The growth, differentiation, and development of an organism is orchestrated by the choreographed expression of a wide array of genes. The switching" on" and" off" of gene expression is the province of transcription factors, which operate singly or in association with other proteins. Usually transcription factors form families, whereas individual members perform specific, distinct, or similar tasks. One such family includes the R~~/NF-KB proteins (NF-KB), which have the unique property of being sequestered in the cytoplasm in association with inhibitory proteins called IKB.

Activation and regulation of NF-KB are tightly controlled by IKB proteins. Through noncovalent association, the IKB proteins mask the nuclear localization signal (NLS) of NF-KB, thereby preventing NF-KB nuclear translocation. Upon stimulation with signaling molecules such as tumor necrosis factor a (TNFa) or lipopolysaccharide (LPS), NF-KB is released from IKB and translocated to the nucleus where it regulates gene transcription. Stimulation and activation of the NF-KB transcription factors do not require protein synthesis, thereby allowing rapid and efficient activation of target genes. This system is particularly utilized in immune, inflammatory, and acute phase responses where rapid activation of defense genes following exposure to pathogens such as bacteria and viruses is critical for survival of an organism. Many pathogenic viruses have evolved enhanced viral replication by including NF-KB target sites in their promoterlenhancer elements and producing proteins that activate NF-KB. Besides the immune responses and viral replication, NF-KB is also implicated in cellular proliferation and programmed cell death. Coincidentally, deregulation of NF-KB activity is directly associated with cellular transformation. The NF-KB homologs, Dorsal and Dif in the fruit fly Drosophila, are involved in the formation of embryonic polarity and insect immunity, respectively. Thus, the understanding of the regulation of RelINF-KB activity is of great interest to a wide variety of basic biological and medical fields. Current data lend credence to the notion that the major regula-