title: Oxytocin modulates markers of the unfolded protein response in Caco2BB gut cells.
abstract: We have shown that oxytocin receptor (OTR) expression in neonatal rat enterocytes is robust from birth to weaning, but OTR function during this period is unknown. We previously reported that oxytocin (OT) stimulation of Caco2BB cells (enterocytes in vitro) inhibits the mammalian target of rapamycin complex 1 (mTORC1) signaling. The unfolded protein response (UPR) is known to protectively reduce translation during endoplasmic reticulum (ER) stress. Because the mTORC1 pathway is linked to cellular stress, we investigated markers of UPR in OT-stimulated Caco2BB cells. We report that OT modulates several factors involved in sensing and translation of ER stress. High OT (62.5 nM) reduced translation initiation factor 4E-BP1 phosphorylation (Ser65), which is known to inhibit cap-dependent translation via its rate-limiting eukaryotic translation initiation factor 4E (eIF4E). Importantly, high OT increased phosphorylation of eukaryotic translation initiation factor 2a (eIF2a) phospho-Ser51, which inhibits eIF2a. High OT also increased protein kinase RNA-like endoplasmic reticulum kinase phosphorylation, a sensor of ER stress and a kinase of eIF2a. Both high and low OT activated inositol requiring enzyme1 (IRE1), which generates the transcription factor X-box binding protein 1 (XBP1) and induces the UPR. We also show that OT modulates XBP1 splicing and induces tribbles 3 (TRIB3; a negative regulator of Akt and protein involved in autophagy) and immunoglobulin binding protein (BiP; ER-chaperone). Taken together, these results indicate that OT modulates sensors of ER stress and autophagy. These findings support our hypothesis that transiently elevated OTR expression in neonatal gut may serve a protective function during a critical postnatal developmental period.
authors.affiliation: Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, NY, 10032, USA, bk2348@columbia.edu.
authors.forename: Benjamin Y
authors.initials: BY
authors.lastname: Klein
authors.forename: Hadassah
authors.initials: H
authors.lastname: Tamir
authors.forename: David L
authors.initials: DL
authors.lastname: Hirschberg
authors.forename: Sara B
authors.initials: SB
authors.lastname: Glickstein
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Ludwig
authors.forename: Martha G
authors.initials: MG
authors.lastname: Welch
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress; D020895:Enterocytes / Q000378:metabolism* / Q000473:pathology*; D047908:Intracellular Signaling Peptides and Proteins; D010121:Oxytocin / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D000071701:Regulatory Factor X Transcription Factors; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism; D056811:Unfolded Protein Response; D000071717:X-Box Binding Protein 1; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D010121:Oxytocin; D010750:Phosphoproteins; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; D019892:eIF-2 Kinase; C499526:Eif4ebp1 protein, rat; C000605545:Xbp1 protein, rat