{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T16:33:08Z","timestamp":1789749188511,"version":"4.0.1"},"reference-count":39,"publisher":"The Endocrine Society","issue":"4","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,4,1]]},"abstract":"<jats:p>Fetal growth restriction (FGR) increases the risk for perinatal complications and predisposes the infant to diabetes and cardiovascular disease later in life. No treatment for FGR is available, and the underlying pathophysiology remains poorly understood. Increased IGFBP-1 phosphorylation has been implicated as an important mechanism by which fetal growth is reduced. However, to what extent circulating IGFBP-1 is phosphorylated in FGR is unknown, and the molecular mechanisms linking FGR to IGFBP-1 phosphorylation have not been established. We used umbilical cord plasma of appropriate for gestational age (AGA) and growth\u2013restricted human fetuses and determined IGFBP-1 and IGF-I concentrations (ELISA) and site-specific IGFBP-1 phosphorylation (Western blotting using IGFBP-1 phospho-site specific antibodies). In addition, we used a baboon model of FGR produced by 30% maternal nutrient restriction and determined mammalian target of rapamycin (mTOR)C1 activity, CK2 expression\/activity, IGFBP-1 expression and phosphorylation, and IGF-I levels in baboon fetal liver by Western blot, enzymatic assay, and ELISA. HepG2 cells and primary fetal baboon hepatocytes were used to explore mechanistic links between mTORC1 signaling and IGFBP-1 phosphorylation. IGFBP-1 was hyperphosphorylated at Ser101, Ser119, and Ser169 in umbilical plasma of human FGR fetuses. IGFBP-1 was also hyperphosphorylated at Ser101, Ser119, and Ser169 in the liver of growth\u2013restricted baboon fetus. mTOR signaling was markedly inhibited, whereas expression and activity of CK2 was increased in growth\u2013restricted baboon fetal liver in vivo. Using HepG2 cells and primary fetal baboon hepatocytes, we established a mechanistic link between mTOR inhibition, CK2 activation, IGFBP-1 hyperphosphorylation, and decreased IGF-I\u2013induced IGF-I receptor autophosphorylation. We provide clear evidence for IGFBP-1 hyperphosphorylation in FGR and identified an mTOR and CK2-mediated mechanism for regulation of IGF-I bioavailability. Our findings are consistent with the model that inhibition of mTOR in the fetal liver, resulting in increased CK2 activity and IGFBP-1 hyperphosphorylation, constitutes a novel mechanistic link between nutrient deprivation and restricted fetal growth.<\/jats:p>","DOI":"10.1210\/en.2013-1759","type":"journal-article","created":{"date-parts":[[2014,1,17]],"date-time":"2014-01-17T12:49:44Z","timestamp":1389962984000},"page":"1327-1339","source":"Crossref","is-referenced-by-count":38,"title":["Liver mTOR Controls IGF-I Bioavailability by Regulation of Protein Kinase CK2 and IGFBP-1 Phosphorylation in Fetal Growth Restriction"],"prefix":"10.1210","volume":"155","author":[{"given":"Majida","family":"Abu Shehab","sequence":"first","affiliation":[{"name":"Departments of Pediatrics (M.A.S., M.B.G.) University of Western Ontario, London, Ontario N6C 2V5, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian","family":"Damerill","sequence":"first","affiliation":[{"name":"Departments of Biochemistry (I.D., T.S., M.B.G.), University of Western Ontario, London, Ontario N6C 2V5, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tong","family":"Shen","sequence":"first","affiliation":[{"name":"Departments of Biochemistry (I.D., T.S., M.B.G.), University of Western Ontario, London, Ontario N6C 2V5, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fredrick J.","family":"Rosario","sequence":"first","affiliation":[{"name":"Center for Pregnancy and Newborn Research (F.J.R., M.N., P.W.N., T.J.), University of Texas Health Science Center San Antonio, Texas 78229"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Nijland","sequence":"first","affiliation":[{"name":"Center for Pregnancy and Newborn Research (F.J.R., M.N., P.W.N., T.J.), University of Texas Health Science Center San Antonio, Texas 78229"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter W.","family":"Nathanielsz","sequence":"first","affiliation":[{"name":"Center for Pregnancy and Newborn Research (F.J.R., M.N., P.W.N., T.J.), University of Texas Health Science Center San Antonio, Texas 78229"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amrita","family":"Kamat","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology and Department of Medicine (A.K.), University of Texas Health Science Center San Antonio, Texas 78229"},{"name":"Geriatric Research Education and Clinical Centers (A.K.), South Texas Veterans Health Care System, San Antonio, Texas 78229"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Jansson","sequence":"first","affiliation":[{"name":"Center for Pregnancy and Newborn Research (F.J.R., M.N., P.W.N., T.J.), University of Texas Health Science Center San Antonio, Texas 78229"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madhulika B.","family":"Gupta","sequence":"first","affiliation":[{"name":"Departments of Pediatrics (M.A.S., M.B.G.) 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