ArticleNeoplasia (New York, N.Y.)2010
Regulation of G(1) arrest and apoptosis in hypoxia by PERK and GCN2-mediated eIF2alpha phosphorylation.
Article in Neoplasia (New York, N.Y.), 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers.
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Who cites it
43 citing papers in PubMed, 68 citations in OpenAlex.
- The integrated stress response in cancer: mechanisms of tumor adaptation and therapeutic targeting.Biochemical Society transactions · 2026Review
- Hypoxia-induced gene expression changes in N. vectensis embryos.Scientific reports · 2026Article
- GCN2 in Cancer: Molecular Mechanisms to Therapeutic Potential.Current cancer drug targets · 2026Review
- Review
- CDH1 Orchestrates Anabolic Events to Promote Cell Cycle Initiation.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- The interaction between GCN2 and eIF2 mediates the resistance of cotton bollworm to the Bacillus thuringiensis Cry1Ac toxin.PLoS pathogens · 2025Article
- GCN2 kinase activation mediates pulmonary vascular remodeling and pulmonary arterial hypertension.JCI insight · 2024Article
- Protein aggregation and biomolecular condensation in hypoxic environments (Review).International journal of molecular medicine · 2024Review
- When autophagy meets placenta development and pregnancy complications.Frontiers in cell and developmental biology · 2024Review
- HIF: a master regulator of nutrient availability and metabolic cross-talk in the tumor microenvironment.The EMBO journal · 2023Review
- Endoplasmic Reticulum Stress of Gut Enterocyte and Intestinal Diseases.Frontiers in molecular biosciences · 2022Review
- Role of indoleamine 2,3-dioxygenase in ischemia-reperfusion injury of renal tubular epithelial cells.Molecular medicine reports · 2021Article
- Raloxifene prevents stress granule dissolution, impairs translational control and promotes cell death during hypoxia in glioblastoma cells.Cell death & disease · 2020Article
- The role of host eIF2α in viral infection.Virology journal · 2020Review
- Targeting Protein Synthesis in Colorectal Cancer.Cancers · 2020Review
- eIF2α phosphorylation and the regulation of translation.Current genetics · 2020Review
- Genomic signatures of high-altitude adaptation in Ethiopian sheep populations.Genes & genomics · 2019Article
- Triazolo[4,5Computational and structural biotechnology journal · 2018Article
- Blocking autophagy enhances the pro-apoptotic effect of bufalin on human gastric cancer cells through endoplasmic reticulum stress.Biology open · 2017Article
- Preconditioning of primary human renal proximal tubular epithelial cells without tryptophan increases survival under hypoxia by inducing autophagy.International urology and nephrology · 2017Article
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
Abstract
Hypoxia is a common microenvironment in solid tumors and is correlated with tumor progression by regulating cancer cell survival. Recent studies suggest that activation of double-stranded RNA-dependent protein kinase-like endoplasmic reticulum-related kinase (PERK) and phosphorylation of alpha subunit of eIF2 (eIF2alpha) confer cell adaptation to hypoxic stress. However, eIF2alpha is still phosphorylated at a lowered level in PERK knockout cells under hypoxic conditions. The mechanism for eIF2alpha kinase(s) (eIF2AK)-increased cell survival is not clear. In this report, we provide evidence that another eIF2AK, the amino acid starvation-dependent general control of amino acid biosynthesis kinase (GCN2), is also involved in hypoxia-induced eIF2alpha phosphorylation. We demonstrate that both GCN2 and PERK mediate the cell adaptation to hypoxic stress. High levels of eIF2alpha phosphorylation lead to G(1) arrest and protect cells from hypoxia-induced apoptosis. Reduced phosphorylation of eIF2alpha by knocking out either PERK or GCN2 suppresses hypoxia-induced G(1) arrest and promotes apoptosis in accompany with activation of p53 signal cascade. However, totally abolishing phosphorylation of eIF2alpha inhibits G(1) arrest without promoting apoptosis. On the basis of our results, we propose that the levels of eIF2alpha phosphorylation serve as a "switch" in regulation of G(1) arrest or apoptosis under hypoxic conditions.
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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.