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

Biochimica Et Biophysica Acta
Alexander ArltHeiner Schäfer

Abstract

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-kappaB 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-kappaB 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-kappaB inhibition accounts for the reduced expression of the anti-apoptotic NF-kappaB target genes Bcl-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 sugge...Continue Reading

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Citations

May 9, 2012·The Journal of Clinical Investigation·Tewfik HamidiJuan Lucio Iovanna
Jan 15, 2011·Developmental and Comparative Immunology·Stephanie WiddisonTracey J Coffey
Nov 30, 2010·European Journal of Cell Biology·Alexander Arlt, Heiner Schäfer
Nov 17, 2010·Cancer Letters·Alexander ArltHeiner Schäfer
Feb 24, 2009·Trends in Biochemical Sciences·Florian Renner, M Lienhard Schmitz
Feb 6, 2013·Expert Opinion on Therapeutic Targets·Mei X WuOleg E Akilov
May 26, 2016·Nucleic Acids Research·Christopher TiedjeMatthias Gaestel
Mar 30, 2017·International Journal of Molecular Sciences·Qifeng ZhouMichael Gramlich
Feb 22, 2011·The Journal of Immunology : Official Journal of the American Association of Immunologists·Susanne Billmann-BornPhilip Rosenstiel
Jul 18, 2008·Biochemical Society Transactions·John M O'Shea, Neil D Perkins
Jan 15, 2011·American Journal of Physiology. Gastrointestinal and Liver Physiology·Rene PahlAlexander Arlt
Jul 17, 2021·The Biochemical Journal·Jack A PrescottSimon J Cook

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