Post-translational modification of RelA(p65) NF-κB

Stimulation with diverse agents activates the NF-κB (nuclear factor κB) transcription factor, affecting inflammatory and immune responses, proliferation, differentiation, apoptosis and tumourigenesis. Determining how NF-κB elicits such distinct responses is essential to understanding NF-κB function in diseased tissues. Recent developments illustrating that post-translational modification of NF-κB subunits influences their nuclear role are discussed. These observations suggest that diagnosis and new therapies based on reprogramming NF-κB activity could be more efficient than total NF-κB inhibition. NF-κB (nuclear factor κB) is a pleiotrophic transcription factor NF-κB is a sequence-specific transcription factor activated by a bewildering array of stimuli including biological agents such as bacterial lipopolysaccharide and inflammatory cytokines, phorbol esters and cytotoxic stimuli such as chemotherapeutic drugs, UV light and ionizing radiation [1]. There are five members of the mammalian NF-κB family, RelA(p65), RelB, c-Rel, p105/p50 and p100/p52, all of which contain homologous N-terminal RHDs (Rel homology domains). NF-κB functions as a homoor heterodimer of these subunits, with the RHD mediating dimerization, DNA binding, nuclear localization and interaction with the inhibitor of NF-κB (IκB) proteins. Generally, NF-κB is found in the cytoplasm of resting cells, anchored to IκB. The ratelimiting step of NF-κB activation therefore involves its release from IκB, allowing NF-κB to translocate to the nucleus. NF-κB is activated in response to hundreds of different stimuli and in turn regulates hundreds of diverse target genes. But how is specificity of NF-κB function achieved? Understanding the complexity of the NF-κB response, and the mechanisms that modify it, is critical if we are to comprehend and ultimately exploit the different roles NF-κB plays in normal tissue and diseases such as cancer. In particular, the ability of anti-cancer therapies (daunorubicin, etoposide, ionizing radiation), tumour initiators (UV, phorbol esters), tumour suppressor proteins (ARF and p53) and oncogenes (Ras and Bcr-Abl) to regulate NF-κB raises the question of how the diverse effects of these stimuli are integrated into a specific transcriptional response. Some are known to trigger an anti-apoptotic or oncogenic NF-κB, whereas others activate an NF-κB that helps to induce apoptosis, consistent with a tumour-suppressor function [2].