Fibroblast growth factors (FGFs) and their receptors play a critical role in the formation and progression of tumors in a variety of tissues including pituitary, endometrial, and breast. FGFs are also important regulators of neoplastic growth and metastasis. However, surprisingly little is known about the molecular mechanisms and components of the FGF signal transduction pathway. Characterization of the mediators of FGF signaling has been hampered by the lack of a convenient, rapid and physiologically relevant assay since FGF responses characterized to date have typically involved induction of cellular proliferation, or differentiation. Our lab has developed an excellent model system with which to define and characterize FGF signaling and regulation of gene expression. This model system utilizes an FGF-responsive prolactin promoter exogenously introduced into pituitary tumor cells. Preliminary results using this system indicate that FGF signal transduction involves protein kinase C (PKC) and the mitogen-activated protein kinases (MAPK), but surprisingly, does not involve the normal upstream activators of MAPK, Ras and Raf-1. I plan to use this unique system to continue characterizing the cytoplasmic components of FGF signal transduction. A transient transfection approach, using dominant-negative, inhibitory or active forms of signaling molecules, and pharmacological inhibitors will be used to delineate components of FGF signaling to the prolactin promoter. Characterization of the basic molecular mechanisms of FGF signal transduction will provide an important foundation for analyzing the contribution of FGF signal transduction in other cancers such as breast and endometrial cancer. Furthermore, elucidation of the components of the FGF signaling pathway may lead to the identification of novel diagnostic or prognostic markers for a variety of cancers and new potential targets for therapeutic intervention.
| Jackson, T A; Schweppe, R E; Koterwas, D M et al. (2001) Fibroblast growth factor activation of the rat PRL promoter is mediated by PKCdelta. Mol Endocrinol 15:1517-28 |
