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A double-stranded RNA-activated protein kinase-dependent pathway mediating stress-induced apoptosis
S D Der1, Y L Yang, C Weissmann
1Department of Cancer Biology, Research Institute, The Cleveland Clinic Foundation, Ohio 44195, USA.
Abstract:
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.
Insights
The interferon-induced, double-stranded RNA-activated protein kinase (PKR) is crucial for stress-induced apoptosis. Mutant mice lacking PKR resist cell death from various stressors, revealing PKR
Area of Science:
- Cellular Biology
- Molecular Biology
- Immunology
Background:
- Apoptosis, or programmed cell death, is a critical cellular process responding to various stresses.
- The precise common mechanisms underlying stress-induced apoptosis are not fully understood.
- The double-stranded RNA-activated protein kinase (PKR) is known to be involved in antiviral responses and cell growth regulation.
Purpose of the Study:
- To investigate the role of PKR in mediating apoptosis induced by diverse cellular stresses.
- To determine if PKR is a common mediator for different apoptosis-inducing stimuli.
Main Methods:
- Utilized gene-targeted mutant mice with homozygous deletions in the PKR gene (Pkr(0/0) mice).
- Assessed apoptotic cell death in mouse embryo fibroblasts (MEFs) from Pkr(0/0) mice.
- Analyzed the activation of transcription factor interferon regulatory factor-1 (IRF-1) and Fas mRNA induction.
Main Results:
- Pkr(0/0) MEFs exhibited resistance to apoptosis induced by double-stranded RNA, tumor necrosis factor-alpha, and lipopolysaccharide.
- Apoptosis suppression in Pkr(0/0) cells was linked to impaired IRF-1 DNA-binding activity.
- Defects in Fas mRNA induction were observed in the absence of PKR.
Conclusions:
- PKR is genetically required for mediating apoptosis in response to multiple stress-related stimuli.
- PKR acts as a central mediator in diverse pathways leading to stress-induced cell death.
- These findings highlight PKR's significant role in cellular stress responses and apoptosis regulation.