Nutritional control of gene expression: how mammalian cells respond to amino acid limitation

Abstract

The amino acid response (AAR) pathway in mammalian cells is designed to detect and respond to amino acid deficiency. Limiting any essential amino acid initiates this signaling cascade, which leads to increased translation of a "master regulator," activating transcription factor (ATF) 4, and ultimately, to regulation of many steps along the pathway of DNA to RNA to protein. These regulated events include chromatin remodeling, RNA splicing, nuclear RNA export, mRNA stabilization, and translational control. Proteins that are increased in their expression as targets of the AAR pathway include membrane transporters, transcription factors from the basic region/leucine zipper (bZIP) superfamily, growth factors, and metabolic enzymes. Significant progress has been achieved in understanding the molecular mechanisms by which amino acids control the synthesis and turnover of mRNA and protein. Beyond gaining additional knowledge of these important regulatory pathways, further characterization of how these processes contribute to the pathology of various disease states represents an interesting aspect of future research in molecular nutrition.

Figure 1

Amino acid limitation regulates multiple steps of gene expression.

Figure 2

Amino acid–dependent alternative splicing of the ATF3 gene. Following amino acid deprivation of HepG2 hepatoma cells, synthesis of alternative mRNA species is observed (23). The ATF3 gene structure and the use of exons A–E in each of the ATF3 mRNA variants is shown. The translation start site (ATG) is the same for all three proteins, but the translation stop codon varies (TAA, TGA, or TAG) in its location and results in truncation of the leucine zipper for ATF3ΔZip2c and ATF3ΔZip3. ATF3ΔZip2c also lacks some of the activation domain as the result of a splice site within exon B.

Figure 3

SNAT2 gene structure and the conserved sequences within intron 1. Panel A depicts the structure of the 16 exons and 15 introns within the human, chimpanzee, mouse, and rat SNAT2 genes (90). The translation start (AUG) and stop (UAA) sites are also shown. Panel B shows the conservation of sequence within intron 1 that contains the amino acid response element (AARE), the CAAT box, and the purine-rich element (PuR). The core sequence of the AARE that is identical to that in the C/EBP homology protein (CHOP) promoter is underlined. The numbers are the nucleotide for that particular species relative to the predicted transcription start site as +1.

Figure 4

Working model for control of the asparagine synthetase (ASNS) gene (see text for details). Transcription factors shown in color have been localized to the ASNS promoter by chromatin immunoprecipitation analysis (24). Unidentified proteins are shown in gray.