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PMID:12672265

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Citation

Widén, C, Gustafsson, JA and Wikström, AC (2003) Cytosolic glucocorticoid receptor interaction with nuclear factor-kappa B proteins in rat liver cells. Biochem. J. 373:211-20

Abstract

The glucocorticoid receptor (GR) acts as an anti-inflammatory factor. To a large extent, this activity is exerted by the interference of pro-inflammatory nuclear factor kappa B (NF-kappa B) activity. In their respective inactive forms, both GR and NF-kappa B reside in the cytoplasm and translocate to the nucleus on relevant stimulation. Previously, p65, a component of the NF-kappa B complex, and GR have been shown to interact physically in vitro, and the interaction is assumed to take place in the nucleus of cells [McKay and Cidlowski (1999) Endocrine Rev. 20, 435-459]. We have studied the interaction between GR and NF-kappa B using in vivo -like conditions. Using immunoaffinity chromatography or immunoprecipitation, combined with Western blotting, we observed that, with endogenous protein levels in cytosolic extracts of rat liver and of H4-II-E-C3 hepatoma cells and in contrast with the current belief, p65, p50 and inhibitory kappa B alpha complex interact with GR, even in the absence of glucocorticoid or an inflammatory signal. The interaction between non-liganded/non-activated GR and p65/p50 has also been verified by both p65 and p50 co-immunoprecipitations. Intracellular localization studies, using Western blotting, revealed that glucocorticoids can decrease tumour necrosis factor alpha (TNFalpha)-induced nuclear entry of p65, whereas glucocorticoid-induced GR translocation was much less affected by TNFalpha. We were also able to demonstrate a nuclear interaction of GR and p65 and p50 using in vivo -like protein concentrations. Furthermore, nuclear GR interaction with heat-shock protein 90 was enhanced distinctly by TNFalpha treatment. In conclusion, our studies suggest a strong interconnectivity between the NF-kappa B and GR-signalling pathways where also, somewhat unexpectedly, a physical interaction in the cytosol constitutes an integral part of GR-NF-kappa B cross-talk.

Links

PubMed PMC1223476 Online version:10.1042/BJ20030175

Keywords

Adrenalectomy; Animals; Cell Nucleus/drug effects; Cell Nucleus/metabolism; Chromatography, Affinity; Cytosol/metabolism; Female; Liver/metabolism; Liver Neoplasms; Liver Neoplasms, Experimental; Models, Biological; NF-kappa B/drug effects; NF-kappa B/metabolism; Rats; Receptors, Glucocorticoid/chemistry; Receptors, Glucocorticoid/drug effects; Receptors, Glucocorticoid/isolation & purification; Receptors, Glucocorticoid/metabolism; Triamcinolone Acetonide/pharmacology; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha/pharmacology

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

RAT:IKBA

enables

GO:0044877: protein-containing complex binding

ECO:0000353: physical interaction evidence used in manual assertion

RGD:2741
RGD:727889

F

Seeded From UniProt

complete

RAT:Q7TQN4

located_in

GO:0005829: cytosol

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

RAT:Q7TQN4

enables

GO:0044877: protein-containing complex binding

ECO:0000353: physical interaction evidence used in manual assertion

RGD:2741
RGD:3171
RGD:3389

F

Seeded From UniProt

complete

RAT:Q7TQN4

part_of

GO:0032991: protein-containing complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

RAT:GCR

enables

GO:0044877: protein-containing complex binding

ECO:0000353: physical interaction evidence used in manual assertion

RGD:3171
RGD:3389
RGD:727889

F

Seeded From UniProt

complete

RAT:GCR

part_of

GO:0032991: protein-containing complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

RAT:KAPCA

part_of

GO:0032991: protein-containing complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

RAT:KAPCA

enables

GO:0044877: protein-containing complex binding

ECO:0000353: physical interaction evidence used in manual assertion

RGD:2741
RGD:3171
RGD:727889

F

Seeded From UniProt

complete


See also

References

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