Master of Science
Dr. Madhulika Gupta
In this study, we provide novel evidence for a role of fetal liver mTOR signaling in regulating IGF-I bioavailability by modulating IGFBP-1 phosphorylation due to hypoxia – a key factor in the development of reduced fetal growth in utero. We utilized HepG2 cells in vitro and demonstrated a link between mTOR inhibition and hypoxia-induced IGFBP-1 phosphorylation. Using a biological assay for IGF-I receptor autophosphorylation, we demonstrated a functional significance for hypoxia-induced IGFBP-1 phosphorylation in reducing IGF-I bioactivity in vitro. Further, we have implicated a mechanistic link to increased CK2 activity within this regulation. We demonstrate that mTOR inhibition induced IGFBP-1 phosphorylation, which was not further enhanced by hypoxia, and that mTOR activation prevented hypoxia-induced IGFBP-1 phosphorylation. Together, we have identified a new mechanism involving mTOR inhibition during hypoxia by which IGFBP-1 phosphorylation, and thus IGF-I bioavailability, is regulated, and also implicate increased CK2 activity as an intermediate process in this mechanism.
Damerill, Ian, "Regulation of IGFBP-1 Phosphorylation in Hypoxia Via mTOR Signaling" (2014). Electronic Thesis and Dissertation Repository. 2473.