MECHANISTIC ASPECTS OF NF-KAPPA-B REGULATION - THE EMERGING ROLE OF PHOSPHORYLATION AND PROTEOLYSIS

Members of the NF-kappa B transcription factor family serve as a prototypical model of inducible transcription factors. As discussed below, NF-kappa B activity is primarily regulated by a group of structurally related proteins collectively referred to as I kappa B (for recent reviews on NF-kappa B and I kappa B, see Beg and Baldwin, 1993; Gilmore and Morin, 1993; Siebenlist et al., 1994; Baeuerle and Henkel, 1994; Thanes and Maniatis, 1995). The NF-KB transcription factor family is an important component in a variety of biological processes, most notably inflammation and immune responses. The requirement for NF-kappa B in these processes is indicated by its ability to regulate genes whose products are critical for these cellular events. These products include cytokines, immunoreceptors, cell adhesion molecules, and acute phase proteins (Siebenlist et al., 1994; Baeuerle and Henkel, 1994). In addition, recent research has shown dramatically that mice containing targeted disruptions of NF-kappa B subunits are compromised in various aspects of immune function and inflammatory responses (Weih at al., 1995; Sha et al., 1995; Burkly et al., 1995; Kontgen et al., 1995; also see Thanes and Maniatis, 1995). A number of pathogenic viruses, including the human immunodeficiency virus, also subvert NF-KB activity for the expression of essential viral genes (Nabel and Baltimore, 1987; Siebenlist et al., 1994; Baeuerle and Henkel, 1994). Finally, genetic alterations in the structure or expression of genes encoding NF-kappa B and I kappa B family members can render these proteins oncogenic, demonstrating an intimate relationship between NF-kappa B function and normal cellular proliferation (Siebenlist et al., 1994; Baeuerle and Henkel, 1994). In this review, we discuss the mechanisms regulating NF-kappa B activity. A particular emphasis has been placed on recent studies, which more clearly define how various modifications to I kappa B, specifically inducible phosphorylation, ubiquitination, and proteasome-driven degradation, contribute to NF-kappa B activation.