ATF4-DEPENDENT TRANSCRIPTION MEDIATES SIGNALING OF AMINO ACID LIMITATION

By M. Kilberg, J. Shan, N. Su. Trends in endocrinology and metabolism, 2009

596 citations recorded by the source corpus.

Mammals respond to dietary nutrient fluctuations; for example, deficiency of dietary protein or an imbalance of essential amino acids activates an amino acid response (AAR) signal transduction pathway, consisting of detection of uncharged tRNA by GCN2 kinase, eIF2α phosphorylation, and ATF4 expression. In concert with heterodimerization partners, ATF4 activates specific genes via a C/EBP-ATF response element (CARE). This review outlines the ATF4-dependent transcriptional mechanisms associated with the AAR, focusing on progress during the last five years. Recent evidence suggests that maternal nutrient deprivation not only has immediate metabolic effects on the fetus, but also triggers gene expression changes in adulthood, possibly through epigenetic mechanisms. Therefore, understanding the transcriptional programs initiated by amino acid limitation is critical and timely.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/1a1fa647a0fd64dd8c0f2cb2b071c0b87950782a

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Citations in the corpus

• Regulation of energy metabolism by long-chain fatty acids. (2014, background): “Transcription of the TRB3 gene is activated by activating transcription factor 4 (ATF4), which is a key mediator of the integrated stress response including a response to amino acid deficiency [114].”
• The Cystine/Glutamate Antiporter System xc − in Health and Disease: From Molecular Mechanisms to Novel Therapeutic Opportunities (2013, unknown): “The common pathway that mediates transcriptional induction by amino acid limitation includes activation of general control non-derepressible-2 (GCN2) protein kinase by free tRNAs and subsequent phosphorylation of the translation initiation factor eIF2a [reviewed in (114)].”
• The eIF2α/ATF4 pathway is essential for stress-induced autophagy gene expression (2013, background): “In addition, we have established that early activation of CHOP transcription and thereafter binding of both CHOP and ATF4 to p62, Nbr1 and Atg7 AAREs are responsible for an increased sensitivity of transcriptional induction of these autophagy genes according to leucine concentration.”
• Nutrient sensing and TOR signaling in yeast and mammals (2017, unknown): “…transporters, enzymes involved in amino acid metabolism (Hinnebusch & Natarajan, 2002; Siu et al , 2002; Averous et al , 2004; Hinnebusch, 2005; Kilberg et al , 2009; Staschke et al , 2010), and factors involved in autophagy (B’chir et al , 2013; Fig 2), thereby allowing adaptation to amino…”
• Amino acid transporter SLC7A11/xCT at the crossroads of regulating redox homeostasis and nutrient dependency of cancer (2018, background): “Subsequently, ATF4 binds to amino acid response elements (AAREs) in gene promoter regions and regulates the transcription of many genes involved in amino acid metabolism and the stress response to adapt to amino acid starvation [49].”