In eukaryotic cells, protein synthesis is regulated in response to various environmental stresses by phosphorylating the alpha subunit of the eukaryotic initiation factor 2 (eIF2alpha). Four different eIF2alpha kinases have been identified in mammalian cells, the heme-regulated inhibitor (HRI), the interferon-inducible RNA-dependent kinase (PKR) and the endoplasmic reticulum-resident kinase (PERK) and GCN2, which was previously characterized from Saccharomyces cerevisiae, Drosophila melanogaster and Neurospora crassa. GCN2 is the unique eIF2alpha kinase present in all eukaryotes from yeast to mammals (1). GCN2, a sensor of amino acid deficiency, plays a key role in yeast and mammals in modulating amino acid metabolism as part of adaptation to nutrient deprivation. The role of GCN2 in adaptation to long-term amino acid deprivation in mammals, however, is poorly understood. GCN2-deficient mice developed liver steatosis and exhibited reduced lipid mobilization. Liver steatosis in Gcn2(-/-) mice was found to be caused by unrepressed expression of lipogenic genes, including Srebp-1c and Fa (2). Results demonstrate that PERK and GCN2 function to cooperatively regulate eIF2alpha phosphorylation and cyclin D1 translation after unfolded protein response pathway activation (3).
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