16 Regulation of Translation Initiation in Mammalian Cells by Amino Acids

Abstract

Translation initiation in mammalian cells is exquisitely sensitive to modulation by variations in amino acid supply. Modulation involves the eIF2/eIF2B, eIF4F, and p70^S6k regulatory steps in translation initiation and, dependent on the prevailing experimental conditions, can manifest as a change in the global rate of protein synthesis and/or a change in translation of specific mRNAs. Limitation of essential amino acids down-regulates global rates of protein synthesis through uncharacterized protein kinases; one modulates phosphorylation of Ser-51 on the α subunit of eIF2 and another modulates phosphorylation of an unidentified site on the ɛ subunit of eIF2B. In contrast, the amino acid leucine, at concentrations within the physiological range, plays a unique role involving modulation of eIF4F and p70^S6k regulatory steps through a mechanism involving the protein kinase mTOR (the mammalian target of rapamycin) (Chapter 6). Leucine may also modulate eIF2B through an mTOR-insensitive mechanism. These effects of leucine appear to involve a ligand-specific recognition site that has some overlap of specificity with isoleucine but not other amino acids. In this chapter, we summarize recent evidence that supports this view of the role of amino acids in the modulation of translation initiation in mammalian cells.

PROTEIN SYNTHESIS IN MAMMALIAN TISSUES IS REGULATED BY VARIATIONS IN AMINO ACID SUPPLY
An abundance of evidence generated from in vivo studies in both humans and animals has established a predominant role for amino acids in the regulation of protein synthesis. Of the nutrients and hormones whose plasma concentrations change in response to food intake in humans,...