Androgen Gene Targets Associated with Apoptosis
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
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.