Sachdev S, Hannink M
Biochemistry Department, University of Missouri-Columbia, Columbia, Missouri 65212, USA.
Mol Cell Biol. 1998 Sep;18(9):5445-56. doi: 10.1128/MCB.18.9.5445.
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.
IkappaBα蛋白既能抑制Rel/NF-κB蛋白的核输入，又能介导Rel/NF-κB蛋白从细胞核输出。我们现在证明，在Crm1介导的核输出的特异性抑制剂雷帕霉素B存在的情况下，c-Rel-IkappaBα复合物稳定地保留在细胞质中。相反，雷帕霉素B处理导致v-Rel-IkappaBα复合物从细胞质快速且完全重新定位到细胞核。在种间异核体试验中，IkappaBα也介导v-Rel的快速核穿梭。因此，v-Rel-IkappaBα复合物的细胞质保留需要持续的核输出。此外，尽管IkappaBα能够掩盖c-Rel衍生的核定位序列（NLS），但在v-Rel-IkappaBα复合物的背景下，IkappaBα无法掩盖v-Rel衍生的NLS。综上所述，我们的结果表明IkappaBα无法抑制v-Rel的核输入。我们已经确定了c-Rel和v-Rel之间的两个氨基酸差异（Y286S和L302P），这将IkappaBα无法抑制突变型c-Rel蛋白的核输入和DNA结合与肿瘤发生联系起来。我们的结果支持一个模型，其中IkappaBα介导的对c-Rel的控制丧失导致c-Rel的致癌激活。
