IEX-1 directly interferes with RelA/p65 dependent transactivation and regulation of apoptosis (2008)

Author(s): Arlt A, Rosenstiel P, Kruse ML, Grohmann F, Minkenberg J, Perkins ND, Folsch UR, Schreiber S, Schafer H

    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-κB 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-κB 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-κB inhibition accounts for the reduced expression of the anti-apoptotic NF-κB 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 suggest a critical role of IEX-1 in the NF-κB dependent regulation of apoptotic responses.

      • Date: 23-12-2007
      • Journal: Biochimica et Biophysica Acta: Molecular Cell Research
      • Volume: 1783
      • Issue: 5
      • Pages: 941-952
      • Publisher: Elsevier BV
      • Publication type: Article
      • Bibliographic status: Published

      Professor Neil Perkins
      Prof of Gene Exp & Signalling