ArticleCell death and differentiation2011
Doxorubicin bypasses the cytoprotective effects of eIF2α phosphorylation and promotes PKR-mediated cell death.
Article in Cell death and differentiation, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
34 citing papers in PubMed, 52 citations in OpenAlex.
- The Integrated Stress Response Protein, eIF2α, Modulates UPRCardiovascular toxicology · 2026Article
- Targeting the epigenome and the integrated stress response to normalize colorectal cancer subclonal plasticity and progression.Cell death & disease · 2026Article
- PKR-Mediated Phosphorylation of eIF2a and CHK1 Is Associated with Doxorubicin-Mediated Apoptosis in HCC1143 Triple-Negative Breast Cancer Cells.International journal of molecular sciences · 2022Article
- PACT promotes the metastasis of basal-like breast cancer through Rac1 SUMOylation and activation.Oncogene · 2022Article
- Double stranded DNA breaks and genome editing trigger loss of ribosomal protein RPS27A.The FEBS journal · 2022Article
- Pediatric glioblastoma cells are sensitive to drugs that inhibit eIF2α dephosphorylation and its phosphomimetic S51D variant.Frontiers in oncology · 2022Article
- Article
- Review
- Perspective: Modulating the integrated stress response to slow aging and ameliorate age-related pathology.Nature aging · 2021Article
- Unfolded Protein Response in Leukemia: From Basic Understanding to Therapeutic Opportunities.Trends in cancer · 2020Review
- Article
- An integrated stress response via PKR suppresses HER2+ cancers and improves trastuzumab therapy.Nature communications · 2019Article
- Mechanism mediated by a noncoding RNA, nc886, in the cytotoxicity of a DNA-reactive compound.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- Bacterial Cytological Profiling Reveals the Mechanism of Action of Anticancer Metal Complexes.Molecular pharmaceutics · 2018Article
- GCN2 deficiency ameliorates doxorubicin-induced cardiotoxicity by decreasing cardiomyocyte apoptosis and myocardial oxidative stress.Redox biology · 2018Article
- Curcumin mitigates axonal injury and neuronal cell apoptosis through the PERK/Nrf2 signaling pathway following diffuse axonal injury.Neuroreport · 2018Article
- NDRG2 contributes to cisplatin sensitivity through modulation of BAK-to-Mcl-1 ratio.Cell death & disease · 2018Article
- PKR: A Kinase to Remember.Frontiers in molecular neuroscience · 2018Review
- Article
- Salubrinal-Mediated Upregulation of eIF2α Phosphorylation Increases Doxorubicin Sensitivity in MCF-7/ADR Cells.Molecules and cells · 2016Article
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The eukaryotic cell responds to various forms of environmental stress by adjusting the rates of mRNA translation thus facilitating adaptation to the assaulting stress. One of the major pathways that control protein synthesis involves the phosphorylation of the α-subunit of eukaryotic initiation factor eIF2 at serine 51. Different forms of DNA damage were shown to induce eIF2α phosphorylation by using PERK, GCN2 or PKR. However, the specificity of the eIF2α kinases and the biological role of eIF2α phosphorylation pathway in the DNA damage response (DDR) induced by chemotherapeutics are not known. Herein, we show that PKR is the eIF2α kinase that responds to DDR induced by doxorubicin. We show that activation of PKR integrates two signaling pathways with opposing biological outcomes. More specifically, induction of eIF2α phosphorylation has a cytoprotective role, whereas activation of c-jun N-terminal kinase (JNK) by PKR promotes cell death in response to doxorubicin. We further show that the proapoptotic effects of JNK activation prevail over the cytoprotection mediated by eIF2α phosphorylation. These findings reveal that PKR can be an important inducer of cell death in response to chemotherapies through its ability to act independently of eIF2α phosphorylation.
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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.