The Transcription Factor Network Associated With the Amino Acid Response in Mammalian Cells

Mammals exhibit multiple adaptive mechanisms that sense and respond to fluctuations in dietary nutrients. Consumption of reduced total dietary protein or a protein diet that is deficient in 1 or more of the essential amino acids triggers wide-ranging changes in feeding behavior and gene expression. At the level of individual cells, dietary protein deficiency is manifested as amino acid (AA) deprivation, which activates the AA response (AAR). The AAR is composed of a collection of signal transduction pathways that terminate in specific transcriptional programs designed to catalyze adaptation to the nutrient stress or, ultimately, undergo apoptosis. Independently of the AAR, endoplasmic reticulum stress activates 3 signaling pathways, collectively referred to as the unfolded protein response. The transcription factor activating transcription factor 4 is one of the terminal transcriptional mediators for both the AAR and the unfolded protein response, leading to a significant degree of overlap with regard to the target genes for these stress pathways. Over the past 5 y, research has revealed that the basic leucine zipper superfamily of transcription factors plays the central role in the AAR. Formation of both homo- and heterodimers among the activating transcription factor, CCAAT enhancer-binding protein, and FOS/JUN families of basic leucine zipper proteins forms the nucleus of a highly integrated transcription factor network that determines the initiation, magnitude, and duration of the cellular response to dietary protein or AA limitation.