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The nucleolar tumor suppressor ARF plays an important role in the tumor surveillance of human cancer. We have found that ARF expression is absent from highly proliferative prostate adenocarcinomas and this correlates with the increased expression of the p53-independent target of NPM. We have created and characterized an immortalized ARF-null prostate epithelial cell line. In addition we have shown that alterations in NPM levels can have dramatic affects on the androgen-dependent cancer cell line, LNCaP, but not PC3 cells which are androgen-independent. We have previously shown that ARF inhibits NPM's nuclear export and cell cycle progression in a p53-indpendent manner. Under this proposal we have defined the mechanism by which this happens. Specifically, ARF binds to NPM preventing its ability to carry both small and large ribosomal subunits out of the nucleus. This results in a decrease in protein synthesis and growth rates contributing to ARF's tumor suppressor function. We are beginning to further define the role of ARF in prostate cell growth. These studies are opening the door to new therapeutic targets in prostate cancer; namely protein synthesis., The original document contains color images.

Prostate cancer is a significant health problem in aging American men. Approximately 350,000 American men were diagnosed and 42,000 deaths were attributed to prostate cancer in 1998. Despite identification of chromosomal regions of instability that are associated with prostate cancer, there are an undetermined series of molecular events that lead to de-differentiation of prostatic epithelial cells and ultimately to prostate carcinoma. The specific genes responsible for neoplastic transformation of the prostate are largely unknown. Nkx3.1 is a homeodomain transcription factor that is expressed in an androgen-dependent and largely prostate specific manner. The Nkx3.1 gene localizes to the chromosomal region 8p21, a region that is often deleted in human prostate cancers. The goals of this study are to overexpress Nkx3.1 in vitro and determine the effects on growth/differentiation, patterns of target gene expression and tumorigenicity of prostate carcinoma cell lines. Expression patterns of Nkx3.1 in human prostate tumor specimens will be examined immunohistochemically, and microdissected prostate tumor samples will be used to search for Nkx3.1 mutations and/or evidence of hypermethylation. Specific cell types and androgen-dependent expression patterns of Nkx3.1 will also be monitored immunohistochemically in mouse prostates. Overall, our work will determine whether loss of Nkx3.1 function is a major cause of prostate cancer.