Involvement of β-catenin and unusual behavior of CBP and p300 in glucocorticosteroid signaling in Schwann cells

Abstract

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 CBP͞p300 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 ␤-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.␤-catenin ͉ coactivator ͉ glucocorticosteroid receptor ͉ nervous system

Corepressive Action of CBP on Androgen Receptor Transactivation in Pericentric Heterochromatin in a Drosophila Experimental Model System

“…CBP/ p300 is a well-established coactivator for several classes of sequence-specific transcriptional factors, including NRs. However, CBP/p300 also transrepresses transcription through protein acetylation by CBP/p300 (16,26). As is consistent with previous findings (55), a molecular dissection of p300 recovered the presence of a transrepressive domain.…”

Steroid Receptor Coactivator 1 Promotes Human Hepatocellular Carcinoma Progression by Enhancing Wnt/β-Catenin Signaling

“…4G), indicating that SRC-1 directly binds to ␤-catenin. This is in agreement with a previous report (23). Furthermore, GST pull-down assays showed that SRC-1 protein interacted with the Arm3-10 domains of ␤-catenin (Fig.…”

Wnt/β-Catenin Signaling Is an Essential and Direct Driver of Myelin Gene Expression and Myelinogenesis

“…This was motivated by our previous finding of a Schwann cellspecific cross talk between ␤-catenin and steroid signaling (Fonte et al, 2005). Our results show that Wnt/␤-catenin signaling is a forward driver of myelin gene expression and myelin compaction.…”

“…Each TCF was targeted with four different sequences of siRNA directed against four different regions of the cognate mRNA. The small interfering ␤-catenin vector was described by Fonte et al (2005). Wnt1 was purchased from Biovision.…”