ArticlePLoS biology2017
Transcriptome analysis of hypoxic cancer cells uncovers intron retention in EIF2B5 as a mechanism to inhibit translation.
Article in PLoS biology, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
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Who cites it
38 citing papers in PubMed, 56 citations in OpenAlex.
- Oxygenaging: A Physiological Framework for Geroscience.Aging cell · 2026Review
- Intron Retention: A Reemerging Paradigm in RNA Biology and Post-Transcriptional Gene Regulation.Genes · 2025Review
- DecodingbioRxiv : the preprint server for biology · 2025Article
- Expression of Truncated Products at the 5'-Terminal Region of RIPK2 and Evolutive Aspects that Support Their Biological Importance.Genome biology and evolution · 2024Article
- Oncofetal SNRPE promotes HCC tumorigenesis by regulating the FGFR4 expression through alternative splicing.British journal of cancer · 2024Article
- SR proteins in cancer: function, regulation, and small inhibitor.Cellular & molecular biology letters · 2024Review
- TRIM25 promotes glioblastoma cell growth and invasion via regulation of the PRMT1/c-MYC pathway by targeting the splicing factor NONO.Journal of experimental & clinical cancer research : CR · 2024Article
- Review
- Novel Genome-Wide Interactions Mediated via BOLL and EDNRA Polymorphisms in Intracranial Aneurysm.Journal of Korean Neurosurgical Society · 2023Article
- Hypoxia-mediated regulation of DDX5 through decreased chromatin accessibility and post-translational targeting restricts R-loop accumulation.Molecular oncology · 2023Article
- DHX38 restricts chemoresistance by regulating the alternative pre-mRNA splicing of RELL2 in pancreatic ductal adenocarcinoma.PLoS genetics · 2023Article
- Poison cassette exon splicing of SRSF6 regulates nuclear speckle dispersal and the response to hypoxia.Nucleic acids research · 2023Article
- Unleashing the potential of catalytic RNAs to combat mis-spliced transcripts.Frontiers in bioengineering and biotechnology · 2023Review
- Oncogenic SRSF3 in health and diseases.International journal of biological sciences · 2023Review
- Chronic hypoxia is associated with transcriptomic reprogramming and increased genomic instability in cancer cells.Frontiers in cell and developmental biology · 2023Article
- Alternative splicing plays key roles in response to stress across different stages of fighting in the fish Betta splendens.BMC genomics · 2022Article
- Biological function and molecular mechanism of SRSF3 in cancer and beyond.Oncology letters · 2022Review
- Bisphenol A Exposure Changes the Transcriptomic and Proteomic Dynamics of Human Retinoblastoma Y79 Cells.Genes · 2021Article
- Vanishing white matter disease expression of truncated EIF2B5 activates induced stress response.eLife · 2020Article
- Alternative splicing in endothelial cells: novel therapeutic opportunities in cancer angiogenesis.Journal of experimental & clinical cancer research : CR · 2020Review
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Authors and funding
10 authors at 4 institutions in 2 countries.
Funding
Abstract
Cells adjust to hypoxic stress within the tumor microenvironment by downregulating energy-consuming processes including translation. To delineate mechanisms of cellular adaptation to hypoxia, we performed RNA-Seq of normoxic and hypoxic head and neck cancer cells. These data revealed a significant down regulation of genes known to regulate RNA processing and splicing. Exon-level analyses classified > 1,000 mRNAs as alternatively spliced under hypoxia and uncovered a unique retained intron (RI) in the master regulator of translation initiation, EIF2B5. Notably, this intron was expressed in solid tumors in a stage-dependent manner. We investigated the biological consequence of this RI and demonstrate that its inclusion creates a premature termination codon (PTC), that leads to a 65kDa truncated protein isoform that opposes full-length eIF2Bε to inhibit global translation. Furthermore, expression of 65kDa eIF2Bε led to increased survival of head and neck cancer cells under hypoxia, providing evidence that this isoform enables cells to adapt to conditions of low oxygen. Additional work to uncover -cis and -trans regulators of EIF2B5 splicing identified several factors that influence intron retention in EIF2B5: a weak splicing potential at the RI, hypoxia-induced expression and binding of the splicing factor SRSF3, and increased binding of total and phospho-Ser2 RNA polymerase II specifically at the intron retained under hypoxia. Altogether, these data reveal differential splicing as a previously uncharacterized mode of translational control under hypoxia and are supported by a model in which hypoxia-induced changes to cotranscriptional processing lead to selective retention of a PTC-containing intron in EIF2B5.
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