Translational Initiation Factor eIF-4E: A LINK BETWEEN CARDIAC LOAD AND PROTEIN SYNTHESIS

Hisayasu Wada,Charles T Ivester,Blase A Carabello,George Cooper,Paul J Mcdermott

doi:10.1074/jbc.271.14.8359

Abstract

To define the coupling mechanism between cardiac load and the rate of protein synthesis, changes in the extent of eIF-4E phosphorylation were measured after imposition of a load. Electrically stimulated contraction of adult feline cardiocytes increased eIF-4E phosphorylation to 34% after 4 h, as compared with 8% phosphorylation in quiescent controls. However, eIF-4E phosphorylation did not increase upon electrical stimulation in the presence of 7.5 mM 2,3-butanedione monoxime, an inhibitor of actin-myosin cross-bridge cycling and active tension development. Treatment of adult cardiocytes with either 0.1 microM insulin or 0.1 microM phorbol 12-myristate 13-acetate increased eIF-4E phosphorylation to 23 and 64%, respectively, but these increases were not blocked by 2,3-butanedione monoxime. In canine models of acute hemodynamic overload in vivo, eIF-4E phosphorylation increased to 23% in response to left ventricular pressure overload as compared with 7% phosphorylation in controls. Acute volume overload had no effect on eIF-4E phosphorylation. These changes in eIF-4E phosphorylation account for differences in anabolic responses to acute pressure versus acute volume overload. These data suggest that eIF-4E phosphorylation is a mechanism by which increased cardiac load is coupled to accelerated rates of protein synthesis.

Highlights

From the Departments of Medicine, Physiology, and Cell Biology and Anatomy, Gazes Cardiac Research Institute and Veterans Administration Medical Center, Charleston, South Carolina 29401-5799
The amount of hypertrophy that develops in vivo is dependent upon the type, severity, and duration of the increased ventricular wall stress imposed by a load, and it can be accounted for by quantitative differences in protein synthesis rates that are intrinsic to the cardiocyte [3,4,5,6,7]
By increasing the activity of eIF-4E through phosphorylation, a specific coupling mechanism is established for enhancing peptide chain initiation and thereby accelerating the steady state rate of protein synthesis

Summary

Introduction

To define the coupling mechanism between cardiac load and the rate of protein synthesis, changes in the extent of eIF-4E phosphorylation were measured after imposition of a load. These changes in eIF-4E phosphorylation account for differences in anabolic responses to acute pressure versus acute volume overload These data suggest that eIF-4E phosphorylation is a mechanism by which increased cardiac load is coupled to accelerated rates of protein synthesis. Changes in the activity of an initiation factor that is rate-limiting for peptide chain initiation would provide a specific mechanism for accelerating cardiocyte protein synthesis. A large number of studies have shown a direct correlation between the extent of eIF-4E phosphorylation and the rate of protein synthesis (10 – 12) It is the least abundant eIF and is present in limiting quantities relative to mRNA and ribosomes [14]. EIF-4E activity is increased by phosphorylation on serine 209, which increases its binding affinity for the m7-GTP caps on mRNA and thereby promotes assembly of eIF-4F in the initiation complex [15]

Methods

Results

Conclusion