Induction of Apoptosis by Double-Stranded-RNA-Dependent Protein Kinase (PKR) Involves the α Subunit of Eukaryotic Translation Initiation Factor 2 and NF-κB
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The double-stranded (ds) RNA-dependent protein kinase (PKR) is a key mediator of antiviral effects of interferon (IFN) and an active player in apoptosis induced by different stimuli. The translation initiation factor eIF-2alpha (alpha subunit of eukaryotic translation initiation factor 2) and IkappaBalpha, the inhibitor of the transcription factor NF-kappaB, have been proposed as downstream mediators of PKR effects. To evaluate the involvement of NF-kappaB and eIF-2alpha in the induction of apoptosis by PKR, we have used vaccinia virus (VV) recombinants that inducibly express PKR concomitantly with a dominant negative mutant of eIF-2alpha or a repressor form of IkappaBalpha. We found that while expression of PKR by a VV vector resulted in extensive inhibition of protein synthesis and induction of apoptosis, coexpression of PKR with a dominant negative mutant of eIF-2alpha (Ser-51-->Ala) reversed both the PKR-mediated translational block and PKR-induced apoptosis. Coexpression of PKR with a repressor form of IkappaBalpha (Ser-32, 36-Ala) also leads to the inhibition of apoptosis by abolishing NF-kappaB induction, while translation remains blocked. Treating cells with two different proteasome inhibitors which block IkappaBalpha degradation, prevented PKR-induced apoptosis, supporting results from coexpression studies. Biochemical analysis and transient assays revealed that PKR expression by a VV vector induced NF-kappaB binding and transactivation. In addition, upregulation of…
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In virus-infected cells, NF-κB and ATF-3 activation by PKR is involved in apoptosis induction.
“NF-kB and ATF-3 activation by PKR is also involved in apoptosis induction as shown in virus-infected cells [69, 174–176].”
From PKR, the double stranded RNA‐dependent protein kinase as a critical target in Alzheimer's disease (2009) · cites this paper as [174]
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Antiviral Actions of Interferons
Samuel, C. E. (2001) · Clinical Microbiology Reviews · doi:10.1128/cmr.14.4.778-809.2001 · Cited by 2,743 · see citing works
The dsRNA protein kinase PKR: Virus and cell control
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PKR, the double stranded RNA‐dependent protein kinase as a critical target in Alzheimer's disease
Morel, M., Couturier, J., Lafay‐Chebassier, C., Paccalin, M., & Page, G. (2009) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2009.00849.x · Cited by 47 · see citing works
- Authors
- Gil, J., Alcamí, J., & Esteban, M.
- Affiliations
- Consejo Superior de Investigaciones Científicas (ES)
- Centro de Investigación, Hospital 12 de Octubre, Carretera de Andalucía 5.400, 28041 Madrid, Spain
- Department of Molecular and Cellular Biology, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas, Campus Universidad Autónoma, 28049 Madrid
- ORCID
- Gil, Jesús
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 1999-07-01
- Volume
- 19
- Issue
- 7
- Pages
- 4653-4663
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC84263
- OpenAlex
- W2147814046
- Cited by
- 199
- References
- 3
- Citations by year
- 2026: 3 · 2025: 1 · 2024: 2 · 2023: 4 · 2022: 3 · 2021: 5 · 2020: 4 · 2019: 2 · 2018: 8 · 2017: 6 · 2016: 6 · 2015: 6 · 2014: 1 · 2013: 5 · 2012: 5
- FWCI
- 6.34
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Molecular and Cellular Biology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Keywords
- PKR, double-stranded RNA-dependent protein kinase, apoptosis, eIF2α, NF-κB, IκBα, vaccinia virus, dominant-negative mutant, proteasome inhibitors, Fas, protein synthesis inhibition
- MeSH terms
- NF-KappaB Inhibitor alpha, Animals, Binding Sites, Chlorocebus aethiops, Cysteine Endopeptidases, DNA-Binding Proteins, Eukaryotic Cells, Genetic Vectors, HeLa Cells, Humans, Multienzyme Complexes, Phosphorylation, RNA, Double-Stranded, Serine, Protein Biosynthesis, Vaccinia virus, Transcriptional Activation, Eukaryotic Initiation Factor-2, Gene Expression, NF-kappa B, 3T3 Cells, Apoptosis, eIF-2 Kinase, I-kappa B Proteins, Proteasome Endopeptidase Complex, Mice
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