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Title: Insulin-like growth factor binding protein-3 and the hyperplastic prostate
Author: Launchbury, R.
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2003
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The role of insulin-like growth binding-protein-3 (IGFBP-3) was investigated in primary cultures of hyperplastic prostate cells in the hope of identifying novel drug targets. Benign prostatic hyperplasia (BPH) is a disease of the ageing male, the aetiology of which is unknown. Growth factors, such as insulin-like growth factor (IGF) are implicated in stimulating the prostate growth which causes hyperplasia. IGFBP-3 is an inhibitory binding protein, which functions to sequester IGF away from its receptor, but also has an IGF-independent action once fragmented. Cellular proteases, including prostate specific antigen (PSA), fragment IGFBP-3, and the resulting fragments have actions independent of the intact protein. The inhibitory action of fragmented IGFBP-3 has been documented in prostate epithelial cell lines, but there are no reports of its action in stromal cells, which is investigated here. Initially, the endogenous production of IGFBP-3 by primary cultures of stroma and epithelium was investigated. RT-PCR showed expression of IGFBP-3 mRNA in both stroma and epithelium, and immunocytochemistry, and Western blotting on cell lysates, indicated IGFBP-3 protein production in both cell types. The localisation of IGFBP-3 in primary cultures was the same as that observed in sections of hyperplastic and malignant prostate tissue. Western blotting on stromal and epithelial conditioned medium showed fragmentation of endogenous IGFBP-3 by cellular proteases. Proteolysis of IGFBP-3 by PSA produced fragments of 22-25kDa and 15kDa. ELISAs showed a large differential in concentration of IGFBP-3 produced by primary stomal and epithelial cells which affected subsequent growth experiments using exogenous protein. Proliferation experiments showed a non-dose dependent inhibitory response to IGFBP-3 by epithelial cells, probably due to sequestration of IGF. No response was observed in stomal cells to intact or fragmented protein, however, due to the high concentration of endogenous IGFBP-3 produced.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available