Regulation of eukaryotic protein synthesis by initiation factors.

Abstract

Protein synthesis is, in one sense, a typical metabolic process which must be regulated to remain within the bounds of available cellular energy resources but also respond to the growth require- ments of the cell. Yet unlike other cellular processes, the products of protein synthesis, enzymes, receptors, structural proteins, etc., directly affect every other cellular process. Hence, the number of input signals controlling the rate of protein synthesis would be expected to be much greater, and the number of regulatory mechanisms employed much more diverse, than for other bio-chemical pathways. Recent studies indicate that the first of these predictions is fulfilled, but surprisingly, the second is not. Protein synthesis is regulated in most cases by changes in either the cellular concentration or phosphorylation state of only a few initiation factors. The purpose of the present article is to review recent results on the mechanisms involved in this regulation. Looking at the past several years in overview, several themes emerge. The primary structures of many initiation factors have now been deter- mined, which has facilitated the determination of phosphorylation sites, their site-directed mutagenesis, and the over- and underexpression of wild type and variant forms in vivo. Such studies have revealed the profound effect of protein synthesis rate on cell growth and phenotype and have produced the unex- pected finding that some initiation factors act as proto-oncogenes or anti-oncogenes. Another theme is that an increasing number of viruses have been shown to cripple the host protein synthesis machinery and antagonize host defense mechanisms as well, but they do so by attacking only a limited number of sites. Finally, genetic approaches in yeast have revealed a regulatory mechanism which is remarkably similar to those of mammalian cells.