REGULATION OF THE DNA-BINDING ACTIVITY OF NF-KAPPA-B

The DNA binding activity of the dimeric sequence-specific transcriptio n factor NF-kappa B can be controlled by a variety of post-translation al mechanisms, including interactions with inhibitor proteins and by i ts redox state. The NF-kappa B family of transcription factors bind to kappa B motif sequences found in promoter and enhancer regions of a w ide range of cellular and viral genes. Normally NF-kappa B family prot eins 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 on e of a wide range of stimuli, typically those associated with the cell ular response to pathogens or stress, proteolytic degradation of I kap pa B inhibitor proteins allows active NF-kappa B to translocate to the nucleus where it activates transcription of responsive genes. The ini tial trigger for I kappa B degradation is a signal-induced site-specif ic phosphorylation by an as yet unidentified kinase, which appears to target I kappa B for the covalent addition of multiple copies of the u biquitin polypeptide. This modification subsequently allows the proteo lytic degradation of the ubiquitinated I kappa B by the cellular 26S m ulticatalytic proteinase (proteasome) complex. It was recently shown t hat increased I kappa B-alpha expression in the cytoplasm leads to I k appa B-alpha accumulating in the nuclear compartment, removing templat e-bound NF-kappa B, and reducing NF-kappa B-dependent transcription. T hese NF-kappa B-I kappa B-alpha complexes could then be actively re-ex ported to the cytoplasm, allowing the cell to respond to further stimu li.