Sd. Der et al., A DOUBLE-STRANDED RNA-ACTIVATED PROTEIN KINASE-DEPENDENT PATHWAY MEDIATING STRESS-INDUCED APOPTOSIS, Proceedings of the National Academy of Sciences of the United Statesof America, 94(7), 1997, pp. 3279-3283
Apoptosis occurs in response to different cellular stresses, including
viral infection, inflammatory cytokines, growth factor deprivation, a
nd UV light, but it Is unclear whether these inducers share a common m
echanism of induction, The interferon-induced, double-stranded RNA-act
ivated protein kinase (PKR) has been implicated in processes that rely
on apoptosis as control mechanisms in vivo, including antiviral activ
ities, cell growth regulation, and tumorigenesis. Here we report that
mouse embryo fibroblasts from mutant mice containing homozygous deleti
ons in the PKR gene (Pkr(o/o) mice) were resistant to apoptotic cell d
eath in response to double-stranded RNA, tumor necrosis factor-alpha,
or lipopolysaccharide, The mechanism underlying the suppression of apo
ptosis in the Pkr(o/o) cells could be attributed to defects in the act
ivation of DNA-binding activity for the transcription factor interfero
n regulatory factor-1 and in Fas mRNA Induction, Thus, these results p
rovide genetic evidence implicating a requirement for PKR In mediating
different forms of stress-related apoptosis.