Regulation of the DNA binding activity of NF-kappa B

Abstract

The DNA binding activity of the dimeric sequence-specific transcription factor NF-kappa B can be controlled by a variety of post-translational mechanisms, including interactions with inhibitor proteins and by its redox state. The NF-kappa B family of transcription factors bind to kappa B motif sequences found in promoter and enhancer regions of a wide range of cellular and viral genes. Normally NF-kappa B family proteins are held in the cytoplasm in an inactive, non-DNA binding form by labile I kappa B inhibitor proteins. When the cell is activated by one of a wide range of stimuli, typically those associated with the cellular response to pathogens or stress, proteolytic degradation of I kappa B inhibitor proteins allows active NF-kappa B to translocate to the nucleus where it activates transcription of responsive genes. The initial trigger for I kappa B degradation is a signal-induced site-specific phosphorylation by an as yet unidentified kinase, which appears to target I kappa B for the covalent addition of multiple copies of the ubiquitin polypeptide. This modification subsequently allows the proteolytic degradation of the ubiquitinated I kappa B by the cellular 26S multicatalytic proteinase (proteasome) complex. It was recently shown that increased I kappa B-alpha expression in the cytoplasm leads to I kappa B-alpha accumulating in the nuclear compartment, removing template-bound NF-kappa B, and reducing NF-kappa B-dependent transcription. These NF-kappa B-I kappa B-alpha complexes could then be actively re-exported to the cytoplasm, allowing the cell to respond to further stimuli.