Hypoxia alters phosphorylation status of insulin‐like growth factor (IGF)‐binding protein‐1 and attenuates biological activities of IGF‐I in HepG2 cell cultures. Issue 9 (2nd July 2013)

• Record Type: Journal Article
• Authors: Tsunawaki, Tomonori; Sakai, Keiji; Momomura, Mai; Wachi, Yuichi; Matsuzawa, Yukiko; Iwashita, Mitsutoshi
• Is Part Of: Journal of obstetrics and gynaecology research. Volume 39:Issue 9(2013:Sep.)
• Page Start: 1367
• Page End: 1373
• Publication Date: 2013-07-02
• Subjects: Gynecology -- Periodicals; Obstetrics -- Periodicals; 618.1005
• DOI: 10.1111/jog.12078
• Languages: English
• ISSNs: 1341-8076

Abstract

<abstract abstract-type="main"> <title>Abstract</title> <sec id="jog12078-sec-0001" sec-type="section"> <title>Aim</title> <p>Insulin‐like growth factor (IGF)‐I is known to stimulate fetal growth. One of the IGF‐binding proteins, IGFBP‐1, suppresses IGF‐I activity, and thereby inhibits fetal growth. Because hypoxic stress in the uterus is known to cause fetal growth restriction, we examined the effects of hypoxia on IGFBP‐1 production and phosphorylation status.</p> </sec> <sec id="jog12078-sec-0002" sec-type="section"> <title>Methods</title> <p>Because liver is a main IGFBP‐1 production site in the fetus, we used a hepatoma cell line, HepG2 cells, that secrete a large amount of IGFBP‐1, express IGF‐I receptors and model fetal liver metabolism <italic>in vitro</italic>. IGFBP‐1 was analyzed by sodium dodecylsulfate polyacrylamide gel electrophoresis (PAGE) following immunoblotting, and IGFBP‐1 phosphorylation status was analyzed by native PAGE following immunoblotting.</p> </sec> <sec id="jog12078-sec-0003" sec-type="section"> <title>Results</title> <p>Total concentrations of IGFBP‐1 in media were higher and the highly phosphorylated isoforms were dominant in low oxygen conditions. Phosphorylation of IGF‐I receptor by IGF‐I was attenuated in low oxygen conditions. IGF‐I‐induced phosphorylation of insulin receptor substrate‐1 (IRS‐1) was attenuated in low oxygen conditions as well. However, attenuated phosphorylation of IGF‐I receptor and IRS‐1 were not observed in low oxygen conditions if the cells were stimulated with LR<sup>3</sup>IGF‐I that has a similar binding affinity to IGF‐I receptor but much less binding affinity to IGFBP‐1 compared to those of native IGF‐I. While IGF‐I‐induced cell proliferation was also inhibited in low oxygen conditions, LR<sup>3</sup>IGF‐I‐stimulated cell proliferation was not inhibited. These findings indicate that low oxygen conditions inhibit IGF‐I action by increasing IGFBP‐1, especially phosphorylated IGFBP‐1, which inhibits IGF‐I action.</p> </sec> <sec id="jog12078-sec-0004" sec-type="section"> <title>Conclusion</title> <p>This study has indicated that hypoxia‐induced IGFBP‐1 production in the fetus may be a conserved physiological mechanism for restricting IGF‐I‐stimulated fetal growth.</p> </sec> </abstract>