The SHH-Gli Pathway Regulates Prostate Growth
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This project will examine the Sonic hedgehog-Gli signal transduction pathway in prostate growth regulation. Sonic hedgehog is a secreted polypeptide that induces morphogenesis at multiple sites in the developing embryo by activating a cascade of transcriptional regulators and growth factors. Shh binds to a transmembrane receptor patched (Ptc), stimulates an intracellular signal transduction pathway, and activates the transcription factor Gli. Gli activation is considered a critically important step since it is the primary mediator of transcriptional activation by Shh. 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. The net effects of Shh on growth depend in part on the balance of activities of Gli and Gli3. We have previously shown that Shh signaling is necessary for the initiation of prostate development. We will now present preliminary studies showing that Gli and Gli3 are both expressed in the developing mouse prostate. We will show that Shh stimulates Gli expression and provide preliminary data showing that dysregulation of Gli expression during development alters prostate cancer. We propose to examine the hypothesis that the Shh-Gli signal transduction pathway regulates normal prostate growth. The proposed experiments will characterize Gli and Gli3 expression in the developing prostate and utilize mutant mice to examine the effect of Gli overexpression, Gli loss of function, and Gli haploinsufficiency on prostate growth. Abnormal morphogenesis will be correlated with changes in expression of Hoxd-13 and BMP-4, two conserved targets of Shh-Gli regulation. Finally, the regulatory interactions between Shh, Gli, Gli3 will be characterized to elucidate the homestatic mechanisms which regulate activity in the Shh pathway. This work is expected to provide novel and important insights into the function of a conserved pathway regulating prostate growth during development. As this pathway is generally inactive in adult tissues but re-activated in human prostate cancer, it has unique promise as a target for pharmacologic intervention to arrest or slow prostate cancer growth.
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