Inhibition of Translational Initiation by Activators of the Glucose-regulated Stress Protein and Heat Shock Protein Stress Response Systems

Abstract

Depletion of endoplasmic reticulum (ER) Ca

Regulation of Protein Synthesis in Ventricular Myocytes by Vasopressin

“…Phosphorylation of this initiation factor correlated closely with hormonal inhibitions of protein synthesis under all experimental conditions tested. As has been observed invariably with agents that inhibit translational initiation by mobilizing ER Ca 2ϩ stores (1,4,5,7,8,17), protein synthesis in cells expressing increased concentrations of ER chaperones was tolerant to inhibition by vasopressin. The mechanism through which vasopressin caused Ca 2ϩ stores of H9c2 cells to be mobilized was not explored.…”

“…Inhibition of the translational process in H9c2 cells by treatment with vasopressin involved imposition of the same mechanisms as those exerted by ionomycin, which destroys intracellular Ca 2ϩ gradients, and thapsigargin, which blocks the Ca 2ϩ -ATPase of the S(E)R. Vasopressin, like ionomycin and thapsigargin (1)(2)(3)(4)(5)(6)(7)17), slowed translation at the initiation step and caused eIF2␣ to become phosphorylated. Phosphorylation of this initiation factor correlated closely with hormonal inhibitions of protein synthesis under all experimental conditions tested.…”

“…An adaptive response, characterized by translational accommodation to continued depletion of ER Ca 2ϩ stores by drugs such as ionomycin or thapsigargin or to the continued presence of a thiol-reducing agent, occurs over several hours. This adaptive response is dependent on increased expression of the ER resident chaperone, GRP78/BiP (1,4,7,8). Inductions of this chaperone and of recovery from translational inhibition depend on activation of grp78 transcription and, in some cell types, a growth-promoting factor.…”

“…This control involves coupling of the rates of mRNA translation to those of protein translocation into the organelle for subsequent processing or folding. Depletion of ER sequestered Ca 2ϩ to slow glycoprotein processing and transport competence, or introduction of a reducing environment to suppress ER processing of proteins with disulfide cross-links, results in the activation of the double-stranded RNA-activated protein kinase, the phosphorylation of eIF2␣, the inhibition of eIF2B, and the slowing of translational initiation (2)(3)(4)(5)(6)). An adaptive response, characterized by translational accommodation to continued depletion of ER Ca 2ϩ stores by drugs such as ionomycin or thapsigargin or to the continued presence of a thiol-reducing agent, occurs over several hours.…”

Phosphorylation of Eukaryotic Translation Initiation Factor 2 Mediates Apoptosis in Response to Activation of the Double-stranded RNA-dependent Protein Kinase

“…PKR activation was also previously demonstrated to occur in response to stress conditions, such as activation of the heat shock response, presence of unfolded protein in the endoplasmic reticulum, growth factor depletion, and increases in cytosolic calcium (23,(41)(42)(43). All of these stress responses are frequently accompanied by apoptosis.…”