The DOI matches its Crossref record; 92 of the 93 references it cites were found in a registry or an index.
Ligand-dependent inhibition of β-catenin/TCF signaling by androgen receptor
Abstract
Beta-catenin signaling may contribute to prostate cancer (CaP) progression. Although beta-catenin is known to upregulate T cell factor (TCF) target gene expression in CaP cells, recent evidence demonstrates its capacity to enhance ligand-dependent androgen receptor (AR) function. Thus, we wished to further understand the interaction between these two pathways. We find in both CaP cells (CWR22-Rv1, LAPC-4, DU145) and non-CaP cells (HEK-293, TSU, SW480, HCT-116) that beta-catenin/TCF-related transcription (CRT), as measured by activation of a synthetic promoter and that of cyclin D1, is inhibited by androgen treatment. This inhibition is AR-dependent, as it only occurs in cells expressing AR endogenously or transiently, and is abrogated by AR antagonists. Additional analyses convey that the ligand-dependent nature of CRT suppression depends on transactivation-competent AR in the nucleus, but not on indirect effects stemming from AR target gene expression. Given the recent work identifying an AR/beta-catenin interaction, and from our finding that liganded AR does not prompt gross changes in the constitutive nuclear localization of TCF4 or mutant beta-catenin, we hypothesized that transcription factor (i.e. AR and TCF) competition for beta-catenin recruitment may explain, in part, androgen-induced suppression of CRT. To address this idea, we expressed an AR mutant lacking its DNA-binding domain (DBD). This receptor could not orchestrate ligand-dependent CRT repression, thereby providing support for those recent data implicating the AR DBD/LBD as necessary for beta-catenin interaction. Further supporting this hypothesis, TCF/LEF over-expression counteracts androgen-induced suppression of CRT, and requires beta-catenin binding activity to do so. Interestingly, TCF4 over-expression potently antagonizes AR function; however, this inhibition may occur independently of beta-catenin/TCF4 interaction. These results from TCF4 over-expression analyses, taken together, provide further evidence that AR-mediated suppression of CRT is a consequence of limiting amounts of beta-catenin, and not AR target gene expression. Our analyses point to a reciprocal balance between AR and CRT function that may shape critical processes during normal prostate development and tumor progression.
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“Since AR competes with TCF4 for β-catenin binding [21], the presence of FKBP52 may be enough to shift β-catenin to favor AR over TCF4.”
From The FKBP52 Cochaperone Acts in Synergy with β-Catenin to Potentiate Androgen Receptor Signaling (2015) · cites this paper as [21]
In the citing paper
“Indeed, ligand-bound AR decreases the transcriptional activity of TCF4 in prostate cancer, colon cancer [21], and neurons [16].”
From The FKBP52 Cochaperone Acts in Synergy with β-Catenin to Potentiate Androgen Receptor Signaling (2015) · cites this paper as [21]
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Metadata
- Authors
- Chesire, D. R., & Isaacs, W. B.
- Affiliations
- Johns Hopkins University (US)
- Corresponding author
- Isaacs, William B
- ORCID
- Isaacs, William B
- Venue
- Oncogene
- Published
- 2002-12-04
- Volume
- 21
- Issue
- 55
- Pages
- 8453-8469
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- OpenAlex
- W1970833195
- Cited by
- 151
- References
- 93
- Citations by year
- 2026: 3 · 2025: 1 · 2024: 2 · 2023: 3 · 2022: 3 · 2021: 8 · 2020: 4 · 2019: 7 · 2018: 2 · 2017: 9 · 2016: 5 · 2015: 5 · 2014: 8 · 2013: 9 · 2012: 10
- FWCI
- 3.36
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Oncogene (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (CA58236, P50CA058236)
- 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 › Cancer Research › Prostate Cancer Treatment and Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
- Keywords
- androgen receptor, β-catenin, TCF/LEF, Wnt signaling, prostate cancer, ligand-dependent transcription, transcription factor competition, TCF4, cyclin D1, DNA-binding domain, transcriptional repression
- MeSH terms
- Animals, Cell Line, Cell Nucleus, Cytoskeletal Proteins, DNA-Binding Proteins, Humans, Ligands, Male, Prostatic Neoplasms, Receptors, Androgen, Transcription Factors, Transcription, Genetic, Tumor Cells, Cultured, Signal Transduction, Trans-Activators, beta Catenin, TCF Transcription Factors, Transcription Factor 7-Like 2 Protein
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