NF-κB: A lesson in family values

NF-KB and the other members of the Rel family of transcriptional activator proteins have been a focal point for understanding how extracellular signals induce the expression of specific sets of genes in higher eukaryotes. Unlike most transcriptional activators, this family of proteins resides in the cytoplasm and must therefore translocate into the nucleus to function. The nuclear translocation of Rel proteins is induced by an extraordinarily large number of agents ranging from bacterial and viral pathogens to immune and inflammatory cytokines to a variety of agents that damage cells. Remarkably, an even larger number of genes appear to be targets for the activation by Rel proteins. As a result of these properties, we are confronted with two intriguing questions: how do multiple signal transduction pathways lead to the activation of NFKB, and how does a particular inducer lead to the activation of only one or a subset of the genes targeted by NFKB? Answers to these questions require a detailed understanding of the pathways of Rel protein activation and the mechanisms by which the genes targeted by Rel proteins are turned on. Here, we review recent progress in understanding the mechanisms involved in the activation of NF-KB, the function of individual Rel family proteins, and synergistic interactions between Rel proteins and other families of transcription factors, leading to specific gene activation. The Rel and IKB Families The Rel protein family has been divided into two groups based on differences in their structures, functions, and modes of synthesis (Baeuerle and Henkel, 1994; Siebenlist et al., 1994). The first group consists of p50 (NF-KB1) and p52 (NF-KB2), which are synthesized as precursor proteins of 105 and 100 kDa, respectively. The mature proteins, which are generated by proteolytic processing, have a so-called Rel homology domain that includes DNAbinding and dimerization domains and a nuclear localization signal. The mature proteins form functional Rel dimers with other members of the family, while dimers containing the unprocessed proteins remain sequestered in the cytoplasm. The second group of Rel proteins, which includes p65 (RelA), Rel (c-Rel), RelB, and the Drosophila Rel proteins dorsal and Dif, are not synthesized as precursors. In addition to the Rel homology domain, they possess one or more transcriptional activation domains. Members of both groups of Rel proteins can form homoor heterodimers; e.g., NF-KB is a p50-p65 heterodimer. Two types of Rel protein complexes are found in the Ub Conjugation Enzymes