ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2011) 25 YEP1.1

New insights into glucocorticoid receptor function

Laura Matthews

University of Manchester, Manchester, UK.

The current model of glucocorticoid receptor (GR) action is well established, whereby GR remains inactive in the cytoplasm until bound by ligand, then rapidly translocates to the nucleus to regulate target genes. However, our recent observations challenge the simplicity of this model and suggest a greater range of GR action.

We have identified a novel pathway in which the GR is recruited to the plasma membrane through binding to the lipid raft marker caveolin-1, and then couples to kinase cascades to mediate Gc effects. Using transcriptome profiling we found that many Gc-regulated genes require co-expression of caveolin-1 for their regulation, indicating that recruitment of GR to the plasma membrane is necessary to regulate a subset of Gc targets.

We have also identified a cytoplasmic role for the constitutive splice variant GRγ. The mechanism for ligand-independent gene regulation by GRγ appears indirect, through the activation of cytoplasmic kinases including JNK and subsequent recruitment of SP1 and AP1 transcription factors. GR therefore mediates some cellular effects in the unliganded state.

In further support of unliganded GR effects, we have identified cell-cycle driven phosphorylation which targets GR to the mitotic spindle, suggesting a role for GR in mitosis. Indeed, GR knockdown cells accumulate in metaphase, and show evidence of multiple spindle defects. It appears therefore, that during mitosis when cells are transcriptionally silenced, GR adopts a new ligand-independent role in directing accurate chromosome segregation.

We have therefore characterised a range of cellular effects that do not require nuclear translocation, and are influenced by GR isoform expression and ligand availability. We also reveal a novel role for GR as a regulator of mitotic progression. Identification of these novel pathways for GR function offer explanations for physiological phenomena including rapid steroid responses, and will inform novel approaches for selective therapeutic drug development in inflammatory disease.

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