Prostate cancer occurs when cells that line the ducts of the prostate gland begin to divide in an uncontrolled manner. The normal function of these cells is to produce proteins that contribute to semen, and in adults they typically divide at a rate that is appropriate only to replace worn out cells. When this process is perturbed so that cells divide faster, the balance is tipped and too many cells begin to accumulate. A great deal of research has focused on finding the signals coming from outside the cell that stimulate prostate cell division, and significant progress has been made in this area. It is now clear that hormones and certain proteins that function as growth factors are capable of causing prostate cells to divide. Presumably, if approaches can be developed to block their effects, the result will be a slowdown in prostate cell growth. However, a major drawback to this approach is that these same hormones and growth factors are involved in the regulation of cell division in most, if not all other tissues, making it difficult to develop a treatment for prostate cancer that does not have significant and potentially detrimental effects in other organs.

Our understanding of signals from within cells that determine when a cell divides has increased dramatically in recent years. An important group of proteins involved in the process are called tumor suppressors because their major role is to suppress cell division. When these proteins do not function properly, which can occur when the genes that code for them become defective or when the protein degrades too quickly in the cell, the result can be inappropriate cell division. Although some tumor suppressor proteins function in all cells, others appear to work only in certain cell types.

Several years ago, our lab identified a new mouse gene that we called NKX-3.1 that was expressed in a prostate-specific manner in adult mice. Subsequent work in both the mice and humans has strongly implicated this gene in the control of prostate cell division, and it is now the best available candidate for a prostate-specific tumor suppressor. Studies of human tumors revealed that the region of chromosome 8 where the NKX-3.1 gene lies is often deleted in prostate tumor cells. Other studies have shown that the NKX-3.1 protein is either absent, or its abundance is extremely low in most prostate tumors. Furthermore, when the NKX-3.1 gene is mutated in mice, their prostate cells begin to overgrow in a manner that is consistent with a disease that, in humans, is believed to be a precursor to prostate cancer.

In this application, we propose to study the regulation of the human NKX-3.1 protein. Our goal is to identify the cellular processes that lead to degradation of this molecule. Recent studies of one of the major pathways that functions to recycle proteins in the cell indicate that there is a high degree of specificity involved. Each member of a large class of proteins, called ubiquitin ligases, functions to tag a handful of proteins for recycling. These proteins are often pre-marked for recycling by a process called phosphorylation. We intend to identify the enzymes, called kinases, that phosphorylate NKX-3.1, and the ubiquitin ligase that marks NKX-3.1 for destruction. Our strategy will involve a combination of several recently developed technologies that together will provide a new powerful approach to identify these proteins. Our hope is that by finding the proteins that regulate NKX-3.1, we will shed light on outstanding new prospects for the development of targeted therapies that will be effective in the treatment of prostate cancer.