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 proto typical 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 rev iews on NF-kappa B and I kappa B, see Beg and Baldwin, 1993; Gilmore a nd Morin, 1993; Siebenlist et al., 1994; Baeuerle and Henkel, 1994; Th anes 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 pr oducts are critical for these cellular events. These products include cytokines, immunoreceptors, cell adhesion molecules, and acute phase p roteins (Siebenlist et al., 1994; Baeuerle and Henkel, 1994). In addit ion, recent research has shown dramatically that mice containing targe ted disruptions of NF-kappa B subunits are compromised in various aspe cts 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; Sieben list et al., 1994; Baeuerle and Henkel, 1994). Finally, genetic altera tions in the structure or expression of genes encoding NF-kappa B and I kappa B family members can render these proteins oncogenic, demonstr ating 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, wh ich more clearly define how various modifications to I kappa B, specif ically inducible phosphorylation, ubiquitination, and proteasome-drive n degradation, contribute to NF-kappa B activation.