Essential Role of PACT-Mediated PKR Activation in Tunicamycin-Induced Apoptosis |
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Authors: | Madhurima Singh Indhira Handy Rekha C Patel |
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Institution: | 1 Department of Biological Sciences, University of South Carolina, 700 Sumter Street, Columbia, SC 29208, USA 2 Department of Cell, Developmental Biology and Anatomy, University of South Carolina, Columbia, SC 29208, USA |
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Abstract: | Cellular stresses such as disruption of calcium homeostasis, inhibition of protein glycosylation, and reduction of disulfide bonds result in accumulation of misfolded proteins in the endoplasmic reticulum (ER) and lead to cell death by apoptosis. Tunicamycin, which is an inhibitor of protein glycosylation, induces ER stress and apoptosis. In this study, we examined the involvement of double-stranded RNA (dsRNA)-activated protein kinase (PKR) and its protein activator PACT in tunicamycin-induced apoptosis. We demonstrate for the first time that PACT is phosphorylated in response to tunicamycin and is responsible for PKR activation by direct interaction. Furthermore, PACT-induced PKR activation is essential for tunicamycin-induced apoptosis, since PACT as well as PKR null cells are markedly resistant to tunicamycin and show defective eIF2α phosphorylation and C/EBP homologous protein (CHOP, also known as GADD153) induction especially at low concentrations of tunicamycin. Reconstitution of PKR and PACT expression in the null cells renders them sensitive to tunicamycin, thus demonstrating that PACT-induced PKR activation plays an essential function in induction of apoptosis. |
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Keywords: | ER endoplasmic reticulum dsRNA double-stranded RNA dsRBMs dsRNA-binding motifs CHOP C/EBP homologous protein MEFs mouse embryonic fibroblasts GRP glucose-regulated protein PKR dsRNA-activated protein kinase wt wild type EGFP enhanced green fluorescent protein PERK PKR-like ER resident kinase eIF2α α subunit of eukaryotic initiation factor 2 GCN-2 general control nonderepressible-2 DMEM Dulbecco's modified Eagle's medium |
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