Fibroblast growth factors (FGF-1 or -2) are present at significant concentrations in most normal tissues in the adult. However, these FGFs are immobilized in an inactive state on the extracellular matrix and it is only poorly understood how they are solubilized and activated to reach their extracellular receptors. One mechanism through which these growth factors can be mobilized is by binding to secreted binding proteins for FGF (FGF-BP or BP). In our previous work we showed that BP can enhance the activity of locally stored, immobilized FGFs and that expression of BP can support tumor growth and angiogenesis of FGF-2 positive non-tumorigenic cells. Recently we identified additional members in the gene family (BP2 and BP3) with similar activity as the original BP1. We did not detect BP1 mRNA in normal adult human tissues and adult mice but found that transformation upregulated BP1 in skin and gut and BP1 was found upregulated in samples from patients with different cancers (colon, breast, pancreatic, squamous cell). We hypothesize that the interactions with the BP family of proteins impacts on the biologic activity levels of FGFs. From our preliminary data we speculate that the efficacy of the different BPs will be different towards different FGFs. Preliminary data suggest that BP1 enhances FGF-1 and -2 activity whilst it inhibits FGF-4 activity. We propose the following specific aims:
Aim 1. To study the protein interaction domains and in vitro function of selected BPs and FGFs.
Aim 2. To study the impact of selected BPs as a transgene during embryogenesis and on tumor progression in carcinogen and oncogene models.
Aim 3. To study the impact of deletion of selected BPs. Chick embryo and mouse models will be employed in developmental and tumor biology studies. ? ? ?
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