PMID- 17947356 OWN - NLM STAT- MEDLINE DCOM- 20080226 LR - 20220309 IS - 0013-7227 (Print) IS - 0013-7227 (Linking) VI - 149 IP - 1 DP - 2008 Jan TI - Oxytocin-induced activation of eukaryotic elongation factor 2 in myometrial cells is mediated by protein kinase C. PG - 131-8 AB - The nonapeptide oxytocin (OT) mediates a wide spectrum of biological action, many of them related to reproduction. Recently, we have shown that OT exerts a trophic effect on uterine smooth muscle cells and induces dephosphorylation, and thus activation, of the translation elongation factor eukaryotic elongation factor 2 (eEF2). The present study was designed to elucidate the mechanisms underlying this novel action of OT in the well-characterized human myometrial cell line hTERT-C3. Pathways known to induce eEF2 dephosphorylation are mammalian target of rapamycin (mTOR), and the MAPKs ERK1/2 and p38. Using a panel of chemical inhibitors of specific signaling pathways, we determined that none of these pathways played a role in OT-mediated eEF2 dephosphorylation. Because the OT receptor is a G protein-coupled receptor linked to Galphaq, we tested the possibility that this OT action was mediated via protein kinase C (PKC). PKC activity was blocked by application of the general PKC chemical inhibitor Go6983 or by incubation with the cell-permeable PKC inhibitor peptide myr-psi PKC. With either approach, the effect of OT on eEF2 dephosphorylation was suppressed, indicating that the PKC pathway is essential for this OT action. Consistent with this idea, we also found that direct stimulation of PKC with the phorbol ester phorbol 12-myristate 13-acetate induced eEF2 dephosphorylation. Moreover, we observed that the stimulatory effect of OT on [(35)S]methionine incorporation into nascent proteins was blocked by PKC inhibition. Overall, these results define a novel hormonal signaling pathway that leads to eEF2 dephosphorylation and activation of protein synthesis. FAU - Devost, Dominic AU - Devost D AD - Department of Pharmacology & Therapeutics, McGill University, 3655 Promenade Sir-William-Osler, Montreal, Quebec, Canada H3G 1Y6. FAU - Carrier, Marie-Eve AU - Carrier ME FAU - Zingg, Hans H AU - Zingg HH LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20071018 PL - United States TA - Endocrinology JT - Endocrinology JID - 0375040 RN - 0 (Eukaryotic Initiation Factor-2) RN - 0 (Protein Kinase Inhibitors) RN - 50-56-6 (Oxytocin) RN - EC 2.7.- (Protein Kinases) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 2.7.11.13 (Protein Kinase C) RN - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 1) RN - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 3) RN - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases) SB - IM MH - Cells, Cultured MH - Eukaryotic Initiation Factor-2/*metabolism MH - Female MH - Humans MH - Mitogen-Activated Protein Kinase 1/metabolism MH - Mitogen-Activated Protein Kinase 3/metabolism MH - Models, Biological MH - Myometrium/*drug effects/metabolism MH - Oxytocin/*pharmacology MH - Phosphorylation/drug effects MH - Protein Biosynthesis/drug effects MH - Protein Kinase C/antagonists & inhibitors/metabolism/*physiology MH - Protein Kinase Inhibitors/pharmacology MH - Protein Kinases/metabolism MH - Signal Transduction/drug effects MH - TOR Serine-Threonine Kinases MH - p38 Mitogen-Activated Protein Kinases/metabolism EDAT- 2007/10/20 09:00 MHDA- 2008/02/27 09:00 CRDT- 2007/10/20 09:00 PHST- 2007/10/20 09:00 [pubmed] PHST- 2008/02/27 09:00 [medline] PHST- 2007/10/20 09:00 [entrez] AID - en.2007-0548 [pii] AID - 10.1210/en.2007-0548 [doi] PST - ppublish SO - Endocrinology. 2008 Jan;149(1):131-8. doi: 10.1210/en.2007-0548. Epub 2007 Oct 18.