Mechanisms linking hypoxia to phosphorylation of insulin-like growth factor binding protein-1 in baboon fetuses with intrauterine growth restriction and in cell culture

Autor: Cun Li, Thomas Jansson, Madhulika B. Gupta, Kyle K. Biggar, Bhawani Jain, Peter W. Nathanielsz, Allan W. Chen, Karen Nygard, Jenica H. Kakadia
Rok vydání: 2021
Předmět:
Vascular Endothelial Growth Factor A
medicine.medical_specialty
Protein Kinase C-alpha
medicine.medical_treatment
Cell Culture Techniques
Hyperphosphorylation
mTORC1
In Vitro Techniques
Mechanistic Target of Rapamycin Complex 1
Biochemistry
Insulin-like growth factor-binding protein
Article
03 medical and health sciences
0302 clinical medicine
Fetus
Internal medicine
Genetics
medicine
Receptors
Erythropoietin
Animals
Humans
Phosphorylation
Protein kinase A
Hypoxia
Molecular Biology
Mechanistic target of rapamycin
Erythropoietin
PI3K/AKT/mTOR pathway
030304 developmental biology
0303 health sciences
Fetal Growth Retardation
biology
Chemistry
Growth factor
Hep G2 Cells
Organ Size
Hypoxia-Inducible Factor 1
alpha Subunit
3. Good health
Insulin-Like Growth Factor Binding Protein 1
Disease Models
Animal
Endocrinology
Fetal Weight
Microscopy
Fluorescence
biology.protein
030217 neurology & neurosurgery
Biotechnology
Papio
Transcription Factors
Zdroj: FASEB J
ISSN: 1530-6860
Popis: Hypoxia increases fetal hepatic insulin-like growth factor binding protein-1 (IGFBP-1) phosphorylation mediated by mechanistic target of rapamycin (mTOR) inhibition. Whether maternal nutrient restriction (MNR) causes fetal hypoxia remains unclear. We used fetal liver from a baboon (Papio sp.) model of intrauterine growth restriction due to MNR (70% global diet of Control) and liver hepatocellular carcinoma (HepG2) cells as a model for human fetal hepatocytes and tested the hypothesis that mTOR-mediated IGFBP-1 hyperphosphorylation in response to hypoxia requires hypoxia-inducible factor-1α (HIF-1α) and regulated in development and DNA-damage responses-1 (REDD-1) signaling. Western blotting (n = 6) and immunohistochemistry (n = 3) using fetal liver indicated greater expression of HIF-1α, REDD-1 as well as erythropoietin and its receptor, and vascular endothelial growth factor at GD120 (GD185 term) in MNR versus Control. Moreover, treatment of HepG2 cells with hypoxia (1% pO2 ) (n = 3) induced REDD-1, inhibited mTOR complex-1 (mTORC1) activity and increased IGFBP-1 secretion/phosphorylation (Ser101/Ser119/Ser169). HIF-1α inhibition by echinomycin or small interfering RNA silencing prevented the hypoxia-mediated inhibition of mTORC1 and induction of IGFBP-1 secretion/phosphorylation. dimethyloxaloylglycine (DMOG) induced HIF-1α and also REDD-1 expression, inhibited mTORC1 and increased IGFBP-1 secretion/phosphorylation. Induction of HIF-1α (DMOG) and REDD-1 by Compound 3 inhibited mTORC1, increased IGFBP-1 secretion/ phosphorylation and protein kinase PKCα expression. Together, our data demonstrate that HIF-1α induction, increased REDD-1 expression and mTORC1 inhibition represent the mechanistic link between hypoxia and increased IGFBP-1 secretion/phosphorylation. We propose that maternal undernutrition limits fetal oxygen delivery, as demonstrated by increased fetal liver expression of hypoxia-responsive proteins in baboon MNR. These findings have important implications for our understanding of the pathophysiology of restricted fetal growth.
Databáze: OpenAIRE
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