Amino acid limitation regulates the expression of genes involved in several specific biological processes through GCN2-dependent and GCN2-independent pathways

Evidence has accumulated that amino acids play an important role in controlling gene expression. Nevertheless, two components of the amino acid control of gene expression are not yet completely understood in mammals: (a) the target genes and biological processes regulated by amino acid availability, and (b) the signaling pathways that mediate the amino acid response. Using large-scale analysis of gene expression, the objective of this study was to gain a better understanding of the control of gene expression by amino acid limitation. We found that a 6 h period of leucine starvation regulated the expression of a specific set of genes: 420 genes were up-regulated by more than 1.8-fold and 311 genes were down-regulated. These genes were involved in the control of several biological processes, such as amino acid metabolism, lipid metabolism and signal regulation. Using GCN2-/- cells and rapamycin treatment, we checked for the role of mGCN2 and mTORC1 kinases in this regulation. We found that (a) the GCN2 pathway was the major, but not unique, signaling pathway involved in the up- and down-regulation of gene expression in response to amino acid starvation, and (b) that rapamycin regulates the expression of a set of genes that only partially overlaps with the set of genes regulated by leucine starvation.