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Brostrom CO, Prostko CR, Kaufman RJ, Brostrom MA: Inhibition of translational initiation by activators of the glucose-regulated stress protein and heat shock protein stress response systems. J Biol Chem. 1996 Oct 4;271(40):24995-5002.
Role of the interferon-inducible double-stranded RNA-activated eukaryotic initiation factor 2alpha kinase.. Depletion of endoplasmic reticulum (ER) Ca2+ perturbs protein folding and processing within the organelle while inhibiting translational initiation through activation of the double-stranded RNA-activated eukaryotic initiation factor (eIF)-2alpha 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 Ca2+ nor slowed peptide chain elongation. Various HSP-inducing chemicals caused rapid phosphorylation of eIF-2alpha. When incubated with double-stranded RNA, extracts derived from arsenite-treated cells displayed greater degrees of phosphorylation of PKR and eIF-2alpha than did control extracts. Cells overexpressing a dominant negative PKR mutation resisted translational inhibition and eIF-2alpha 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 Ca2+-mobilizing agents or arsenite. Following induction of the HSPs by arsenite, cells remained susceptible to induction of the GRPs by Ca2+-mobilizing agents. Conversely, cells possessing induced GRP contents in response to Ca2+-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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