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Reversible phosphorylation of eukaryotic initiation factor 2α in response to endoplasmic reticular signaling (1993)

Prostko, Christopher R. ; Brostrom, Margaret A. ; Brostrom, Charles O.

Springer

Molecular and cellular biochemistry 127-128 (1993), S. 255-265

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ISSN: 1573-4919

Keywords: eIF-2 phosphorylation ; eIF-2B activity ; endoplasmic reticulum ; sequestered Ca2+ ; translational initiation ; protein translocation and processing

Source: Springer Online Journal Archives 1860-2000

Topics: Biology , Chemistry and Pharmacology , Medicine

Notes: Abstract Agents, such as EGTA, thapsigargin, and ionophore A23187, that mobilize sequestered Ca2+ from the endoplasmic reticulum (ER) or dithiothreitol (DTT) that compromises the oxidizing environment of the organelle, disrupt early protein processing and inhibit translational initiation. Increased phosphorylation of eIF-2α (5-fold) and inhibition of eIF-2B activity (50%) occur in intact GH3 cells exposed to these agents for 15 min (Prostkoet al. J. Biol. Chem. 267: 16751–16754, 1992). Alterations in eIF-2α phosphorylation and translational activity in response to EGTA were reversed by addition of Ca2+ in excess of chelator while responses to DTT were reversible by washing. Exposure for 3 h to either A23187 or DTT, previously shown to induce transcription-dependent translational recovery, resulted in dephosphorylation of eIF-2α in a manner blocked by antinomycin D. Phosphorylation of eIF-2α in response to A23187 or DTT was not prevented by conventional inhibitors of translation including cycloheximide, pactamycin, puromycin, or verrucarin. Prolonged inhibition of protein synthesis to deplete the ER of substrates for protein processing resulted in increased eIF-2α phosphorylation, decreased eIF-2B activity, and reduced monosome content that were indicative of time-dependent blockade; these inhibitors did not abolish polysomal content. Superphosphorylation of eIF-2α occurred upon exposure of these preparations to either A23187 or DTT. Tunicamycin, an inhibitor of co-translational transfer of core oligosaccharide, provoked rapid phosphorylation of eIF-2α and inhibition of translational initiation whereas sugar analog inhibitors of glycoprotein processing did neither. A flow of processible protein to the ER does not appear to be required for the phosphorylation of eIF-2α in response to ER perturbants. We hypothesize that perturbation of the translocon, rather than suppression of protein processing, initiates the signal emanating from the ER culminating in eIF-2α phosphorylation and translational repression.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1007/BF01076776

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Ca2+ and hormones interact synergistically to stimulate rapidly both prolactin production and overall protein synthesis in pituitary tumor cells (1984)

Brostrom, Margaret A. ; Brostrom, Charles O. ; Bocckino, Stephen B. ; [et al.]

New York, NY [u.a.] : Wiley-Blackwell

Journal of Cellular Physiology 121 (1984), S. 391-401

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ISSN: 0021-9541

Keywords: Life and Medical Sciences ; Cell & Developmental Biology

Source: Wiley InterScience Backfile Collection 1832-2000

Topics: Biology , Medicine

Notes: Effects of Ca2+ and hormones on short-term protein synthesis were examined utilizing intact Ca2+-depleted and Ca2+-restored GH3 pituitary tumor cells as a model system. Amino acid incorporation by cells in complete growth medium during short incubations was markedly reduced by EGTA concentrations in excess of Ca2+. Thyrotropin-releasing hormone (TRH) rapidly enhanced amino acid incorporation and prolactin production, with both effects being reserved by EGTA in excess of extracellular Ca2+ or prevented by cellular Ca2+ depletion. Epidermal growth factor and phorbol myristate acetate (PMA) also stimulated amino acid incorporation and prolactin production; absolute increases in protein synthesis provided by these agents were significantly greater in Ca2+-restored than in Ca2+-depleted preparations. TRH and PMA concentrations which raised prolactin production were identical to those increasing the rate of amino acid incorporation into overall protein. The extracellular Ca2+ concentration dependencies of amino acid incorporation and prolactin production were similar and were unchanged by hormone. PMA, the most efficacious of the agents tested, and Ca2+ promoted incorporation of amino acid into the same spectrum of proteins. Stimulation of protein synthesis by hormones was not attributable to alterations in amino acid uptake, attachment to substrata, hormone binding, protein catabolism or transcription. Trifluoperazine selectively prevented the stimulation by Ca2+ of amino acid incorporation and prolactin production. Unlike total prolactin, the total protein content of GH3 cells during these short incubations was not altered by Ca2+, hormones or trifluoperazine. It is proposed that hormones and Ca2+, which have been demonstrated to regulate prolactin secretion and prolactin mRNA transcription in GH3 cells, also exert translational controls which serve to facilitate the overall expression of the prolactin gene.

Additional Material: 5 Ill.