ArticleThe EMBO journal2010
The GCN2-ATF4 pathway is critical for tumour cell survival and proliferation in response to nutrient deprivation.
Article in The EMBO journal, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 478 papers.
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Who cites it
478 citing papers in PubMed, 692 citations in OpenAlex.
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- Cancer-associated mitochondrial homeostasis disrupted and retrograde signaling activated.Medical oncology (Northwood, London, England) · 2026Review
- GCN2 in proteostasis: structural logic, signalling networks and disease.The FEBS journal · 2026Review
- Direct pharmacological targeting of asparagine synthetase to overcome resistance to L-asparaginase in ALL therapy.JCI insight · 2026Article
- Allosteric disordering of eIF2B regulates the integrated stress response.Nature chemical biology · 2026Article
- ATF4 coordinates amino acid and nucleotide synthesis with selective protein translation to ensure proper DNA replication timing in leukemia cells.Nature communications · 2026Article
- SIRT2 mediates integrated stress response by deacetylating and stabilizing 4E-BP1 to suppress translation.EMBO reports · 2026Article
- ATF4 promotes immune evasion in oral squamous cell carcinoma by suppressing autophagic PD-L1 degradation.Journal for immunotherapy of cancer · 2026Article
- Mapping the GDF15 arm of the integrated stress response in human cells and tissues.Communications biology · 2026Article
- Glutamine-Linked Cellular Stress Responses in Viral Infection: Mechanisms, Crosstalk, and Future Perspectives.International journal of molecular sciences · 2026Review
- Metabolic and transcriptional plasticity supports CD8Immunity · 2026Article
- Elevated GCN2 levels in cancer cells confer protection from mitotic stress and faster cell movement.Cellular oncology (Dordrecht, Netherlands) · 2026Article
- Suppression rather than activation of the integrated stress response (GCN2-ATF4) pathway extends lifespan in the fly.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- A Novel Potent and Selective GCN2 Inhibitor, APL-4098, Has Antileukemic Activity through Dysregulation of Mitochondrial Function.Clinical cancer research : an official journal of the American Association for Cancer Research · 2026Article
- The remarkable legacy of the K6/ODC mouse: mechanisms of polyamine-promoted tumorigenesis revealed.Amino acids · 2026Review
- Article
- Dissecting Complex Interactions Between Ferroptosis and the Proteasome.bioRxiv : the preprint server for biology · 2026Article
- ATM functions as a rheostat of metabolic stress in small-cell lung cancer.bioRxiv : the preprint server for biology · 2026Article
- Mannose metabolic pathway senses glucose supply and regulates cell fate decisions.The Journal of biological chemistry · 2026Article
418 more citing papers are in PubMed but not listed here.
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Authors and funding
10 authors at 3 institutions in 1 country.
Funding
Abstract
The transcription factor ATF4 regulates the expression of genes involved in amino acid metabolism, redox homeostasis and ER stress responses, and it is overexpressed in human solid tumours, suggesting that it has an important function in tumour progression. Here, we report that inhibition of ATF4 expression blocked proliferation and survival of transformed cells, despite an initial activation of cytoprotective macroautophagy. Knockdown of ATF4 significantly reduced the levels of asparagine synthetase (ASNS) and overexpression of ASNS or supplementation of asparagine in trans, reversed the proliferation block and increased survival in ATF4 knockdown cells. Both amino acid and glucose deprivation, stresses found in solid tumours, activated the upstream eukaryotic initiation factor 2alpha (eIF2alpha) kinase GCN2 to upregulate ATF4 target genes involved in amino acid synthesis and transport. GCN2 activation/overexpression and increased phospho-eIF2alpha were observed in human and mouse tumours compared with normal tissues and abrogation of ATF4 or GCN2 expression significantly inhibited tumour growth in vivo. We conclude that the GCN2-eIF2alpha-ATF4 pathway is critical for maintaining metabolic homeostasis in tumour cells, making it a novel and attractive target for anti-tumour approaches.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.