Involvement of {beta}-catenin and unusual behavior of CBP and p300 in glucocorticosteroid signaling in Schwann cells.
In the nervous system, glucocorticosteroid hormones play a major role during development and adult life. Myelin-forming cells are among the targets of glucocorticosteroids, which have been shown to promote myelination both in the central and peripheral nervous system. Glucocorticosteroid-stimulated gene transcription is mediated by the glucocorticosteroid receptor (GR) that recruits coactivators of the p160 family, forming a docking platform for secondary coactivators, such as cAMP-response element binding protein (CREB)-binding protein (CBP) or its close homologue, p300. Here, we investigated the role of CBP and p300 in mouse Schwann cells (MSC80). We show that, although the CBP/p300 binding domain of steroid receptor coactivator-1 is crucial for GR transactivation, neither CBP nor p300 enhanced GR transcriptional activation, as shown by overexpression and small interfering RNA (siRNA) knocking-down experiments. Unexpectedly, overexpression of p300, considered as a coactivator of the GR, resulted in inhibition of GR transcriptional activity. Studies with p300 deletion mutants demonstrated that p300-dependent repression is related to its acetyltransferase activity. Functional and pull-down assays showed that beta-catenin may be the coactivator replacing CBP in the GR transcriptional complex. Our results suggest the formation of a GR-coactivator complex within Schwann cells, indicating that glucocorticosteroids may act by means of unusual partners in the nervous system, and we show a repressive effect of p300 on nuclear receptors.
Fonte
Cosima
C
Unité Mixte de Recherche 488 and Equipe 120 Institut National de la Santé et de la Recherche Médicale 80, Rue du Général Leclerc, 94276 Le Kremlin-Bicêtre Cedex, France.
Grenier
Julien
J
Trousson
Amalia
A
Chauchereau
Anne
A
Lahuna
Olivier
O
Baulieu
Etienne-Emile
EE
Schumacher
Michael
M
Massaad
Charbel
C
D000818:Animals; D050882:CREB-Binding Protein / Q000378:metabolism*; D005786:Gene Expression Regulation; D005938:Glucocorticoids / Q000378:metabolism*; D007150:Immunohistochemistry; D008156:Luciferases; D051379:Mice; D034741:RNA, Small Interfering / Q000235:genetics; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D012583:Schwann Cells / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D014162:Transfection; D051176:beta Catenin / Q000378:metabolism*; D050880:p300-CBP Transcription Factors / Q000378:metabolism*
D005938:Glucocorticoids; D034741:RNA, Small Interfering; D011965:Receptors, Glucocorticoid; D051176:beta Catenin; D008156:Luciferases; D050882:CREB-Binding Protein; D050880:p300-CBP Transcription Factors