University of Virginia Health System

Within cells there exists a fine balance between survival and death. One of the earliest steps in the development of cancer is the ability of a cell to escape death. It is now well established that cells die through an orderly process known as programmed cell death or apoptosis. However, cells are able to overcome apoptotic pathways by upregulating gene products that inactivate the cell death machinery. Our group was among the first to describe that the transcription factor NF-kB is involved in the inhibition of cell death. Classical NF-kB, composed of a p50/p65 neterodimer protein complex, is ubiquitously expressed in cells. The activation of NF-kB by various stimuli, including tumor necrosis factor, stimulates the production of gene products that protect cells from apoptosis. Interestingly, the involvement of NF-kB in suppressing cell death implicates this transcription factor in cancer progression. Moreover, we have found that NF-kB is activated in response to chemotherapy and irradiation, and is required to overcome cell death by these agents. Therefore, the use of NF-kB inhibitors would have important implications for increasing the effectiveness of standard cancer therapy. Our laboratory is broadly interested in understanding transcrptional control of NF-kB by addressing four basic questions. First, we would like to determine the signaling pathways that are utilized by stress inducers to activate NF-kB-dependent gene expression. Second, we would like to elucidate how these stress pathways induce the transcriptional activation of NF-kB. In particular, determine whether DNA-binding, chromatin rearrangement and recruitment of co-activators are important in this process. Third, we would like to identify gene products regulated by NF-kB that are responsible for blocking apoptosis. Finally, we would like to identify and characterize pharmacological agents that inhibit NF-kB activation and determine whether these agents can be used in combination with standard cancer therapies. To address these questions our laboratory utilizes human cancer cell lines, as well as more complex human xenograft tumor models propagated in nude mice. It is a combination of these two experimental models that wil allow us to understand NF-kB regulated processes and to determine how these components are important in human cancer.