Gcn4

Gcn4, a basic leucine zipper protein, is the primary regulator of the transcriptional response to amino acid starvation (Hinnebusch and Fink, 1983). It is regulated at multiple levels, all of which alter the amount of Gcn4 present within the cell. Gcn4 is regulated at the level of protein stability, with its half-life ranging from approximately 2 minutes under growth in rich medium to 10 minutes under amino acid starvation conditions (Shemer et al., 2002). This degradation is mediated by the ubiquitin-conjugating enzymes Rad6 and Cdc34 (Kornitzer et al., 1994), and requires phosphorylation by the nuclear cyclin-dependent kinases Pho85 (Meimoun et al., 2000) or Srb10 (Chi et al., 2001).

Gcn4 is also regulated at the level of translation. Modulation of the activity of translation initiation machinery leads to an increase in the synthesis of Gcn4 protein under conditions of amino acid starvation. Under non-starvation conditions, ribosomal complexes are diverted to ORFs upstream of the Gcn4 coding region (Hinnebusch, 1984; Hinnebusch, 1997; Hinnebusch et al., 1988; Mueller and Hinnebusch, 1986; Thireos et al., 1984).

Finally, there is evidence that Gcn4 is also regulated transcriptionally. In strains carrying mutations that abolish translational regulation, there is nonetheless an increase in the levels both of Gcn4 protein and mRNA levels following induction of the amino acid starvation response (Albrecht et al., 1998).

Interestingly, the binding site for Gcn4, TGASTCA, is also recognized by the unrelated transcriptional regulator Bas1 (Springer et al., 1996). It is thought that this overlapping specificity serves as a mechanism for cross-regulation of adenine biosynthesis by both regulators.