Control of transcription of eukaryotic gene expression is regulated by the interaction of sequence specific DNA-binding proteins with cis-acting regulatory elements positioned near genes. The laboratory is particularly interested in the control of transcription factors that pre-exist in cells and in the mechanisms that lead to their activation. A major research effort in the laboratory is the study of the transcription factor known as NF-kB. In most cells of the body NF-kB is found in the cytoplasm where it is associated with an inhibitor protein known as IkB. Treatment of cells with agents such as tumor necrosis factor, interleukin-1, T cell mitogens, or certain growth factors leads to the rapid phosphoryation and degradation of IkB, allowing NF-kB to translocate into the nucleus and regulate gene expression. One focus of the laboratory is the dissection of the signal transduction pathways that control the regulation of NF-kB. For example, we have shown that TNF leads to the phosphorylation of NF-kB and we are currently identifying the kinase involved in this process and the potential effects on NF-kB transcriptional activity. Other research approaches include the study of the differential targeting of distinct IkBs, which control whether NF-kB is transiently or persistently activated and the study of how calcium activates NF-kB. We are also studying how the anti-inflammatory cytokine IL-10 functions to block NF-kB.

Our recent data indicate that NF-kB dysregulation is a mediator of a variety of human diseases. For example, we have found that a number of oncogenes activate NF-kB and that NF-kB is required for these oncogenes to induce cellular transformation. Additionally, we have found that the activation of NF-kB suppresses programmed cell death (apoptosis) induced by several potential apoptotic stimuli. Consistent with the ability of NF-kB to suppress apoptosis, we recently showed that the ability of oncogenic Ras to transform cells requires the activation of NF-kB to suppress transformation-associated apoptosis. Additionally, we have found a significant improvement in tumor responses to radiation and chemotherapy by blocking NF-kB. Thus, the ability to block NF-kB and its apoptotic function leads to dramatically increased apoptosis induced by the cancer therapy. Future directions include determining the mechanisms whereby NF-kB suppresses apoptosis and developing novel approaches to inhibit NF-kB (such as gene therapy with a modified form of IkB or by the identification of small molecular inhibitors of the kinases involved in activating NF-kB). These approaches will be applied to the potential therapy of the inflammatory diseases and cancers with which NF-kB activation is associated.