Loss of IkappaB Alpha-mediated Control over Nuclear Import and DNA Binding Enables Oncogenic Activation of C-Rel

The IkappaB alpha protein is able both to inhibit nuclear import of Rel/NF-kappaB proteins and to mediate the export of Rel/NF-kappaB proteins from the nucleus. We now demonstrate that the c-Rel-IkappaB alpha complex is stably retained in the cytoplasm in the presence of leptomycin B, a specific inhibitor of Crm1-mediated nuclear export. In contrast, leptomycin B treatment results in the rapid and complete relocalization of the v-Rel-IkappaB alpha complex from the cytoplasm to the nucleus. IkappaB alpha also mediates the rapid nuclear shuttling of v-Rel in an interspecies heterokaryon assay. Thus, continuous nuclear export is required for cytoplasmic retention of the v-Rel-IkappaB alpha complex. Furthermore, although IkappaB alpha is able to mask the c-Rel-derived nuclear localization sequence (NLS), IkappaB alpha is unable to mask the v-Rel-derived NLS in the context of the v-Rel-IkappaB alpha complex. Taken together, our results demonstrate that IkappaB alpha is unable to inhibit nuclear import of v-Rel. We have identified two amino acid differences between c-Rel and v-Rel (Y286S and L302P) which link the failure of IkappaB alpha to inhibit nuclear import and DNA binding of a mutant c-Rel protein to oncogenesis. Our results support a model in which loss of IkappaB alpha-mediated control over c-Rel leads to oncogenic activation of c-Rel.