Nuclear transcription factor NF-kappa B: role in biology and medicine.
Bharat B. AggarwalYasunari TakadaShishir ShishodiaAngelica M. Gutierrez‐BarreraOommen V. OommenHaruyo IchikawaYuh BabaAshok Kumar
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The inducible transcription factor nuclear factor-kappa B (NF-kappaB) plays a central role in regulation of many immune, inflammatory and carcinogenic responses. While normal activation of NF-kappaB is required for cell survival and immunity, aberrant regulation of NF-kappaB leads to development of many pathological states especially those involved in acute inflammation. Recent advances in our knowledge of the signaling mechanisms those control the activation of NF-kappaB highlights the intriguing aspect of NF-kappaB regulation, namely the ability of many different signal transduction pathways originating from a wide variety of inducing mechanisms to converge on a single target, the NF-kappaB/IkappaB complex. In this review we summarize our current understanding of the NF-kappaB signaling pathways, their role in various cellular responses and the potential of using NF-kappaB as a therapeutic target in modern medicine.Cite
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Summary: Signaling leading to the survival or apoptosis of immune system cells must be balanced to ensure the normal mounting and extinguishing of immune responses. One of the essential regulators of immune cell survival is the transcription factor nuclear factor κB (NF‐κB). NF‐κB is critical for the activation of T and B lymphocytes and is a central coordinator of innate and adaptive immunity. Pathogen recognition, whether mediated via the Toll‐like receptors or via the antigen‐specific T‐ and B‐cell receptors, initiates the activation of distinct signal transduction pathways that activate NF‐κB. Activation of NF‐κB by these pathways is necessary for lymphocyte activation, expansion, and effector function in response to infection. In addition, recent work has shown that the aberrant activation of NF‐κB by these pathways can contribute to the development of autoimmunity, chronic inflammation, or lymphoid malignancy. There is thus an urgent need to understand the exact molecular details of these signal transduction cascades so that we may develop novel therapeutics. This article will review the specific signal transduction pathways that mediate NF‐κB activation in response to antigen receptor ligation in T and B lymphocytes. These newly defined pathways, which are essential for adaptive immune responses, are built around the key adapter protein, Bcl‐10. Bcl‐10 is known to participate in chromosomal translocations in human mucosa‐associated lymphoid tissue lymphomas.
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Over the past few years, the transcription factor nuclear factor (NF)-kappaB and the proteins that regulate it have emerged as a signaling system of pre-eminent importance in human physiology and in an increasing number of pathologies. While NF-kappaB is present in all differentiated cell types, its discovery and early characterization were rooted in understanding B-cell biology. Significant research efforts over two decades have yielded a large body of literature devoted to understanding NF-kappaB's functioning in the immune system. NF-kappaB has been found to play roles in many different compartments of the immune system during differentiation of immune cells and development of lymphoid organs and during immune activation. NF-kappaB is the nuclear effector of signaling pathways emanating from many receptors, including those of the inflammatory tumor necrosis factor and Toll-like receptor superfamilies. With this review, we hope to provide historical context and summarize the diverse physiological functions of NF-kappaB in the immune system before focusing on recent advances in elucidating the molecular mechanisms that mediate cell type-specific and stimulus-specific functions of this pleiotropic signaling system. Understanding the genetic regulatory circuitry of NF-kappaB functionalities involves system-wide measurements, biophysical studies, and computational modeling.
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▪ Abstract The transcription factor NF-κB, more than a decade after its discovery, remains an exciting and active area of study. The involvement of NF-κB in the expression of numerous cytokines and adhesion molecules has supported its role as an evolutionarily conserved coordinating element in the organism's response to situations of infection, stress, and injury. Recently, significant advances have been made in elucidating the details of the pathways through which signals are transmitted to the NF-κB:IκB complex in the cytosol. The field now awaits the discovery and characterization of the kinase responsible for the inducible phosphorylation of IκB proteins. Another exciting development has been the demonstration that in certain situations NF-κB acts as an anti-apoptotic protein; therefore, elucidation of the mechanism by which NF-κB protects against cell death is an important goal. Finally, the generation of knockouts of members of the NF-κB/IκB family has allowed the study of the roles of these proteins in normal development and physiology. In this review, we discuss some of these recent findings and their implications for the study of NF-κB.
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