Phosphorylation of translation initiation factor 2 alpha is a highly conserved mechanism for down-regulating protein synthesis in response to starvation or stress. The yeast eIF-2 alpha kinase GCN2 is stimulated by deprivation for amino acids or purines. In addition to inhibiting general protein synthesis, GCN2 specifically stimulates translation of GCN4, a transcriptional activator of amino acid biosynthetic genes. HRI is an eIF-2 alpha kinase that is activated in rabbit reticulocytes by heme-deprivation and stress conditions that elicit the heat-shock response. The eIF-2 alpha kinase DAI is activated by double-stranded RNA during viral infections and is an important component of the interferon response. DAI has also been implicated as a tumor suppressor. These protein kinases provide an important means of coupling the rate of protein synthesis and cell division to environmental conditions.