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 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 (Pkr(0/0) mice) were resistant to apoptotic cell death in response to double-stranded RNA, tumor necrosis factor-alpha, or lipopolysaccharide. The mechanism underlying the suppression of apoptosis in the Pkr(0/0) cells 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.
Der
S D
SD
Department of Cancer Biology, Research Institute, The Cleveland Clinic Foundation, Ohio 44195, USA.
Yang
Y L
YL
Weissmann
C
C
Williams
B R
BR
D000818:Animals; D017209:Apoptosis; D004268:DNA-Binding Proteins / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D050856:Interferon Regulatory Factor-1; D051379:Mice; D018345:Mice, Knockout; D010750:Phosphoproteins / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D012330:RNA, Double-Stranded / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013312:Stress, Physiological / Q000378:metabolism / Q000473:pathology*; D019892:eIF-2 Kinase; D019014:fas Receptor / Q000235:genetics
D004268:DNA-Binding Proteins; C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1; C494258:Irf1 protein, mouse; D010750:Phosphoproteins; D012330:RNA, Double-Stranded; D012333:RNA, Messenger; D019014:fas Receptor; D017346:Protein Serine-Threonine Kinases; D019892:eIF-2 Kinase