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NF-kappaB transcription factors are involved in the cellular response to stress, and are regulated by inhibitor (IkappaB) proteins, which prevent NF-kappaB-mediated transcription by maintaining NF-kappaB in the cytoplasm. Proteins from other pathways are also known to regulate NF-kappaB negatively, notably the glucocorticoid receptor (GR) and IL-4-responsive STAT6. Both pathways were shown to inhibit NF-kappaB-mediated transcription, by expressing either STAT6 or GR and activating the respective pathways. Using fluorescent fusion proteins, we show that GR alters the timing of activated p65 NF-kappaB nuclear occupancy by increasing the export rate of p65 and is independent of whether GR is present as a dimer or monomer. Expression of STAT6 was also shown to alter p65 nuclear occupancy but appeared to affect the import rate and hence the overall maximal level of p65 translocation. Activating STAT6 with IL-4 prior to activating NF-kappaB significantly increased this inhibition. Investigation of IkappaBa showed that activated STAT6 inhibited TNFalpha-mediated IkappaBa phosphorylation and degradation, whereas GR activation did not alter IkappaBalphakinetics. This demonstrates a clear separation of two distinct mechanisms of inhibition by STAT6 and GR upon the NF-kappaB pathway.

Original publication




Journal article


J Cell Sci

Publication Date





2495 - 2503


Active Transport, Cell Nucleus, Cell Nucleus, Feedback, Physiological, Genes, Regulator, HeLa Cells, Humans, I-kappa B Proteins, Interleukin-4, Mifepristone, NF-KappaB Inhibitor alpha, NF-kappa B, Receptors, Glucocorticoid, Recombinant Fusion Proteins, STAT6 Transcription Factor, Signal Transduction, Stress, Physiological, Trans-Activators, Tumor Necrosis Factor-alpha