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

• Published in: Neurobiology of disease Vol. 59; pp. 165 - 176
• Main Authors: Yin, Ying, Zhang, Xiufen, Li, Zaiwang, Deng, Lingxiao, Jiao, Guoqing, Zhang, Bin, Xie, Ping, Mu, Huijun, Qiao, Weizhen, Zou, Jian
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.11.2013; Elsevier
• Subjects: Astrocyte activation; Astrocytes - drug effects; Astrocytes - metabolism; beta Catenin - genetics; beta Catenin - metabolism; Brain Neoplasms - pathology; Cell Cycle - physiology; Cell Movement - drug effects; Cell Movement - physiology; Cell Proliferation; Cells, Cultured; Gene Expression Regulation, Neoplastic - physiology; Glioma - pathology; Glioma malignancy; Glucocorticoid receptor β; Glucocorticoids - metabolism; Glucocorticoids - pharmacology; Green Fluorescent Proteins - genetics; Green Fluorescent Proteins - metabolism; Humans; Neoplasm Invasiveness; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neurology; Receptors, Glucocorticoid - genetics; Receptors, Glucocorticoid - metabolism; Signal Transduction - drug effects; Signal Transduction - physiology; TCF Transcription Factors - genetics; TCF Transcription Factors - metabolism; Transcriptional Activation; β-Catenin; β-Catenin; Glioma malignancy; Glucocorticoid receptor β; Astrocyte activation
• ISSN: 0969-9961; 1095-953X; 1095-953X
• DOI: 10.1016/j.nbd.2013.07.013

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 β (GRβ), not GRα, is upregulated and acts as a regulator of gliosis after injury. In addition, our results suggest that GRβ interacts with β-catenin and is a necessary component for proliferation and migration in both injured astrocytes and glioma cells. Further analysis indicated GRβ/β-catenin interaction as a key modulator of astrocyte reactivity through sustained Wnt/β-catenin/TCF signaling in its dominant-negative effect on GRα mediated trans-repression by a GSK-3β-independent manner. These findings expand our knowledge of the mechanism of GRβ 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. •GRβ was overexpressed and associated with β-catenin in nuclei of injured astrocytes.•Down-regulation of GRβ diminishes the reactive astrocyte phenotype.•GRβ enhances β-catenin/TCF-dependent transcriptional activity.•The Wnt/β-catenin signal pathway regulates the GRβ cellular distribution.•GRβ is associated with the pathogenesis of glioma and primary glioma cell phenotype.