PMID- 32744097
OWN - NLM
STAT- MEDLINE
DCOM- 20201230
LR  - 20211204
IS  - 1522-1555 (Electronic)
IS  - 0193-1849 (Print)
IS  - 0193-1849 (Linking)
VI  - 319
IP  - 3
DP  - 2020 Sep 1
TI  - Hyperphosphorylation of fetal liver IGFBP-1 precedes slowing of fetal growth in 
      nutrient-restricted baboons and may be a mechanism underlying IUGR.
PG  - E614-E628
LID - 10.1152/ajpendo.00220.2020 [doi]
AB  - In cultured fetal liver cells, insulin-like growth factor (IGF) binding protein 
      (IGFBP)-1 hyperphosphorylation in response to hypoxia and amino acid deprivation 
      is mediated by inhibition of mechanistic target of rapamycin (mTOR) and 
      activation of amino acid response (AAR) signaling and casein kinase (CK)2. We 
      hypothesized that fetal liver mTOR inhibition, activation of AAR and CK2, and 
      IGFBP-1 hyperphosphorylation occur before development of intrauterine growth 
      restriction (IUGR). Pregnant baboons were fed a control (C) or a maternal 
      nutrient restriction (MNR; 70% calories of control) diet starting at gestational 
      day (GD) 30 (term GD 185). Umbilical blood and fetal liver tissue were obtained 
      at GD 120 (C, n = 7; MNR, n = 10) and 165 (C, n = 7; MNR, n = 8). Fetal weights 
      were unchanged at GD 120 but decreased at GD 165 in the MNR group (-13%, P = 
      0.03). IGFBP-1 phosphorylation, as determined by parallel reaction monitoring 
      mass spectrometry (PRM-MS), immunohistochemistry, and/or Western blot, was 
      enhanced in MNR fetal liver and umbilical plasma at GD 120 and 165. IGF-I 
      receptor autophosphorylation(Tyr1135) (-64%, P = 0.05) was reduced in MNR fetal 
      liver at GD 120. Furthermore, fetal liver CK2 (alpha/alpha'/beta) expression, CK2beta 
      colocalization, proximity with IGFBP-1, and CK2 autophosphorylation(Tyr182) were 
      greater at GD 120 and 165 in MNR vs. C. Additionally, mTOR complex (mTORC)1 
      (p-P70S6K(Thr389), -52%, P = 0.05) and mTORC2 (p-Akt(Ser473), -56%, P < 0.001) 
      activity were decreased and AAR was activated (p-GCN2(Thr898), +117%, P = 0.02; 
      p-eIF2alpha(Ser51), +294%, P = 0.002; p-ERK(Thr202), +111%, P = 0.03) in MNR liver at 
      GD 120. Our data suggest that fetal liver IGFBP-1 hyperphosphorylation, mediated 
      by mTOR inhibition and both AAR and CK2 activation, is a key link between 
      restricted nutrient and oxygen availability and the development of IUGR.
FAU - Kakadia, Jenica H
AU  - Kakadia JH
AD  - Department of Biochemistry, University of Western Ontario, London, Ontario, 
      Canada.
FAU - Jain, Bhawani B
AU  - Jain BB
AD  - Department of Biochemistry, University of Western Ontario, London, Ontario, 
      Canada.
FAU - Biggar, Kyle
AU  - Biggar K
AD  - Institute of Biochemistry, Carleton University, Ottawa, Ontario, Canada.
FAU - Sutherland, Austen
AU  - Sutherland A
AD  - Department of Biochemistry, University of Western Ontario, London, Ontario, 
      Canada.
FAU - Nygard, Karen
AU  - Nygard K
AD  - Biotron Integrated Microscopy Facility, University of Western Ontario, London, 
      Ontario, Canada.
FAU - Li, Cun
AU  - Li C
AD  - University of Wyoming, Laramie, Wyoming.
AD  - Southwest National Primate Research Center, San Antonio, Texas.
FAU - Nathanielsz, Peter W
AU  - Nathanielsz PW
AD  - University of Wyoming, Laramie, Wyoming.
AD  - Southwest National Primate Research Center, San Antonio, Texas.
FAU - Jansson, Thomas
AU  - Jansson T
AD  - Division of Reproductive Sciences, Department of Obstetrics and Gynecology, 
      University of Colorado Anschutz Medical Campus, Aurora, Colorado.
FAU - Gupta, Madhulika B
AU  - Gupta MB
AD  - Department of Biochemistry, University of Western Ontario, London, Ontario, 
      Canada.
AD  - Department of Pediatrics, University of Western Ontario, London, Ontario, Canada.
AD  - Children's Health Research Institute, London, Ontario, Canada.
LA  - eng
GR  - P01 HD021350/HD/NICHD NIH HHS/United States
GR  - R03HD078313/GF/NIH HHS/United States
GR  - R03HD093950/GF/NIH HHS/United States
GR  - R03 HD093950/HD/NICHD NIH HHS/United States
GR  - P51 OD011133/OD/NIH HHS/United States
GR  - R03 HD078313/HD/NICHD NIH HHS/United States
GR  - P01HD021350/GF/NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20200803
PL  - United States
TA  - Am J Physiol Endocrinol Metab
JT  - American journal of physiology. Endocrinology and metabolism
JID - 100901226
RN  - 0 (Amino Acids)
RN  - 0 (Insulin-Like Growth Factor Binding Protein 1)
RN  - EC 2.7.11.1 (Casein Kinase II)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Amino Acids/metabolism
MH  - Animals
MH  - Casein Kinase II/metabolism
MH  - Female
MH  - *Fetal Development
MH  - Fetal Growth Retardation/*metabolism
MH  - Food Deprivation
MH  - Gestational Age
MH  - Insulin-Like Growth Factor Binding Protein 1/*metabolism
MH  - Liver/embryology/*metabolism
MH  - Organ Size
MH  - *Papio
MH  - Phosphorylation
MH  - Placenta/metabolism
MH  - Pregnancy
MH  - TOR Serine-Threonine Kinases/metabolism
PMC - PMC7642856
OTO - NOTNLM
OT  - TOR serine-threonine kinases
OT  - casein kinase II
OT  - fetal insulin-like growth factor I
OT  - primates
COIS- No conflicts of interest, financial or otherwise, are declared by the authors.
EDAT- 2020/08/04 06:00
MHDA- 2020/12/31 06:00
PMCR- 2021/09/01
CRDT- 2020/08/04 06:00
PHST- 2020/08/04 06:00 [pubmed]
PHST- 2020/12/31 06:00 [medline]
PHST- 2020/08/04 06:00 [entrez]
PHST- 2021/09/01 00:00 [pmc-release]
AID - E-00220-2020 [pii]
AID - 10.1152/ajpendo.00220.2020 [doi]
PST - ppublish
SO  - Am J Physiol Endocrinol Metab. 2020 Sep 1;319(3):E614-E628. doi: 
      10.1152/ajpendo.00220.2020. Epub 2020 Aug 3.