of p70 S6 kinase, phospholipase C, or tyrosine phosphorylation. Most importantly, treatment of aortic SMC with PD 98059 potently inhibited AII-stimulated protein synthesis with a half-maximal inhibitory concentration of 4.3 μM. The effect of PD 98059 was not restricted to AII, since the compound also blocked to various extent the induction of protein synthesis by growth factors acting through tyrosine kinase receptors, G protein-coupled receptors, or protein kinase C. These results provide strong evidence that activation of ERK isoforms is an obligatory step for growth factor-induced protein synthesis in aortic SMC.

Footnotes

  • Recipient of a Heart and Stroke Foundation of Canada studentship.

  • * This work was supported in part by grants from the National Cancer Institute of Canada and the Medical Research Council of Canada. The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

  • Received October 19, 1995.
  • Revision received March 5, 1996.
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