Rb/E2F in Hormone Signaling of Prostate Epithelium

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DESCRIPTION (provided by applicant): This laboratory has compiled extensive evidence supporting a novel role for the retinoblastoma gene product (pRb) and it's transcriptional regulatory partner, E2F1 in the regulation of androgen receptor expression and function. These findings have important implications for the regulation of prostate epithelial growth and survival. The lethal nature of the Rb knockout in mouse embryos has precluded gene disruption experiments to examine such a role for Rb in the prostate gland. To circumvent this problem and to initiate functional studies of Rb in the prostate gland, my laboratory has utilized an innovative approach to "rescue" Rb-/- prostate precursor rudiments from mouse embryos prior to their death with which we have generated the first viable Rb-/- prostate tissues and Rb-/-prostate epithelial cell lines. These models provide a unique experimental platform with which to investigate the physiologic consequences of Rb deletion on prostate epithelium. Using this technology, we have made the compelling observation that the loss of Rb results in non-transformed cells that exhibit increased expression of AR protein and mRNA, and in the presence of stromal growth factors, increased AR activity. We have also discovered that the specific loss of Rb results in immortalized prostate tissue and cells that are insensitive to apoptotic stimuli possibly due to an attenuated mitochondrial/caspase-9 pathway. Based on these findings, we hypothesize that Rb and AR are interacting components of a precisely regulated but poorly understood mechanism that controls the growth and survival of prostate epithelium. The proposed studies will determine the role of Rb/E2F 1 in the regulation of AR transcription and AR activity in cultured prostate epithelial cells and in recombinant prostate tissue in vivo. We will determine if Rb deletion results in increased AR responsiveness to paracrine growth factors secreted by prostate stromal cells and elucidate the specific signaling pathways that regulate AR function in this hormone-independent fashion. Lastly we will determine if the apoptotic mitochondrial/caspase-9 pathway is attenuated in the Rb-/- cells and tissue recombinants.