The transcription factor NF-kB plays an important role in innate immunity by augmenting the expression of many inducible immediate response genes. NF-kB acts as an unifying element in the body's response to infection and injury, and thus is an important mediator of natural immunity in vertebrates. It is also an essential element for the replication of different viruses, including HIV. NF-kB belongs to a family of proteins known as the Rel family, which includes oncogenes and developmental morphogens. Chromosomal translocations involving members of this family have been linked to the development of human B-cell lymphomas and leukemias. Therefore understanding how NF-kB activity is regulated has great relevance towards understanding how some cancers and immunodeficiencies develop. The primary objective of their proposal is to understand how the NF-kB/Rel-transcription factors are regulated. The investigator wishes to determine how IL-1, an inducer that activates NF-kB transduces its signals to cause the phosphorylation and degradation of IkB molecules. He proposes to trace the steps from the receptor to the target, namely the IkB-alpha and IkB-beta proteins. He will work his way downstream from the IL-1 receptor by characterizing and cloning the proteins that interact with the cytosolic domain of the IL-1 receptor, using both biochemical affinity purification and yeast two-hybrid screening techniques. He will also try to identify, characterize and clone the kinase(s) responsible for inducible phosphorylation of IkB-alpha and IkB-beta. He will continue to examine and elucidate the role of the catalytic subunit of PKA that he has discovered and identified as a component of cytosolic NF-kB: IkB-beta complexes. To determine whether the insights gained from studying the differential regulation of IkB-alpha and IkB-beta in cell lines represent the physiological process, he proposes to disrupt the gene encoding IkB-beta using homologous recombination techniques.
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