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NF-kappa B signalling is inhibited by glucocorticoid receptor and STAT6 via distinct mechanisms

Lookup NU author(s): Dr Glyn NelsonORCiD


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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 IkappaBalpha showed that activated STAT6 inhibited TNFalpha-mediated IkappaBalpha phosphorylation and degradation, whereas GR activation did not alter IkappaBalpha kinetics. This demonstrates a clear separation of two distinct mechanisms of inhibition by STAT6 and GR upon the NF-kappaB pathway.

Publication metadata

Author(s): Nelson G, Wilde GJC, Spiller DG, Kennedy SM, Ray DW, Sullivan E, Unitt JF, White MRH

Publication type: Article

Publication status: Published

Journal: Journal of Cell Science

Year: 2003

Volume: 116

Issue: 12

Pages: 2495-2503

Print publication date: 15/06/2003

ISSN (print): 0021-9533

ISSN (electronic): 1477-9137

Publisher: The Company of Biologists Ltd


DOI: 10.1242/jcs.00461


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