The loss of only the first 497 amino acids of proto-dbl is sufficient to activate its oncogenic potential, indicating that sequences within this region regulate dbl transforming activity in a negative manner. Deletions in these regions showed that the proto-dbl putative coil-coiled region and the region preceding it are responsible for regulation of transformation; both have to be removed to maximally activate proto-dbl oncogenic potential. We also found a direct correlation between proto-dbl half life at the level of its transforming activity. The keratinocyte growth factor (KGF), isolated in our laboratory, was found to be a member of the FGFs. KGF is unique among FGF members due to its mitogenic activity on epithelial cells but not fibroblasts. Using the T7 expression system, large quantities of biologically active KGF were obtained which are now being used to study the effect of KGF in vivo and in vitro, as well as the interaction of KGF with its own receptor. The bacterial expression system is being utilized to study KGF structure/function either by creating mutations within the KGF coding region or by generating chimeric molecules between KGF and other FGF members which have binding and mitogenic properties different than those of KGF. By using this we are hoping to learn the determinants dictating KGF-specific interactions with epithelial cells and how the structure of other FGFs, such as aFGF and bFGF, influences their multiple activities. In order to understand signal transduction mediated by KGF, we initiated studies to isolate relevant receptor cDNAs. We generated a human probe related to flg, the putative homolog of the avian bFGF receptor with which we screened human fibroblast and keratinocyte cDNA libraries. Several cDNAs were isolated and characterized. Results indicate the existence of two related receptor molecules. Moreover, within the bFGF receptor gene there is a great deal of heterogeneity which is likely the consequence of RNA processing.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Intramural Research (Z01)
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Division of Cancer Epidemiology and Genetics
United States
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