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Inhibition of translational initiation by activators of the glucose-regulated stress protein and heat shock protein stress response systems. Role of the interferon-inducible double-stranded RNA-activated eukaryotic initiation factor 2alpha kinase



Inhibition of translational initiation by activators of the glucose-regulated stress protein and heat shock protein stress response systems. Role of the interferon-inducible double-stranded RNA-activated eukaryotic initiation factor 2alpha kinase



Journal of Biological Chemistry 271(40): 24995-25002



Depletion of endoplasmic reticulum (ER) Ca-2+ perturbs protein folding and processing within the organelle while inhibiting translational initiation through activation of the double-stranded RNA-activated eukaryotic initiation factor (eIF)-2-alpha kinase (PKR) (Prostko, C. R., Dholakia, J. N., Brostrom, M. A., and Brostrom, C. O. (1995) J. Biol. Chem. 270, 6211-6215). The glucose-regulated stress protein (GRP) chaperones are subsequently induced. We now report that sodium arsenite, a prototype for stressors fostering cytoplasmic protein misfolding, also inhibits translational initiation through activation of PKR while subsequently inducing the heat shock protein (HSP) chaperones. Arsenite neither mobilized ER-associated Ca-2+ nor slowed peptide chain elongation. Various HSP-inducing chemicals caused rapid phosphorylation of eIF-2-alpha. When incubated with double-stranded RNA, extracts derived from arsenite-treated cells displayed greater degrees of phosphorylation of PKR and eIF-2-alpha than did control extracts. Cells overexpressing a dominant negative PKR mutation resisted translational inhibition and eIF-2-alpha phosphorylation in response to ER or cytoplasmic stressors. Induction of either the HSP or GRP chaperones was accompanied by development of translational tolerance to either Ca-2+-mobilizing agents or arsenite. Following induction of the HSPs by arsenite, cells remained susceptible to induction of the GRPs by Ca-2+-mobilizing agents. Conversely, cells possessing induced GRP contents in response to Ca-2+-mobilizing agents readily induced the HSPs in response to arsenite. It is concluded that the two chaperone systems function independently except for their mutual suppression of PKR.

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Accession: 008881202

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PMID: 8798781



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