IEX-1 directly interferes with RelA/p65 dependent transactivation and regulation of apoptosis

Arlt, A., Rosenstiel, Philip, Kruse, M. L., Grohmann, F., Minkenberg, J., Perkins, N. D., Folsch, U. R., Schreiber, Stefan and Schafer, H. (2008) IEX-1 directly interferes with RelA/p65 dependent transactivation and regulation of apoptosis Biochimica et Biophysica Acta - Molecular Cell Research, 1783 (5). pp. 941-952.

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The early response gene IEX-1 plays a complex role in the regulation of apoptosis. Depending on the cellular context and the apoptotic stimulus, IEX-1 is capable to either enhance or suppress apoptosis. To further dissect the molecular mechanisms involved in the modulation of apoptosis by IEX-1, we analysed the molecular crosstalk between IEX-1 and the NF-kappa B pathway. Using GST-pulldown assays, a direct interaction of IEX-1 with the C-terminal region of the subunit RelA/p65 harbouring the transactivation domain of the NF-kappa B transcription factor was shown. This interaction negatively regulates RelA/p65 dependent transactivation as shown by GAL4-and luciferase assay and was confirmed for the endogenous proteins by co-immunoprecipitation experiments. Using deletion constructs, we were able to map the C-terminal region of IEX-1 as the critical determinant of the interaction with RelA/p65. We could further show, that IEX-1 mediated NF-kappa B inhibition accounts for the reduced expression of the anti-apoptotic NF-kappa B target genes Bc1-2, Bcl-xL, cIAP1 and cIAP2, thereby sensitizing cells for apoptotic stimuli. Finally, ChIP-assays revealed that IEX-1 associates with the promoter of these genes. Altogether, our findings suggest a critical role of IEX-1 in the NF-kappa B dependent regulation of apoptotic responses. (C) 2007 Elsevier B.V All rights reserved.

Document Type: Article
Keywords: NF-κB; apoptosis; Signal transduction; IEX-1; IAP; Chromatin
Research affiliation: Kiel University
OceanRep > The Future Ocean - Cluster of Excellence
Refereed: Yes
ISSN: 0167-4889
Projects: Future Ocean
Date Deposited: 15 Oct 2010 09:21
Last Modified: 15 Jun 2016 10:52

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