ArticleNature cell biology2019
A MYC-GCN2-eIF2α negative feedback loop limits protein synthesis to prevent MYC-dependent apoptosis in colorectal cancer.
Article in Nature cell biology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 63 papers.
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Who cites it
63 citing papers in PubMed, 90 citations in OpenAlex.
- RAS pathway mutations orchestrate chromatin reconfiguration and transcriptional rewiring in colorectal cancer.Cell communication and signaling : CCS · 2026Article
- Article
- Mitochondrial metabolite transporters at the crossroads of metabolic reprogramming, epigenetic regulation and therapeutic vulnerabilities in colorectal cancer.Molecular biology reports · 2026Review
- Increased mRNA translation delays tumour initiation and exposes a therapeutic vulnerability in lung cancer.Molecular cancer · 2026Article
- Elevated GCN2 levels in cancer cells confer protection from mitotic stress and faster cell movement.Cellular oncology (Dordrecht, Netherlands) · 2026Article
- The integrated stress response in cancer: mechanisms of tumor adaptation and therapeutic targeting.Biochemical Society transactions · 2026Review
- DKC1-mediated pseudouridylation of rRNA targets hnRNP A1 to sustain IRES-dependent translation and ATF4-driven metabolic adaptation.Science advances · 2025Article
- Novel endoplasmic reticulum stress-related gene signature unveils CDKN3 as a prognosticator in neuroblastoma.Translational pediatrics · 2025Article
- Activation of the integrated stress response and loss of cFLIPCell death discovery · 2025Article
- Targeting PKC as a Therapeutic Strategy to Overcome Chemoresistance in TNBC by Restoring Aurora Kinase B Expression.Journal of cellular and molecular medicine · 2025Article
- MYC Drives mRNA Pseudouridylation to Mitigate Proliferation-Induced Cellular Stress during Cancer Development.Cancer research · 2024Article
- Multifaceted role of GCN2 in tumor adaptation and therapeutic targeting.Translational oncology · 2024Review
- GCN2 kinase activation mediates pulmonary vascular remodeling and pulmonary arterial hypertension.JCI insight · 2024Article
- Comprehensive analysis of microRNAs modulated by histone deacetylase inhibitors identifies microRNA-7-5p with anti-myeloma effect.International journal of hematology · 2024Article
- The stress sensor GCN2 differentially controls ribosome biogenesis in colon cancer according to the nutritional context.Molecular oncology · 2024Article
- The significant role of amino acid metabolic reprogramming in cancer.Cell communication and signaling : CCS · 2024Review
- Upstream open reading frames: new players in the landscape of cancer gene regulation.NAR cancer · 2024Review
- C16, a PKR inhibitor, suppresses cell proliferation by regulating the cell cycle via p21 in colorectal cancer.Scientific reports · 2024Article
- Integrated whole transcriptome profiling revealed a convoluted circular RNA-based competing endogenous RNAs regulatory network in colorectal cancer.Scientific reports · 2024Article
- Loss of Anti-Tumor Efficacy by Polyamine Blocking Therapy in GCN2 Null Mice.Biomedicines · 2023Article
3 more citing papers are in PubMed but not listed here.
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Authors and funding
30 authors at 4 institutions in 2 countries.
Funding
Abstract
Tumours depend on altered rates of protein synthesis for growth and survival, which suggests that mechanisms controlling mRNA translation may be exploitable for therapy. Here, we show that loss of APC, which occurs almost universally in colorectal tumours, strongly enhances the dependence on the translation initiation factor eIF2B5. Depletion of eIF2B5 induces an integrated stress response and enhances translation of MYC via an internal ribosomal entry site. This perturbs cellular amino acid and nucleotide pools, strains energy resources and causes MYC-dependent apoptosis. eIF2B5 limits MYC expression and prevents apoptosis in APC-deficient murine and patient-derived organoids and in APC-deficient murine intestinal epithelia in vivo. Conversely, the high MYC levels present in APC-deficient cells induce phosphorylation of eIF2α via the kinases GCN2 and PKR. Pharmacological inhibition of GCN2 phenocopies eIF2B5 depletion and has therapeutic efficacy in tumour organoids, which demonstrates that a negative MYC-eIF2α feedback loop constitutes a targetable vulnerability of colorectal tumours.
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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.