Related resources
Full-text held externally
- DOI: 10.1242/jcs.00461
Search for item elsewhere
University researcher(s)
Academic department(s)
NF-kB signalling is ihhibited by glucocorticoid receptor and STAT6 via distinct mechanisms
Nelson G, Wilde GJ, Spiller DG, Kennedy SM, Ray DW, Sullivan E, Unitt JF, White MRH
J Cell Sci. 2003;116:2495-2503.
Access to files
Full-text and supplementary files are not available from Manchester eScholar. Full-text is available externally using the following links:
Full-text held externally
- DOI: 10.1242/jcs.00461
Abstract
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.
Keyword(s)
Hela Cells; Humans; STAT6 Transcription Factor; agonists: Receptors, Glucocorticoid; antagonists & inhibitors: Trans-Activators; drug effects: Feedback, Biochemical; drug effects: Genes, Regulator; drug effects: I-kappa B Proteins; drug effects: Signal Transduction; genetics: Active Transport, Cell Nucleus; genetics: Cell Nucleus; genetics: NF-kappa B; genetics: Stress, Physiological; pharmacology: Interleukin-4; pharmacology: Mifepristone; pharmacology: Recombinant Fusion Proteins; pharmacology: Tumor Necrosis Factor-alpha