Cited by 13Wnt/β-catenin signaling in development and cancerDevelopmental Biology and Gene RegulationSignaling Pathways in Disease

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

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Costa, Ângela M. Sousa, Pereira-Castro, Isabel, Ricardo, Elisabete, Spencer, Forrest, Fisher, Shannon, Costa, Luís Teixeira da·2013·PLoS ONE

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.

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  • AES regulates androgen receptor genes' transcriptional activity and Notch and Wnt signaling, and acts as a tumor suppressor.

    “AES is a distinct member of the family of Groucho/Transducin-like enhancers of split genes; it regulates androgen receptor genes’ transcriptional activity and Notch and Wnt signaling, and acts as a tumor suppressor [19].”

    From Untranslated Region Sequences and the Efficacy of mRNA Vaccines against Tuberculosis (2024) · cites this paper as [19]

    The Introduction (page unavailable) identifies GRG5/AES as a distinct short Groucho family member, and the Results (page unavailable) show that it downregulates Wnt/β-catenin signaling. The paper also cites a study of AES inhibition of androgen receptor-mediated transcription (References, page unavailable). The passages found do not establish that AES regulates Notch signaling or acts as a tumor suppressor; the tumor-suppressor references concern APC, not AES. (LLM, conf=0.88)

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Cited by

Sorted by citations

Authors
Costa, Â. M. S., Pereira-Castro, I., Ricardo, E., Spencer, F., Fisher, S., & Costa, L. T. D.
Affiliations
  • Universidade do Porto (PT)
  • Johns Hopkins University (US)
  • University of Pennsylvania (US)
Corresponding author
  • Fisher, Shannon
  • Costa, Luís Teixeira da
Venue
PLoS ONE
Published
2013-07-01
Volume
8
Issue
7
Pages
e67694
ISSN
1932-6203 (ISSN-L)
OpenAlex
W2082247896
Cited by
13
References
1
Citations by year
2024: 1 · 2023: 1 · 2022: 1 · 2021: 1 · 2020: 1 · 2018: 3 · 2017: 2 · 2016: 1 · 2015: 1 · 2014: 1
FWCI
0.38
Type
journal article
Language
en
Open access
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
Funders
Fundação para a Ciência e a Tecnologia (COMPETE, SFRH/BD/24402/2005, PEst-C/AGR/UI0115/2011, UI0115, SFRH/BD/44264/2008)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
Keywords
TCF4, TCF/LEF transcription factors, Wnt signaling, transcriptional repression, β-catenin, dorsoventral patterning, zebrafish embryonic development, intestinal epithelium
MeSH terms
Animals, Humans, Repressor Proteins, Zebrafish, Signal Transduction, Transcriptional Activation, Down-Regulation, Up-Regulation, Gene Expression Regulation, Developmental, Amino Acid Motifs, Zebrafish Proteins, Wnt Proteins, beta Catenin, Co-Repressor Proteins, HEK293 Cells, Transcription Factor 7-Like 2 Protein, Protein Interaction Maps

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