Glucocorticoid receptor β regulates injury-mediated astrocyte activation and contributes to glioma pathogenesis via modulation of β-catenin/TCF transcriptional activity

Astrocytes react to central nervous system (CNS) injury and participate in gliotic responses, imparting negative, as well as positive effects on axonal regeneration. Despite the considerable biochemical and morphological changes astrocytes undergo following insult, and the known influence of steroids on glial activation, details surrounding glucocorticoid receptor expression and activity are lacking. Such mechanistic information is essential for advancing and enhancing therapies in the treatment of CNS injuries. Using an in vitro wound-healing assay, we found glucocorticoid receptor beta (GR beta), not GR alpha, is upregulated and acts as a regulator of gliosis after injury. In addition, our results suggest that GR beta interacts withfl-catenin and is a necessary component for proliferation and migration in both injured astrocytes and glioma cells. Further analysis indicated GR beta/beta-catenin interaction as a key modulator of astrocyte reactivity through sustained Wnt/beta-catenin/TCF signaling in its dominant-negative effect on GR alpha mediated trans-repression by a GSK-3 beta-independent manner. These findings expand our knowledge of the mechanism of GR beta action in promoting astrocyte proliferation and migration following injury and in glioma. This information furthers our understanding the function of glucocorticoid receptor in CNS injury and disease, as well as in the basic biochemical responses astrocytes undergo in response to injury and glioma pathogenesis. (C) 2013 Elsevier Inc. All rights reserved.