Dr. Mark L. Day, Ph.D
The main objective of this research is to establish a mechanism by which apoptosis of anchorage-dependent prostate epithelium is regulated by integrin/extracellular matrix interaction requiring the RB gene product.
The rationale for this research is based on our preliminary studies that have demonstrated induction of the RB gene and activation of the encoded protein (Rb) preceding castration-induced apoptosis in rat ventral prostate. In anchorage-dependent human prostate cells, we have demonstrated that rapid dephosphorylation (activation) of Rb preceded detachment-induced apoptosis. Furthermore, Rb activation and apoptosis were completely inhibited by adherence to fibronectin or by forced expression of the Rb inhibitory oncogene, E1a.
These results, coupled with the observation that overexpression of the RB functional domain is cytotoxic to LNCaP cells, strongly suggested a regulatory role for integrin receptors and Rb in apoptosis of anchorage-dependent prostate epithelium. These novel findings, although compelling, fall short of firmly establishing functional roles for integrins and Rb in anchorage-regulated apoptosis of prostate epithelium.
Therefore, the objective of our proposal begins by identifying the integrin receptor(s) that initiates apoptosis in anchorage-dependent, human prostate cells and to demonstrate that this signal results in the activation of Rb prior to apoptosis. Additionally, we will establish that Rb function is required for integrin-mediated apoptosis of anchorage-dependent, human prostate cells and human prostate epithelium. We anticipate results from these investigations will support our central hypothesis: That the transduction of signals by integrin receptors initiates Rb activation and apoptosis of prostate epithelium.