Asparagine synthetase: regulation by cell stress and involvement in tumor biology
- 15 April 2013
- journal article
- review article
- Published by American Physiological Society in American Journal of Physiology-Endocrinology and Metabolism
- Vol. 304 (8), E789-E799
- https://doi.org/10.1152/ajpendo.00015.2013
Abstract
Asparagine synthetase (ASNS) catalyzes the conversion of aspartate and glutamine to asparagine and glutamate in an ATP-dependent reaction. The enzyme is ubiquitous in its organ distribution in mammals, but basal expression is relatively low in tissues other than the exocrine pancreas. Human ASNS activity is highly regulated in response to cell stress, primarily by increased transcription from a single gene located on chromosome 7. Among the genomic elements that control ASNS transcription is the C/EBP-ATF response element (CARE) within the promoter. Protein limitation or an imbalanced dietary amino acid composition activate the ASNS gene through the amino acid response (AAR), a process that is replicated in cell culture through limitation for any single essential amino acid. Endoplasmic reticulum stress also increases ASNS transcription through the PERK-eIF2-ATF4 arm of the unfolded protein response (UPR). Both the AAR and UPR lead to increased synthesis of ATF4, which binds to the CARE and induces ASNS transcription. Elevated expression of ASNS protein is associated with resistance to asparaginase therapy in childhood acute lymphoblastic leukemia and may be a predictive factor in drug sensitivity for certain solid tumors as well. Activation of the GCN2-eIF2-ATF4 signaling pathway, leading to increased ASNS expression appears to be a component of solid tumor adaptation to nutrient deprivation and/or hypoxia. Identifying the roles of ASNS in fetal development, tissue differentiation, and tumor growth may reveal that ASNS function extends beyond asparagine biosynthesis.Keywords
This publication has 108 references indexed in Scilit:
- Dynamic changes in genomic histone association and modification during activation of the ASNS and ATF3 genes by amino acid limitationBiochemical Journal, 2012
- The GCN2-ATF4 pathway is critical for tumour cell survival and proliferation in response to nutrient deprivationThe EMBO Journal, 2010
- Circulating tumour cells demonstrate an altered response to hypoxia and an aggressive phenotypeBritish Journal of Cancer, 2010
- ATF4-dependent transcription mediates signaling of amino acid limitationTrends in Endocrinology & Metabolism, 2009
- GCN2 Protein Kinase Is Required to Activate Amino Acid Deprivation Responses in Mice Treated with the Anti-cancer Agent l-AsparaginaseOnline Journal of Public Health Informatics, 2009
- Protein or amino acid deprivation differentially regulates the hepatic forkhead box protein A (FOXA) genes through an activating transcription factor-4-independent pathwayJournal of Hepatology, 2009
- A feedback transcriptional mechanism controls the level of the arginine/lysine transporter cat-1 during amino acid starvationBiochemical Journal, 2007
- Activation of the ATF3 gene through a co-ordinated amino acid-sensing response programme that controls transcriptional regulation of responsive genes following amino acid limitationBiochemical Journal, 2006
- Coping with stress: eIF2 kinases and translational controlBiochemical Society Transactions, 2006
- Reinitiation involving upstream ORFs regulates ATF4 mRNA translation in mammalian cellsProceedings of the National Academy of Sciences of the United States of America, 2004