The NF-κB regulatory network

Allan R. Brasier

Nuclear factor (NF)-kappaB is a family of seven structurally related transcription factors that play a central role in cardiovascular growth, stress response, and inflammation by controlling gene network expression. Although the NF- kappaB subunits are ubiquitously expressed, their actions are regulated in a celltype and stimulus-specific manner, allowing for a diverse spectrum of effects. For example, NF-kappalB is activated by cytokines, reactive oxygen species, bacterial cell wall products, vasopressors, viral infection, and DNA damage. Recent molecular dissection of its mechanisms for activation has shown that NF-kappalB can be induced by the so-called "canonical" and "noncanonical" pathways, leading to distinct patterns in the individual subunits activated and downstream genetic responses produced. The canonical pathway involves activating the IkappalB kinase (IKK) with subsequent phosphorylation-induced proteolysis of the IkappaBalpha inhibitors and consequent nuclear translocation of the Rel A transcriptional activator. Recent work using high-density oligonucleotide arrays have begun to systematically dissect the scope of the gene network under canonical NF-kappaB control and have yielded important insights into biological pathways controlled by it. This pathway controls expression of noncontiguous, functionally discrete groups of genes ("regulons"), whose temporal expression occurs in waves. Moreover, its mode of activation (oscillatory or monophasic) plays an important role in determining the spectrum of target genes expressed. By contrast, the noncanonical NF-kappaB activation pathway involves activating the NF-kappaB inducing kinase (NIK) to stimulate IKKalpha-induced phosphorylation and proteolytic processing of the 100-kDa cytoplasmic NF-kappaB2 precursor. Activated NF-kappaB2 then forms a complex with Rel B and NIK to translocate into the nucleus thereby activating a distinct set of genes. Although the noncanonical pathway has been most clearly linked to control of adaptive immunity, recent intriguing studies have implicated this pathway in viral induced stress response and in the metabolic syndrome. In this way, a single family of transcription factors can respond to diverse stimuli to regulate cardiovascular homeostasis.