ArticleMolecular biology of the cell2015
Involvement of general control nonderepressible kinase 2 in cancer cell apoptosis by posttranslational mechanisms.
Article in Molecular biology of the cell, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 32 citations in OpenAlex.
- GCN2 in proteostasis: structural logic, signalling networks and disease.The FEBS journal · 2026Review
- CD147 promotes NSCLC metastasis by inducing secretory autophagy-dependent exosome secretion via TRIM56-mediated ubiquitination and degradation of GCN2.Cell death and differentiation · 2026Article
- Palmitic acid aggravates atopic dermatitis by regulating SGK1/NEDD4L-involved cutaneous neuroimmune inflammation through driving TRPV1 and MRGPRB2 S-palmitoylation.Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2026Article
- Activation of the integrated stress response and loss of cFLIPCell death discovery · 2025Article
- Article
- Multifaceted role of GCN2 in tumor adaptation and therapeutic targeting.Translational oncology · 2024Review
- Integrated Stress Response (ISR) Pathway: Unraveling Its Role in Cellular Senescence.International journal of molecular sciences · 2023Review
- Potential roles of NEDD4 and NEDD4L and their utility as therapeutic targets in high‑incidence adult male cancers (Review).Molecular and clinical oncology · 2023Review
- Multiple Roles of the Stress Sensor GCN2 in Immune Cells.International journal of molecular sciences · 2023Review
- NEDD4L in human tumors: regulatory mechanisms and dual effects on anti-tumor and pro-tumor.Frontiers in pharmacology · 2023Review
- Limiting glutamine utilization activates a GCN2/TRAIL-R2/Caspase-8 apoptotic pathway in glutamine-addicted tumor cells.Cell death & disease · 2022Article
- Unraveling the Potential Role of NEDD4-like E3 Ligases in Cancer.International journal of molecular sciences · 2022Review
- GCN2: roles in tumour development and progression.Biochemical Society transactions · 2022Review
- NEDD4L-induced ubiquitination mediating UBE2T degradation inhibits progression of lung adenocarcinoma via PI3K-AKT signaling.Cancer cell international · 2021Article
- Insights Into the Biological Role of NEDD4L E3 Ubiquitin Ligase in Human Cancers.Frontiers in oncology · 2021Review
- Effects of GCN2/eIF2α on myocardial ischemia/hypoxia reperfusion and myocardial cells injury.American journal of translational research · 2019Article
- GCN2 deficiency ameliorates doxorubicin-induced cardiotoxicity by decreasing cardiomyocyte apoptosis and myocardial oxidative stress.Redox biology · 2018Article
- GCN2 is a potential prognostic biomarker for human papillary renal cell carcinoma.Cancer biomarkers : section A of Disease markers · 2018Article
- Decreased ATF4 expression as a mechanism of acquired resistance to long-term amino acid limitation in cancer cells.Oncotarget · 2017Article
Corrections and comments
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Authors and funding
10 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
General control nonderepressible kinase 2 (GCN2) is a promising target for cancer therapy. However, the role of GCN2 in cancer cell survival or death is elusive; further, small molecules targeting GCN2 signaling are not available. By using a GCN2 level-based drug screening assay, we found that GCN2 protein level critically determined the sensitivity of the cancer cells toward Na(+),K(+)-ATPase ligand-induced apoptosis both in vitro and in vivo, and this effect was largely dependent on C/EBP homologous protein (CHOP) induction. Further analysis revealed that GCN2 is a short-lived protein. In A549 lung carcinoma cells, cellular β-arrestin1/2 associated with GCN2 and maintained the GCN2 protein level at a low level by recruiting the E3 ligase NEDD4L and facilitating consequent proteasomal degradation. However, Na(+),K(+)-ATPase ligand treatment triggered the phosphorylation of GCN2 at threonine 899, which increased the GCN2 protein level by disrupting the formation of GCN2-β-arrestin-NEDD4L ternary complex. The enhanced GCN2 level, in turn, aggravated Na(+),K(+)-ATPase ligand-induced cancer cell apoptosis. Our findings reveal that GCN2 can exert its proapoptotic function in cancer cell death by posttranslational mechanisms. Moreover, Na(+),K(+)-ATPase ligands emerge as the first identified small-molecule drugs that can trigger cancer cell death by modulating GCN2 signaling.
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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.