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Molecular and Cellular Biology, September 1998, p. 5445-5456, Vol. 18, No. 9
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Loss of Ikappa Balpha -Mediated Control over Nuclear Import and DNA Binding Enables Oncogenic Activation of c-Rel

Shrikesh Sachdev and Mark Hannink*

Biochemistry Department, University of Missouri---Columbia, Columbia, Missouri 65212

Received 13 March 1998/Returned for modification 30 April 1998/Accepted 10 June 1998

The Ikappa Balpha protein is able both to inhibit nuclear import of Rel/NF-kappa B proteins and to mediate the export of Rel/NF-kappa B proteins from the nucleus. We now demonstrate that the c-Rel-Ikappa Balpha 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-Ikappa Balpha complex from the cytoplasm to the nucleus. Ikappa Balpha 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-Ikappa Balpha complex. Furthermore, although Ikappa Balpha is able to mask the c-Rel-derived nuclear localization sequence (NLS), Ikappa Balpha is unable to mask the v-Rel-derived NLS in the context of the v-Rel-Ikappa Balpha complex. Taken together, our results demonstrate that Ikappa Balpha 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 Ikappa Balpha to inhibit nuclear import and DNA binding of a mutant c-Rel protein to oncogenesis. Our results support a model in which loss of Ikappa Balpha -mediated control over c-Rel leads to oncogenic activation of c-Rel.

* Corresponding author. Mailing address: Biochemistry Department, University of Missouri---Columbia, Columbia, MO 65212. Phone: (573) 882-7971. Fax: (573) 884-4597. E-mail: hanninkm{at}missouri.edu.

Molecular and Cellular Biology, September 1998, p. 5445-5456, Vol. 18, No. 9
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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