This project is focused on the elucidation of molecular mechanisms by which the immunologically important NF-kappaB transcription factors can be activated. In addition to leading to a better basic understanding of signaling processes, identification of the molecular components of signaling pathways will also reveal potential targets for therapeutic intervention to block activation of NF-kappaB in various diseases. Inflammatory diseases, for example, are often driven by the undesirable activation of NF-kappaB. In addition, expression of the human immunodeficiency virus (HIV) and other clinically relevant viruses depends in large part on activation of NF-kappaB, making these transcription factors and their regulators also potential targets for controlling the spread of HIV and other viruses. Most inflammatory signals stimulate the classical NF-kappaB activation pathway, which is mediated by the IKK kinase complex, the target of many signaling cascades. The IKK complex then phosphorylates the small inhibitory IkappaB proteins, causing their proteolytic degradation and thus frees NF-kappaB transcription factor dimers to translocate to the nucleus and to regulate target genes. We are presently studying the functions of proximal components of this pathway, including the CIKS protein previously cloned in this laboratory as a binding partner of the IKK complex. In addition to the classical pathway of activation, NF-kappaB can also be activated via a non-classical pathway, independent of the IKK complex. This second pathway involves processing of the p100 precursor form of NF kappaB2 to the p52 form, which leads to activation of p52/RelB heterodimers. Based on analyis of B cell defects in NF-kappaB2 knockout mice, we previously identified the TNF family member BAFF as the physiologic inducer of this second activation pathway in B cells. In addition, this pathway is activated by the lymphotoxin beta receptor in stromal cells, where it contributes importantly to stromal cell-dependent immune functions. We are investigating by what mechanisms these receptors signal the processing of p100 to p52, and have discovered that the loss of the receptor-associated adaptor TRAF3 unexpectedly leads to increased, rather than decreased processing. Some of the functions of NF-kappaB2 (and thus the non-classical pathway) may be redundant with those of the IkappaB-related regulator Bcl-3, since mice lacking both proteins show a severe inflammation not seen in mice lacking only one or the other of these proteins. As part of our efforts to identify these particular functions we have discovered that Bcl-3?s activities are modulated by the GSK-3 kinase. We have also begun to investigate for signaling defects in NF-kappaB2 deficient hepatocytes, muscle cells and adipocytes, since NF-kappaB2 deficient mice are protected from obesity-induced insulin resistance.
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