7 Translational Control of GCN4: Gene-specific Regulation by Phosphorylation of elF2

Abstract

OVERVIEW OF GCN4 TRANSLATIONAL CONTROL When subjected to various kinds of starvation, stress, or certain viral infections, mammalian cells respond by reducing the overall rate of protein synthesis by phosphorylating the α-subunit of translation initiation factor-2 (eIF2) (see Clemens; Mathews; Katze; Duncan; Schneider; all this volume). This down-regulation of protein synthesis is presumably a means of conserving resources and limiting cell division under adverse growth conditions or of preventing virus multiplication. Studies on the yeast Saccharomyces cerevisiae have shown that eIF2α becomes phosphorylated when cells are deprived of an amino acid or purine and that this event leads to an inhibition of translation by the same mechanism that operates in mammalian cells. Interestingly, it also regulates the translation of a specific mRNA encoding the transcription factor GCN4, causing increased synthesis of GCN4 protein under conditions in which the translation of other yeast messenger RNAs is being reduced. GCN4 activates transcription of at least 40 different genes encoding amino acid biosynthetic enzymes (Hinnebusch 1988); thus, the induction of GCN4 alleviates the limitation for nutrients that triggers phosphorylation of eIF2 in yeast. The extent of eIF2 phosphorylation required to induce GCN4 translation is too low to cause a significant reduction in the rate of general protein synthesis. Consequently, GCN4 expression is a very sensitive indicator of the activity of eIF2 and associated translation initiation factors. The unique induction of GCN4 translation under starvation conditions is mediated by four short upstream open reading frames (uORFs) in the leader of GCN4 mRNA, located between...