The transcription factor network associated with the amino acid response in mammalian cells

Abstract

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.

Figure 1

Signal transduction pathways of the amino acid (AA) response (AAR). The AAR represents a collection of signal transduction pathways that are activated by AA deprivation of mammalian cells. There are differences between cell types, such as which mitogen-activated protein kinases are activated, but the central pathway of general control nonderepressible 2 (GCN2)–eukaryotic initiation factor 2–activating transcription factor 4 (ATF4) appears to be ubiquitously expressed and regulated in all tissues. Likewise, the phosphorylation of ATF2 may well be a universal response, but the tissue distribution of the nuclear factor κB (NF-κB) activation has not been established. The autoregulatory induction of cJUN by the AAR occurs in cultured transformed cells to a much greater extent than in nontransformed counterparts, although the response has not yet been studied in vivo. The initial AA sensor for the cJUN and phosphorylated ATF2 (p-ATF2) pathways has not been determined conclusively. Interestingly, the 4 pathways shown rely on a variety of molecular mechanisms. The synthesis of ATF4 protein is translationally controlled, the phosphorylation of preexisting cJUN and ATF2 protein is mediated by mitogen-activated protein kinase signaling, and NF-κB activation occurs as a consequence of disassociation, but not degradation, of IκB. See the text for additional details. GPCR, G protein–coupled receptor; IκB, inhibitory kappa beta; JNK, c-Jun N-terminal kinase; MEK/ERK, mitogen-activated protein kinase/extracellular-regulated kinase.

Figure 2

The basic leucine zipper (bZIP) transcription factor network of the amino acid response (AAR). The core of the transcription factor network that has been identified thus far to mediate the AAR consists of primarily bZIP family members. Several are transcriptionally activated by activating transcription factor (ATF) 4 [ATF3, CCAAT enhancer-binding protein homologous protein (CHOP), and CCAAT enhancer-binding protein (C/EBP) β] and then subsequently act to feedback inhibit the ATF4 signal as part of a self-limiting ATF4 program described in the text. C/EBPβ and cJUN are illustrated in the figure, but other members of the C/EBP and FOS/JUN families are known to be induced in expression by the AAR and/or contribute to regulation of AAR target genes. The solid arrows represent direct activation of the indicated gene, whereas the solid bars represent transcriptional antagonism of ATF4 action on AAR target genes. The dashed gray arrows indicate that ATF2 and cJUN stabilize the ATF4 protein by an unknown mechanism.