Evidence map›Paper›PMID 26714229›Full record

ArticleMolecular endocrinology (Baltimore, Md.)2016

Hypoxia Increases IGFBP-1 Phosphorylation Mediated by mTOR Inhibition.

Ian Damerill, Kyle K Biggar, Majida Abu Shehab, Shawn Shun-Cheng Li, Thomas Jansson, Madhulika B Gupta

Open access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Molecular endocrinology (Baltimore, Md.), 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.

0numbers the graph read from it
0cells of the map it votes in
23citing papers in PubMed
2.2field-weighted citation impact, top 11% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

23 citing papers in PubMed, 25 citations in OpenAlex.

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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

6 authors at 3 institutions in 2 countries.

Ian DamerillDepartment of Biochemistry (I.D., K.K.B., S.S.-C.L., M.B.G.), University of Western Ontario, London, Ontario, N6C 2V5 Canada; Department of Obstetrics and Gynecology (T.J.), University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045; Department of Pediatrics (M.B.G.), University of Western Ontario, London, N6C 2V5 Canada; and Children's Health Research Institute (M.A.S., M.B.G.), University of Western Ontario, London, Ontario, N6C 2V5 Canada.
Kyle K BiggarDepartment of Biochemistry (I.D., K.K.B., S.S.-C.L., M.B.G.), University of Western Ontario, London, Ontario, N6C 2V5 Canada; Department of Obstetrics and Gynecology (T.J.), University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045; Department of Pediatrics (M.B.G.), University of Western Ontario, London, N6C 2V5 Canada; and Children's Health Research Institute (M.A.S., M.B.G.), University of Western Ontario, London, Ontario, N6C 2V5 Canada.
Majida Abu ShehabDepartment of Biochemistry (I.D., K.K.B., S.S.-C.L., M.B.G.), University of Western Ontario, London, Ontario, N6C 2V5 Canada; Department of Obstetrics and Gynecology (T.J.), University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045; Department of Pediatrics (M.B.G.), University of Western Ontario, London, N6C 2V5 Canada; and Children's Health Research Institute (M.A.S., M.B.G.), University of Western Ontario, London, Ontario, N6C 2V5 Canada.
Shawn Shun-Cheng LiDepartment of Biochemistry (I.D., K.K.B., S.S.-C.L., M.B.G.), University of Western Ontario, London, Ontario, N6C 2V5 Canada; Department of Obstetrics and Gynecology (T.J.), University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045; Department of Pediatrics (M.B.G.), University of Western Ontario, London, N6C 2V5 Canada; and Children's Health Research Institute (M.A.S., M.B.G.), University of Western Ontario, London, Ontario, N6C 2V5 Canada.
Thomas JanssonDepartment of Biochemistry (I.D., K.K.B., S.S.-C.L., M.B.G.), University of Western Ontario, London, Ontario, N6C 2V5 Canada; Department of Obstetrics and Gynecology (T.J.), University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045; Department of Pediatrics (M.B.G.), University of Western Ontario, London, N6C 2V5 Canada; and Children's Health Research Institute (M.A.S., M.B.G.), University of Western Ontario, London, Ontario, N6C 2V5 Canada.
Madhulika B GuptaDepartment of Biochemistry (I.D., K.K.B., S.S.-C.L., M.B.G.), University of Western Ontario, London, Ontario, N6C 2V5 Canada; Department of Obstetrics and Gynecology (T.J.), University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045; Department of Pediatrics (M.B.G.), University of Western Ontario, London, N6C 2V5 Canada; and Children's Health Research Institute (M.A.S., M.B.G.), University of Western Ontario, London, Ontario, N6C 2V5 Canada.
Western University · CAChildren’s Health Research Institute · CAUniversity of Colorado Anschutz Medical Campus · US

Funding

PILOT STUDY--SUBSTRATE METABOLISM IN EXTREMELY LOW BIRTH WEIGHT INFANTSP30DK048520 · NIDDK · UNIVERSITY OF COLORADO DENVER · PI Edward L Melanson · 1995 to 2026
$32.6M
IGFBP-1 hyperphosphorylation in IUGR: Role of mTOR and CK2R03HD078313 · NICHD · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · PI GUPTA, MADHULIKA, JANSSON, THOMAS · 2014 to 2015
$147k
NICHD NIH HHS HD 078313NICHD NIH HHS R03 HD078313
6 · The paper itself

Abstract

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.

Indexed as

Adaptor Proteins, Signal TransducingAmino Acid SequenceAnimalsBinding SitesCarrier ProteinsCell HypoxiaGene SilencingHep G2 CellsHumansInsulin-Like Growth Factor Binding Protein 1Insulin-Like Growth Factor IIntracellular Signaling Peptides and ProteinsMass SpectrometryMechanistic Target of Rapamycin Complex 1Mechanistic Target of Rapamycin Complex 2Molecular Sequence DataAdaptor Proteins, Signal TransducingCarrier ProteinsDEPTOR protein, humanInsulin-Like Growth Factor Binding Protein 1Insulin-Like Growth Factor IIntracellular Signaling Peptides and ProteinsMechanistic Target of Rapamycin Complex 1Mechanistic Target of Rapamycin Complex 2Multiprotein ComplexesPhosphoserineRapamycin-Insensitive Companion of mTOR ProteinReceptor, IGF Type 1Regulatory-Associated Protein of mTORRICTOR protein, humanRPTOR protein, humanSirolimusTOR Serine-Threonine Kinases

Identifiers

PMID26714229
PMCPMC4792228
OpenAlexW2203417024

What OpenQuestion holds

Textmetadata
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.