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Selective Recruitment of p160 Coactivators on Glucocorticoid-Regulated Promoters in Schwann Cells

Institut National de la Santé et de la Recherche Médicale (INSERM) (J.G., A.T., A.L., P.L., M.S., C.M.), Unité 488, Institut Fédératif de Recherche (IFR) 93, 94276 Le Kremlin-Bicêtre Cedex, France; Centre National de la Recherche Scientifique (A.C.), Unité Propre de Recherche 9079, 94800 Villejuif, France; INSERM (L.A., A.G.-M.), Unité 135, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris, IFR93, 94275 Le Kremlin-Bicêtre Cedex, France; and Faculté de Médecine Paris-Sud (A.G.-M., C.M.), 94276 Le Kremlin-Bicêtre Cedex, France

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

In the nervous system, glucocorticoid hormones play a major role during development and throughout life. We studied the mechanisms of action of the glucocorticoid receptor (GR) and its interactions with p160 coactivator family members [steroid receptor coactivator (SRC)-1 (a and e), SRC-2 and SRC-3] in mouse Schwann cells (MSC80). We found that the three p160s were expressed in MSC80 cells. We have shown by functional overexpression and RNA interference experiments that the recruitment of these coactivators by the GR is promoter dependent. A minimal promoter containing two glucocorticoid response elements, (GRE)2-TATA, recruits SRC-1 (a and e) and SRC-3, whereas SRC-2 is excluded. Within the context of the more complex mouse mammary tumor virus promoter, GR recruits SRC-1e and SRC-2, whereas SRC-1a and SRC-3 are not implicated. Furthermore, we have identified cytosolic aspartate aminotransferase as a GR target gene in MSC80 cells by microarray experiments. The GR recruits exclusively SRC-1e in the context of the cytosolic aspartate aminotransferase promoter. Because SRC-1 is the omnipresent coactivator of GR, we further investigated the interactions between GR and this coactivator in Schwann cells by reporter assays and immunocytochemistry experiments with deleted forms of SRC-1. We have shown that SRC-1 unexpectedly interacts with GR via its two nuclear receptor binding domains, thus providing a novel mechanism of GR signaling within the nervous system.

NURSA Molecule Pages Link:

Nuclear Receptors:   GR

Coregulators:   RIP140  |  SRC-1  |  GRIP1  |  AIB1

Ligands:   Dexamethasone  |  Progesterone

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