Heat Shock Increases the Association of Binding Protein-1 with Initiation Factor 4E

Robert G.J Vries,Andrea Flynn,Jashmin C Patel,Xuemin Wang,Richard M Denton,Christopher G Proud

doi:10.1074/jbc.272.52.32779

Robert G.J Vries, Andrea Flynn + Show 4 more

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https://doi.org/10.1074/jbc.272.52.32779

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Abstract

The effects of heat shock on the regulation of the cap-binding initiation factor 4E (eIF4E) and its inhibitory binding protein, 4E-BP1, have been examined in Chinese hamster ovary cells and in cardiac myocytes. Heat shock increased the association between eIF4E and 4E-BP1, and this was associated with a dephosphorylation of 4E-BP1. These effects did not appear to be due wholly to decreased activity of the p70 S6 kinase pathway, which is implicated in the control of 4E-BP1, and they were not mediated by the stress-activated p38 microtubule-associated protein kinase pathway. Increased binding of 4E-BP1 to eIF4E correlated with a decrease in the amount of eIF4G which co-purified with the latter. This could account for the previously observed impairment of eIF4F function during heat shock, and, since heat shock protein mRNAs are believed to be relatively cap-independent, could provide a mechanism for the selective up-regulation of the synthesis of heat shock proteins and other stress proteins during heat shock.

Highlights

Initiation factor 4E1 plays a key role in mRNA translation in eukaryotic cells
The findings presented here show that heat shock results in increased association of eIF4E with 4E-BP1
While this work was in progress, similar findings were reported by Feigenblum and Schneider [55] for human embryonic kidney [293] cells, no analysis of the effect on eIF4G association or of the signaling pathways involved was provided, and the events described here in response to heat shock are much more rapid than in 293 cells (3– 4 h)

Summary

Introduction

Initiation factor 4E (eIF4E) plays a key role in mRNA translation in eukaryotic cells. Two additional proteins that interact with eIF4E were discovered [21] They are termed 4E-BP1 and 4E-BP2 (eIF4E binding proteins 1 and 2) and each of them inhibits cap-dependent mRNA translation, implying that they block the function of eIF4E in peptide-chain initiation [22]. 4E-BP1 ( known as PHAS-I) is a phosphoprotein whose state of phosphorylation increases in response to insulin (22, 24 –27), insulin-like growth factor-1 [28] or angiotensin II [29] This causes its dissociation from eIF4E and should result in the alleviation of the inhibition of eIF4E. We find that heat shock markedly increases the amount of 4E-BP1 bound to eIF4E and, reduces the association of eIF4E with eIF4G, as expected from the competition between these proteins for a com-

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