Nuclear factor (NF)-κB is perhaps the most intensely studied eukaryotic transcription factor, mainly because of its pivotal role in controlling varied biological effects ranging from inflammatory-,immune-, and stress-induced responses to cell fate decisions such as proliferation, differentiation, tumorigenesis, and apoptosis. The mammalian NF-κB family consists of five members: RelA (p65), RelB, c-Rel, NF-κB1 (p50 and its precursor p105), and NF-κB2 (p52 and its precursor p100). These proteins share a conserved N-terminal 300-amino acid Rel homology domain (RHD) that contains a nuclear localization signal (NLS) and is responsible for dimerization, sequence-specific DNA binding, and interaction with inhibitory IκB proteins (Figure 86.1A). A critical feature of RelA, RelB, and c-Rel that distinguishes them from p50 and p52 is the presence of a transactivation domain (TAD) within the carboxy-terminal region of these proteins (Figure 86.1A).

The diverse biological effects of NF-κB are mediated, in part, by the ability of NF-κB proteins to form numerous homo- and heterodimers that differentially regulate target genes (1). For example, p50 and p52 homodimers serve as repressors, whereas dimers containing RelA or c-Rel are transcriptional activators. Heterodimers of RelB with either p50 or p52 display a greater regulatory flexibility, and function both as an activator and a repressor (1,2). Accumulating evidence suggests that activation of specific dimers is mediated by distinct upstream signaling pathways, which in turn are activated in a stimulus- and cell-specific manner (2,3). This chapter begins with an overview of the current state of knowledge about NF-κB, and then discusses the role for this fascinating transcription factor in the endothelium.