Date of Award
1996
Degree Type
Dissertation
Degree Name
Doctor of Philosophy
Abstract
The insulin-like growth factors (IGFs) regulate the growth and differentiation of a wide variety of tissues, including the brain. The biologic actions of IGFs are modulated by a family of six IGF binding proteins (IGFBPs), which, like IGFs, are synthesized as paracrine factors. We hypothesized that the IGFBPs synthesized by astroglial cells, are regulated by growth factors produced in the developing brain, and modulate the growth of these cells. Primary astroglial cells synthesized IGFBP-2 and IGFBP-3 which were upregulated in a dose dependent manner by IGF-I, IGF-II, and very high concentrations of insulin, suggesting that the growth factors regulate their own modulating IGFBPs. Transforming growth factor-{dollar}\alpha{dollar}, epidermal growth factor, and acidic and basic fibroblast growth factors differentially regulated IGFBP biosynthesis suggesting interaction among growth factor systems via IGFBPs. Overexpression of IGFBP-2 in the C6 glioma cell line resulted in clones with variable growth rates. Clones secreting high levels of IGFBP-2 and IGF-I, maintained a similar growth rate, whereas those which expressed moderate levels of IGFBP-2 and low levels of IGF-I, had significantly reduced growth rates. The slow growing clones also had a membrane associated IGFBP which was deduced to be IGFBP-5. Exogenous addition of IGF-I accelerated growth rates of the wild type and the fast growing clones, but not those which had cell surface associated IGFBP-5, suggesting the importance of this IGFBP in cellular growth. Futhermore, C6 cells, which have a low level of expression of connexin43 synthesized high levels of IGF-I and negligible amounts of IGFBP-2. C6 cells overexpressing a connexin43 cDNA have reduced growth rates and expressed less IGF-I and different IGFBP profiles. These studies suggested that (i) astroglial IGFBPs are regulated by various growth factors synthesized within the brain and (ii) growth of astroglial cells is regulated by a coordinated interaction between IGFs and IGFBPs, and specific properties of the latter.
Recommended Citation
Bradshaw, Sheri Lynn, "Astroglial Insulin-like Growth Factor Binding Proteins: Regulation Of Synthesis And Relationship To Cell Growth" (1996). Digitized Theses. 2608.
https://ir.lib.uwo.ca/digitizedtheses/2608