Eukaryotic organisms have developed elaborate mechanisms to ensure that gene expression is tightly regulated, thereby allowing only certain genes to be expressed in response to a particular developmental or extracellular signal. This selective expression of genes is controlled primarily by the activation of gene-specific transcription factors that can regulate their target genes both positively and negatively. In several cases, preexisting but inactive transcription factor complexes are present that can be subsequently activated in response to a particular signal. One of the most elegant and evolutionarily conserved examples of this class is provided by transcription factors belonging to the Rel family, which includes the mammalian NF-KB and the Drosophila Dorsal proteins. NF-KB was identified initially as a heterodimer of a 50-kD protein (pS0) and a 65-kD (p65) protein that was bound in the cytoplasm to a cytoplasmic retention protein called IKB (for review, see Grilli et al. 1993)(p50 and p65 have recently been renamed NFKB1 and RelA, respectively). Activation of NF-KB, which is induced by numerous agents including mitogens and inflammatory cytokines, involves its dissociation from IKB, allowing free NF-KB to be transported into the nucleus where it can regulate genes involved primarily in immune and inflammation responses, as well as certain genes involved in cell proliferation (for review, see Grilli et al. 1993). Similarly, in Drosophila, the activation of the Toll receptor leads to the disruption of the complex between the Drosophila IKB homolog, Cactus, and the Dorsal protein (Stein et al. 1991; Norris and Manley 1992), allowing translocation of Dorsal into the nucleus where it can regulate genes involved in the formation of the dorsoventral axis.

The idea that IKB proteins function as inhibitory cytoplasmic retention proteins has developed from these studes. However, recent discoveries and the characterization of novel forms of IKB proteins suggest that cytoplasmic retention may be just one mechanism by which these proteins function.