PMID- 32502935
OWN - NLM
STAT- MEDLINE
DCOM- 20210527
LR  - 20211204
IS  - 1872-8057 (Electronic)
IS  - 0303-7207 (Linking)
VI  - 512
DP  - 2020 Jul 15
TI  - Inhibition of decidual IGF-1 signaling in response to hypoxia and leucine 
      deprivation is mediated by mTOR and AAR pathways and increased IGFBP-1 
      phosphorylation.
PG  - 110865
LID - S0303-7207(20)30165-9 [pii]
LID - 10.1016/j.mce.2020.110865 [doi]
AB  - Decidual mechanistic target of rapamycin (mTOR) is inhibited, amino acid response 
      (AAR) and protein kinase CK2 are activated, and IGF (insulin-like growth factor) 
      binding protein (IGFBP)-1 is hyperphosphorylated in human intrauterine growth 
      restriction (IUGR). Using decidualized human immortalized endometrial stromal 
      cells (HIESC), we hypothesized that hypoxia and leucine deprivation causing 
      inhibition of decidual IGF-1 signaling is mediated by mTOR, AAR, CK2 and IGFBP-1 
      phosphorylation. Mass spectrometry demonstrated that hypoxia (1% O(2)) or 
      rapamycin increased IGFBP-1 phosphorylation singly at Ser101/119/169 (confirmed 
      using immunoblotting) and dually at pSer169 + 174. Hypoxia resulted in mTOR 
      inhibition, AAR and CK2 activation, and decreased IGF-1 bioactivity, with no 
      additional changes with rapamycin + hypoxia. Rapamycin and/or hypoxia promoted 
      colocalization of IGFBP-1 and CK2 (dual-immunofluorescence and proximity ligation 
      assay). Leucine deprivation showed similar outcomes. Changes in IGFBP-1 
      phosphorylation regulated by mTOR/AAR signaling and CK2 may represent a novel 
      mechanism linking oxygen and nutrient availability to IGF-1 signaling in the 
      decidua.
CI  - Copyright (c) 2020. Published by Elsevier B.V.
FAU - Abu Shehab, Majida
AU  - Abu Shehab M
AD  - Department of Pediatrics, University of Western Ontario, London, ON, Canada.
FAU - Biggar, Kyle
AU  - Biggar K
AD  - Department of Biology and Institute of Biochemistry, Carleton University, Ottawa, 
      ON, Canada. Electronic address: kyle_biggar@carleton.ca.
FAU - Kakadia, Jenica H
AU  - Kakadia JH
AD  - Department of Biochemistry, University of Western Ontario, London, ON, Canada.
FAU - Dhruv, Manthan
AU  - Dhruv M
AD  - Department of Biochemistry, University of Western Ontario, London, ON, Canada.
FAU - Jain, Bhawani
AU  - Jain B
AD  - Department of Biochemistry, University of Western Ontario, London, ON, Canada.
FAU - Nandi, Pinki
AU  - Nandi P
AD  - Department of Pediatrics, University of Western Ontario, London, ON, Canada.
FAU - Nygard, Karen
AU  - Nygard K
AD  - Biotron Integrated Microscopy Facility, University of Western Ontario, London, 
      ON, Canada.
FAU - Jansson, Thomas
AU  - Jansson T
AD  - Department of Obstetrics and Gynecology, Division of Reproductive Sciences, 
      University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
FAU - Gupta, Madhulika B
AU  - Gupta MB
AD  - Department of Pediatrics, University of Western Ontario, London, ON, Canada; 
      Department of Biochemistry, University of Western Ontario, London, ON, Canada; 
      Children's Health Research Institute, London, ON, Canada. Electronic address: 
      mbgupta@uwo.ca.
LA  - eng
GR  - R01 HD089980/HD/NICHD NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20200605
PL  - Ireland
TA  - Mol Cell Endocrinol
JT  - Molecular and cellular endocrinology
JID - 7500844
RN  - 0 (Amino Acid Transport Systems)
RN  - 0 (IGFBP1 protein, human)
RN  - 0 (Insulin-Like Growth Factor Binding Protein 1)
RN  - 0 (Receptors, Amino Acid)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (Casein Kinase II)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - GMW67QNF9C (Leucine)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Amino Acid Transport Systems/metabolism
MH  - Casein Kinase II/metabolism
MH  - Cell Hypoxia/*physiology
MH  - Cells, Cultured
MH  - Decidua/drug effects/*metabolism
MH  - Down-Regulation/drug effects
MH  - Female
MH  - Humans
MH  - Insulin-Like Growth Factor Binding Protein 1/metabolism
MH  - Leucine/*deficiency/pharmacology
MH  - Phosphorylation
MH  - Receptors, Amino Acid/metabolism
MH  - Signal Transduction/drug effects/physiology
MH  - Sirolimus/pharmacology
MH  - TOR Serine-Threonine Kinases/metabolism
OTO - NOTNLM
OT  - Biological availability
OT  - Humans
OT  - Intrauterine growth restriction
OT  - Maternal-fetal exchange
OT  - Pregnancy
COIS- Declaration of competing interest The authors report no conflicts of interest 
      related to this work.
EDAT- 2020/06/06 06:00
MHDA- 2021/05/28 06:00
CRDT- 2020/06/06 06:00
PHST- 2020/01/15 00:00 [received]
PHST- 2020/05/10 00:00 [revised]
PHST- 2020/05/10 00:00 [accepted]
PHST- 2020/06/06 06:00 [pubmed]
PHST- 2021/05/28 06:00 [medline]
PHST- 2020/06/06 06:00 [entrez]
AID - S0303-7207(20)30165-9 [pii]
AID - 10.1016/j.mce.2020.110865 [doi]
PST - ppublish
SO  - Mol Cell Endocrinol. 2020 Jul 15;512:110865. doi: 10.1016/j.mce.2020.110865. Epub 
      2020 Jun 5.