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

• 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
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.94.7.3279

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.