Selective recruitment of p160 coactivators on glucocorticoid-regulated promoters in Schwann cells.
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.
Institut National de la Santé et de la Recherche Médicale Unité 488, 80 rue du Général Leclerc, 94276 Le Kremlin-Bicêtre Cedex, France.
Julien
J
Grenier
Amalia
A
Trousson
Anne
A
Chauchereau
Larbi
L
Amazit
Audrey
A
Lamirand
Philippe
P
Leclerc
Anne
A
Guiochon-Mantel
Michael
M
Schumacher
Charbel
C
Massaad
D000818:Animals; D024443:Aspartate Aminotransferase, Cytoplasmic / Q000235:genetics; D003593:Cytoplasm / Q000737:chemistry; D005786:Gene Expression Regulation; D051548:Histone Acetyltransferases; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics; D051379:Mice; D056920:Nuclear Receptor Coactivator 1; D051958:Nuclear Receptor Coactivator 2; D056921:Nuclear Receptor Coactivator 3; D011401:Promoter Regions, Genetic / Q000235:genetics*; D017434:Protein Structure, Tertiary / Q000235:genetics / Q000502:physiology; D034622:RNA Interference; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D020218:Response Elements / Q000235:genetics; D012583:Schwann Cells / Q000378:metabolism*; D017384:Sequence Deletion / Q000235:genetics; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000032:analysis / Q000235:genetics / Q000502:physiology
C498002:Ncoa2 protein, mouse; D051958:Nuclear Receptor Coactivator 2; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D015534:Trans-Activators; D014157:Transcription Factors; D051548:Histone Acetyltransferases; C538861:Ncoa1 protein, mouse; C538867:Ncoa3 protein, mouse; D056920:Nuclear Receptor Coactivator 1; D056921:Nuclear Receptor Coactivator 3; D024443:Aspartate Aminotransferase, Cytoplasmic