Regulation of NF-kappaB function

In the 20 years since its discovery, research into the NF-kappaB (nuclear factor-kappaB) family of transcription factors has revealed an amazing diversity of functions. NF-kappaB proteins are regulators of the immune, inflammatory, stress, proliferative and apoptotic responses of a cell to a very large number of different stimuli. NF-kappaB complexes can be found in all cell types, indicating that the number of different contexts in which NF-kappaB can become induced is enormous. Moreover, many reports suggest apparently opposing or contradictory functions for NF-kappaB. It is clear that it is not simply enough to understand the pathways leading to nuclear localization and DNA binding of NF-kappaB subunits. It is also important that we comprehend the regulation of NF-kappaB subunit functionality if we are to understand the NF-kappaB pathway as a whole. These issues include the mechanisms controlling the specificity and timing of genes regulated by NF-kappaB under particular circumstances. They also include the reasons why NF-kappaB subunits can sometimes repress rather than activate transcription and how the NF-kappaB response is integrated with other important transcription factor pathways in the cell, such as the induction of the p53 tumour suppressor following DNA damage or oncogene activation. Understanding the mechanisms that regulate NF-kappaB function has important implications for our understanding of the role that NF-kappaB subunits play in human inflammatory diseases and cancer, and could also impact on the use of future NF-kappaB-based clinical therapies.