{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T01:20:57Z","timestamp":1788916857369,"version":"build-2803163510"},"reference-count":64,"publisher":"The Endocrine Society","issue":"2","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2016,2,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>In fetal growth restriction (FGR), fetal growth is limited by reduced nutrient and oxygen supply. Insulin-like growth factor I (IGF-I) is a key regulator of fetal growth and IGF binding protein -1(IGFBP-1) is the principal regulator of fetal IGF-I bioavailability. Phosphorylation enhances IGFBP-1's affinity for IGF-I. Hypoxia induces IGFBP-1 hyperphosphorylation, markedly decreasing IGF-I bioavailability. We recently reported that fetal liver IGFBP-1 hyperphosphorylation is associated with inhibition of the mechanistic target of rapamycin (mTOR) in a nonhuman primate model of FGR. Here, we test the hypothesis that IGFBP-1 hyperphosphorylation in response to hypoxia is mediated by mTOR inhibition. We inhibited mTOR either by rapamycin or small interfering RNA (siRNA) targeting raptor (mTOR complex [mTORC]1) and\/or rictor (mTORC2) in HepG2 cells cultured under hypoxia (1% O2) or basal (20% O2) conditions. Conversely, we activated mTORC1 or mTORC1+mTORC2 by silencing endogenous mTOR inhibitors (tuberous sclerosis complex 2\/DEP-domain-containing and mTOR-interacting protein). Immunoblot analysis demonstrated that both hypoxia and inhibition of mTORC1 and\/or mTORC2 induced similar degrees of IGFBP-1 phosphorylation at Ser101\/119\/169 and reduced IGF-I receptor autophosphorylation. Activation of mTORC1+mTORC2 or mTORC1 alone prevented IGFBP-1 hyperphosphorylation in response to hypoxia. Multiple reaction monitoring-mass spectrometry showed that rapamycin and\/or hypoxia increased phosphorylation also at Ser98 and at a novel site Ser174. In silico structural analysis indicated that Ser174 was in close proximity to the IGF-binding site. Together, we demonstrate that signaling through the mTORC1 or mTORC2 pathway is sufficient to induce IGFBP-1 hyperphosphorylation in response to hypoxia. This study provides novel understanding of the cellular mechanism that controls fetal IGFBP-1 phosphorylation in hypoxia, and we propose that mTOR inhibition constitutes a mechanistic link between hypoxia, reduced IGF-I bioavailability and FGR.<\/jats:p>","DOI":"10.1210\/me.2015-1194","type":"journal-article","created":{"date-parts":[[2015,12,29]],"date-time":"2015-12-29T18:00:20Z","timestamp":1451412020000},"page":"201-216","source":"Crossref","is-referenced-by-count":24,"title":["Hypoxia Increases IGFBP-1 Phosphorylation Mediated by mTOR Inhibition"],"prefix":"10.1210","volume":"30","author":[{"given":"Ian","family":"Damerill","sequence":"first","affiliation":[{"name":"Department of Biochemistry (I.D., K.K.B., S.S.-C.L., M.B.G.), University of Western Ontario, London, Ontario, N6C 2V5 Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyle K.","family":"Biggar","sequence":"first","affiliation":[{"name":"Department of Biochemistry (I.D., K.K.B., S.S.-C.L., M.B.G.), University of Western Ontario, London, Ontario, N6C 2V5 Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Majida","family":"Abu Shehab","sequence":"first","affiliation":[{"name":"Department of Biochemistry (I.D., K.K.B., S.S.-C.L., M.B.G.), University of Western Ontario, London, Ontario, N6C 2V5 Canada"},{"name":"Children's Health Research Institute (M.A.S., M.B.G.), University of Western Ontario, London, Ontario, N6C 2V5 Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shawn Shun-Cheng","family":"Li","sequence":"first","affiliation":[{"name":"Department of Biochemistry (I.D., K.K.B., S.S.-C.L., M.B.G.), University of Western Ontario, London, Ontario, N6C 2V5 Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Jansson","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology (T.J.), University of Colorado Anschutz Medical Campus, Aurora, Colorado 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