The NF-κB Family of Transcription Factors and Its Regulation
Abstract
Nuclear factor-κB (NF-κB) consists of a family of transcription factors that play critical roles in inflammation, immunity, cell proliferation, differentiation, and survival. Inducible NF-κB activation depends on phosphorylation-induced proteosomal degradation of the inhibitor of NF-κB proteins (IκBs), which retain inactive NF-κB dimers in the cytosol in unstimulated cells. The majority of the diverse signaling pathways that lead to NF-κB activation converge on the IκB kinase (IKK) complex, which is responsible for IκB phosphorylation and is essential for signal transduction to NF-κB. Additional regulation of NF-κB activity is achieved through various post-translational modifications of the core components of the NF-κB signaling pathways. In addition to cytosolic modifications of IKK and IκB proteins, as well as other pathway-specific mediators, the transcription factors are themselves extensively modified. Tremendous progress has been made over the last two decades in unraveling the elaborate regulatory networks that control the NF-κB response. This has made the NF-κB pathway a paradigm for understanding general principles of signal transduction and gene regulation.
Following the identification of NF-κB (nuclear factor-κB) as a regulator of κB light chain expression in mature B and plasma cells by Sen and Baltimore, inducibility of its activity in response to exogenous stimuli was demonstrated in various cell types (Sen et al. 1986b; Sen et al. 1986a). Years of intense research that followed demonstrated that NF-κB is expressed in almost all cell types and tissues, and specific NF-κB binding sites are present in the promoters/enhancers of a large number of genes. It is now well-established that NF-κB plays a critical role in mediating responses to a remarkable diversity of external stimuli, and thus is a pivotal element in multiple physiological and pathological processes. The progress made in the past two decades in understanding how different stimuli culminate in NF-κB activation and how NF-κB activation is translated into a cell-type- and situation-specific response has made the NF-κB pathway a paradigm for understanding signaling mechanisms and gene regulation. Coupled with the large number of diseases in which dysregulation of NF-κB has been implicated, the continuing interest into the regulatory mechanisms that govern the activity of this important transcription factor can be easily explained.
Because of its ability to influence expression of numerous genes, the activity of NF-κB is tightly regulated at multiple levels. The primary mechanism for regulating NF-κB is through inhibitory IκB proteins (IκB, inhibitor of NF-κB), and the kinase that phosphorylates IκBs, namely, the IκB kinase (IKK) complex. A number of post-translational modifications also modulate the activity of the IκB and IKK proteins as well as NF-κB molecules themselves. In this article, we introduce the major players in the NF-κB signaling cascade and describe the key regulatory steps that control NF-κB activity. We highlight the basic principles that underlie NF-κB regulation, and many of these topics are discussed in depth in other articles on the subject.
Footnotes
Editors: Louis M. Staudt and Michael Karin
Additional Perspectives on NF-κB available at www.cshperspectives.org