COUP-TF Upregulates NGFI-A Gene Expression through an Sp1 Binding Site

Abstract

There are two COUP-TF genes, COUP-TFI and COUP-TFII (for a review, see reference 58), which share a high degree of homology in their DBDs and putative LBDs. In addition, COUP-TFI and COUP-TFII are highly conserved among different species, suggesting that they play important roles in development. Although the expression of COUP-TFI and COUP-TFII is highly overlapping in mice (24, 43), COUP-TFI is abundantly expressed in the central and peripheral nervous system, while COUP-TFII is highly expressed in the mesenchymal component of the developing organs (46). Based on this expression pattern, we have proposed that COUP-TFI is important for neural development and that COUP-TFII is important in organogenesis through the regulation of mesenchymal cell-epithelial cell interactions. Indeed, the targeted disruption of either of these two genes in mice results in a lethal phenotype. COUP-TFI-deficient mice show defects in the development of the central and peripheral nervous systems (47; unpublished observations), whereas mutation of the COUP-TFII gene results in defects in the heart and vasculature formation (unpublished observations).Vasculature and organ formation requires very tight communication between epithelial cell and mesenchymal cell populations (7). This communication is essential for the differentiation of these two cell types (14). Since COUP-TFII is highly expressed in the mesenchyme but is undetectable in the epithelium of most organs, it is likely that COUP-TFII plays an important role in mesenchymal cell-epithelial cell interactions during organogenesis. This process has been well studied for the prostate, where several growth factors and the extracellular matrix are involved in this communication between the mesenchyme and the epithelium (11,19).COUP-TFs are able to bind to a variety of dispositions of the basic AGGTCA motif, including those recognized by the receptors of retinoic acid (RAR), thyroid hormone, and vitamin D (13). This ability makes COUP-TFs capable of competing for the response elements of these receptors, thus acting as passive repressors of the transcriptional activation induced by them (12,13,56). Another mechanism of passive repression by COUP-TFs involves their ability to heterodimerize with the 9-cis retinoic acid receptor (RXR), reducing its availability for other nuclear receptors that use it as a partner. In addition, COUP-TFs contain an active repression domain within their putative LBDs (1,31). This repression domain is capable of interacting with corepressors such as SMRT and N-CoR (50), molecules that can recruit histone deacetylase activities to the DNA to suppress transcription (2,23,39).

Estrogen-related receptor-γ and peroxisome proliferator-activated receptor-γ coactivator-1α regulate estrogen-related receptor-α gene expression via a conserved multi-hormone response element

“…Embedded within the GC-rich region are 11 consensus Sp1-binding sites and this region is estrogen responsive even though there is no typical ERE (Liu et al 2003). The estrogen response may be mediated through a protein-protein interaction of Sp1 and ER (Pipaon et al 1999, Saville et al 2000. This GC-rich region, however, is not responsive to other ligand-dependent or -independent nuclear receptors examined in this study (Fig.…”

Isolation of a Novel Family of C2H2 Zinc Finger Proteins Implicated in Transcriptional Repression Mediated by Chicken Ovalbumin Upstream Promoter Transcription Factor (COUP-TF) Orphan Nuclear Receptors

“…A similar mechanism of repression was suggested in the case of another C 2 H 2 zinc finger protein, RP58 (40). Pipaon and colleagues recently demonstrated that COUP-TF I positively regulates NGF-IA expression through a putative Sp1 binding site (41). Sp1, like both CTIPs, is a C 2 H 2 zinc finger protein.…”

Nuclear Orphan Receptors Regulate Transcription of the Gene for the Human Luteinizing Hormone Receptor

“…Their repressive functions were found enhanced by interaction with two common nuclear receptor corepressors, NcoR (nuclear receptor corepressor) and SMRT (silencing mediator of retinoic acid and thyroid hormone receptor (24)). Furthermore, EAR3/COUP-TFI has been shown to interact directly with Sp1 protein, independent of the EAR3/ COUP-TFI binding site, to enhance the activation of target gene transcription (25,26). It still remains to be determined whether EAR3/COUP-TFI-mediated repression of the hLHR promoter activity requires a direct interaction between EAR3/ COUP-TFI and Sp1 protein.…”