A Double-Stranded RNA-Activated Protein Kinase-Dependent Pathway Mediating Stress-Induced Apoptosis

Apoptosis occurs in response to different cellular stresses, including viral infection, inflammatory cytokines, growth factor deprivation, and UV light, but it is unclear whether these inducers share a common mechanism of induction. The interferon-induced, double-stranded RNA-activated protein kinas...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 1997-04, Vol.94 (7), p.3279-3283
Main Authors: Der, Sandy D., Yang, Yi-Li, Weissmann, Charles, Bryan R. G. Williams
Format: Article
Language:English
Subjects:
Actinomycin
Animals
Apoptosis
Biological Sciences
Cell death
Cell lines
Cells
DNA-Binding Proteins - metabolism
Double stranded RNA
eIF-2 Kinase
fas Receptor - genetics
Fibroblasts
Gene expression regulation
Genetics
HeLa Cells
Humans
Interferon Regulatory Factor-1
Messenger RNA
Mice
Mice, Knockout
Phosphoproteins - metabolism
Phosphorylation
Protein-Serine-Threonine Kinases - metabolism
Proteins
Ribonucleic acid
RNA
RNA, Double-Stranded - metabolism
RNA, Messenger - genetics
RNA, Messenger - metabolism
Stress, Physiological - metabolism
Stress, Physiological - pathology
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Summary:Apoptosis occurs in response to different cellular stresses, including viral infection, inflammatory cytokines, growth factor deprivation, and UV light, but it is unclear whether these inducers share a common mechanism of induction. The interferon-induced, double-stranded RNA-activated protein kinase (PKR) has been implicated in processes that rely on apoptosis as control mechanisms in vivo, including antiviral activities, cell growth regulation, and tumorigenesis. Here we report that mouse embryo fibroblasts from mutant mice containing homozygous deletions in the PKR gene (Pkro/omice) were resistant to apoptotic cell death in response to double-stranded RNA, tumor necrosis factor-α , or lipopolysaccharide. The mechanism underlying the suppression of apoptosis in the Pkro/ocells could be attributed to defects in the activation of DNA-binding activity for the transcription factor interferon regulatory factor-1 and in Fas mRNA induction. Thus, these results provide genetic evidence implicating a requirement for PKR in mediating different forms of stress-related apoptosis.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.94.7.3279