Components of the Hedgehog signaling pathway play a role in a variety of human developmental abnormalities and in the pathogenesis of several human cancers. This proposal will examine the Sonic hedgehog-Gli signal transduction pathway in the regulation of prostate growth during development and during prostate cancer progression. This pathway is generally inactive in adult tissues but reactivated in human prostate cancer. Sonic hedgehog (Shh) is a secreted polypeptide that induces morphogenesis at multiple sites in the developing embryo via the activation of a cascade of transcriptional regulators and growth factors. Shh binds to a transmembrane receptor and by activating an intracellular signal transduction pathway activates the transcription factor Gli. Negative regulation of the Shh-Gli pathway is exerted by a homologous gene Gli3 which represses Shh expression and opposes the transcriptional activity of Gli. Previous studies by the applicant have demonstrated that Shh signaling pathways is essential for the initiation of the mouse prostate development and that both Gli and Gli 3 are expressed in the developing prostate. Shh expression is specific to the prostatic portion of the urogenital sinus and is restricted to the epithelium. The primary goal of the proposed studies is to characterize Gli and Gli3 expression in the developing prostate and by utilizing mutant mice to examine the effect of Gli overexpression, Gli loss of function and Gli3 insufficiency on prostate growth. The regulatory interactions between Shh, Gli and Gli3 will be characterized to elucidate the regulation of Shh pathway during normal homeostasis and during prostate cancer growth. This will be accomplished by utilizing: in vitro methods to analyze the regulation of Gli and Gli3 expression, mutant and transgenic mice to characterize the growth effects and compensatory response to Gli dysregulation and Gli3 insufficiency and evaluate the functional significance of these counter regulatory responses by creating Gli/Gli3 double mutants. The proposed studies are expected to provide a novel mechanistic insight into the functional significance of a conserved pathway regulating prostate growth during development with potential clinical implications as a target for pharmacologic intervention in prostate cancer treatment.
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