GRG5/AES Interacts with T-Cell Factor 4 (TCF4) and Downregulates Wnt Signaling in Human Cells and Zebrafish Embryos

Abstract

Transcriptional control by TCF/LEF proteins is crucial in key developmental processes such as embryo polarity, tissue architecture and cell fate determination. TCFs associate with β-catenin to activate transcription in the presence of Wnt signaling, but in its absence act as repressors together with Groucho-family proteins (GRGs). TCF4 is critical in vertebrate intestinal epithelium, where TCF4-β-catenin complexes are necessary for the maintenance of a proliferative compartment, and their abnormal formation initiates tumorigenesis. However, the extent of TCF4-GRG complexes’ roles in development and the mechanisms by which they repress transcription are not completely understood. Here we characterize the interaction between TCF4 and GRG5/AES, a Groucho family member whose functional relationship with TCFs has been controversial. We map the core GRG interaction region in TCF4 to a 111-amino acid fragment and show that, in contrast to other GRGs, GRG5/AES-binding specifically depends on a 4-amino acid motif (LVPQ) present only in TCF3 and some TCF4 isoforms. We further demonstrate that GRG5/AES represses Wnt-mediated transcription both in human cells and zebrafish embryos. Importantly, we provide the first evidence of an inherent repressive function of GRG5/AES in dorsal-ventral patterning during early zebrafish embryogenesis. These results improve our understanding of TCF-GRG interactions, have significant implications for models of transcriptional repression by TCF-GRG complexes, and lay the groundwork for in depth direct assessment of the potential role of Groucho-family proteins in both normal and abnormal development.

Glucocorticoid Receptor β Acts as a Co-activator of T-Cell Factor 4 and Enhances Glioma Cell Proliferation

“…Unlike p15Rs [32], the involvement of GRβ in Wnt signaling does not appear to occur through disrupting or enhancing the interaction of β-catenin and TCF-4. The present observation that the N terminus of TCF-4, which serves as the binding site for β-catenin [35], allowed for binding to GRβ implies that GRβ may competes with inhibitory factors like p15Rs [36] and GRG5/AES [37] for binding to TCF-4.…”

Improving mRNA-Based Therapeutic Gene Delivery by Expression-Augmenting 3′ UTRs Identified by Cellular Library Screening

“…47 AES is a distinct member of the Groucho/Transducin-like enhancer of split gene family, and it regulates androgen receptor transcriptional activity and Notch and Wnt signaling and acts as a tumor suppressor gene. [48][49][50] We validated the identified 3 0 UTR motives in two common applications for mRNA-based gene delivery. First, we studied their usefulness for vaccination with antigen-encoding mRNA.…”

Controlling the Messenger: Regulated Translation of Maternal mRNAs in Xenopus laevis Development

“…In addition to Cripto-1, other Bic-C target mRNAs encode proteins implicated in Nodal/TGFβ signaling, including the Smad4b (Chang et al 2006) and Oct25 transcription factors (Cao et al 2008), and Coco (referred to as Dand5 in mammals), a secreted signaling antagonist (Bell et al 2003; Vonica and Brivanlou 2007; Bates et al 2013). Cripto-1 has also been implicated as a regulator of Wnt signaling (Kraus et al 2012; Maisonneuve et al 2009), and therefore it is interesting that some Bic-C target mRNAs, such as the AES/GRG5 transcription factor (Costa et al 2013) and the Ddx5 RNA helicase (Guturi et al 2014), encode proteins known to affect Wnt signaling.…”