The overall goal of our research is to understand why 96% of human prostate adenocarcinomas lose ARF expression even though they are actively proliferating. We hypothesize that loss of ARF leads to deregulated protein synthesis which helps to drive prostate tumorigenesis through a selective mRNA translational program. To test these hypotheses, we are using mouse modeling and in vitro cell culture studies. Because Arf-null mice die by nine months of age from sarcomas and lymphomas before prostate disease can fully develop, we are developing 2 prostate specific knockout models for prostate tumorigenesis: Pb-Cre/Arf-flox and Pb-Cre/Arf-flox/p53-flox. Also, we are using siRNAs directed against p14ARF in primary human prostate epithelial cells to assess the effects of ARF loss on ribosome biogenesis and cell growth and proliferation. Furthering our understanding of the molecular events behind prostate tumorigenesis will help guide identification and therapeutic strategies.