PMID- 24437487
OWN - NLM
STAT- MEDLINE
DCOM- 20140519
LR  - 20211203
IS  - 1945-7170 (Electronic)
IS  - 0013-7227 (Print)
IS  - 0013-7227 (Linking)
VI  - 155
IP  - 4
DP  - 2014 Apr
TI  - Liver mTOR controls IGF-I bioavailability by regulation of protein kinase CK2 and 
      IGFBP-1 phosphorylation in fetal growth restriction.
PG  - 1327-39
LID - 10.1210/en.2013-1759 [doi]
AB  - 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-restricted 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-restricted baboon fetus. mTOR signaling was markedly 
      inhibited, whereas expression and activity of CK2 was increased in 
      growth-restricted 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-induced 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.
FAU - Abu Shehab, Majida
AU  - Abu Shehab M
AD  - Departments of Pediatrics (M.A.S., M.B.G.) and Biochemistry (I.D., T.S., M.B.G.), 
      Children's Health Research Institute (M.B.G.), University of Western Ontario, 
      London, Ontario N6C 2V5, Canada; Center for Pregnancy and Newborn Research 
      (F.J.R., M.N., P.W.N., T.J.), Department of Obstetrics and Gynecology and 
      Department of Medicine (A.K.), University of Texas Health Science Center San 
      Antonio, Texas 78229; and Geriatric Research Education and Clinical Centers 
      (A.K.), South Texas Veterans Health Care System, San Antonio, Texas 78229.
FAU - Damerill, Ian
AU  - Damerill I
FAU - Shen, Tong
AU  - Shen T
FAU - Rosario, Fredrick J
AU  - Rosario FJ
FAU - Nijland, Mark
AU  - Nijland M
FAU - Nathanielsz, Peter W
AU  - Nathanielsz PW
FAU - Kamat, Amrita
AU  - Kamat A
FAU - Jansson, Thomas
AU  - Jansson T
FAU - Gupta, Madhulika B
AU  - Gupta MB
LA  - eng
GR  - P01 HD021350/HD/NICHD NIH HHS/United States
GR  - I01 BX001744/BX/BLRD VA/United States
GR  - R03 HD078313/HD/NICHD NIH HHS/United States
GR  - HD 21350/HD/NICHD NIH HHS/United States
GR  - P51 OD011133/OD/NIH HHS/United States
GR  - HD 078313/HD/NICHD NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20140117
PL  - United States
TA  - Endocrinology
JT  - Endocrinology
JID - 0375040
RN  - 0 (Insulin-Like Growth Factor Binding Protein 1)
RN  - 67763-96-6 (Insulin-Like Growth Factor I)
RN  - EC 2.7.10.1 (Receptor, IGF Type 1)
RN  - EC 2.7.11.1 (Casein Kinase II)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Animals
MH  - Casein Kinase II/*metabolism
MH  - Disease Models, Animal
MH  - Electrophoresis, Gel, Two-Dimensional
MH  - Enzyme-Linked Immunosorbent Assay/methods
MH  - Female
MH  - Fetal Growth Retardation/*etiology/metabolism
MH  - Gene Silencing
MH  - Hep G2 Cells
MH  - Hepatocytes/cytology
MH  - Humans
MH  - Insulin-Like Growth Factor Binding Protein 1/*metabolism
MH  - Insulin-Like Growth Factor I/*metabolism
MH  - Papio
MH  - Phosphorylation
MH  - Pregnancy
MH  - Pregnancy, Animal
MH  - RNA Interference
MH  - Receptor, IGF Type 1/metabolism
MH  - TOR Serine-Threonine Kinases/*metabolism
MH  - Transgenes
PMC - PMC3959599
EDAT- 2014/01/21 06:00
MHDA- 2014/05/20 06:00
PMCR- 2015/04/01
CRDT- 2014/01/21 06:00
PHST- 2014/01/21 06:00 [entrez]
PHST- 2014/01/21 06:00 [pubmed]
PHST- 2014/05/20 06:00 [medline]
PHST- 2015/04/01 00:00 [pmc-release]
AID - EN-13-1759 [pii]
AID - 10.1210/en.2013-1759 [doi]
PST - ppublish
SO  - Endocrinology. 2014 Apr;155(4):1327-39. doi: 10.1210/en.2013-1759. Epub 2014 Jan 
      17.