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Differential Recruitment of p160 Coactivators by Glucocorticoid Receptor between Schwann Cells and Astrocytes

Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche (UMR) 488 (J.G., A.T., M.S., C.M.), Institut Fédératif de Recherche 93, 94276 Le Kremlin-Bicêtre Cedex, France; Faculté de Médecine Paris-Sud (J.G., A.T., M.S., C.M.) 94270 Le Kremlin-Bicêtre Cedex, France; Centre National de la Recherche Scientifique (CNRS) UMR 8125 (A.C.), Institut Gustave Roussy, 94805 Villejuif, France; and Biologie Cellulaire des Membranes (J.C.), Institut Jacques Monod, UMR 7592 CNRS/Universités Paris 6 et Paris 7, 75251 Paris Cedex 05, France

Address all correspondence and requests for reprints to: Charbel Massaad, Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche 488, 80 rue du Général Leclerc, 94276, Le Kremlin-Bicêtre, Cedex. E-mail: massaad{at}kb.inserm.fr.

In the nervous system, glucocorticoids can exert beneficial or noxious effects, depending on their concentration and the duration of hormonal stimulation. They exert their effects on neuronal and glial cells by means of their cognate receptor, the glucocorticoid receptor (GR), which recruits the p160 coactivator family members SRC-1 (steroid receptor coactivator 1), SRC-2, and SRC-3 after hormone binding. In this study, we investigated the molecular pathways used by the GR in cultured glial cells of the central and the peripheral nervous systems, astrocytes and Schwann cells (MSC80 cells), respectively. We performed functional studies based on transient transfection of a minimal glucocorticoid-sensitive reporter gene into the glial cells to test the influence of overexpression or selective inhibition by short interfering RNA of the three p160 coactivator family members on GR transactivation. We demonstrate that, depending on the glial cell type, GR differentially recruits p160 family members: in Schwann cells, GR recruited SRC-1a, SRC-1e, or SRC-3, whereas in astrocytes, SRC-1e and SRC-2, and to a lesser extent SRC-3, were active toward GR signaling. The C-terminal nuclear receptor-interacting domain of SRC-1a participates in its exclusion from the GR transcriptional complex in astrocytes. Immunolocalization experiments revealed a cell-specific intracellular distribution of the p160s, which was dependent on the duration of the hormonal induction. For example, within astrocytes, SRC-1 and SRC-2 were mainly nuclear, whereas SRC-3 unexpectedly localized to the lumen of the Golgi apparatus. In contrast, in Schwann cells, SRC-1 showed a nucleocytoplasmic shuttling depending on hormonal stimulation, whereas SRC-2 remained strictly nuclear and SRC-3 remained predominantly cytoplasmic. Altogether, these results highlight the cell specificity and the time dependence of p160s recruitment by the activated GR in glial cells, revealing the complexity of GR-p160 assembly in the nervous system.

NURSA Molecule Pages Link:

Nuclear Receptors:   GR  |  PR

Coregulators:   RIP140  |  SRC-1  |  GRIP1  |  AIB1

Ligands:   Dexamethasone

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