A dominant repression domain in Tbx3 mediates transcriptional repression and cell immortalization: relevance to mutations in Tbx3 that cause ulnar-mammary syndrome

Carlson, H.

doi:10.1093/hmg/10.21.2403

Cited by 108Developmental Biology and Gene RegulationCongenital limb and hand anomaliesGenomics and Chromatin Dynamics

A dominant repression domain in Tbx3 mediates transcriptional repression and cell immortalization: relevance to mutations in Tbx3 that cause ulnar-mammary syndrome

Carlson, H.·2001·Human Molecular Genetics

DOI 10.1093/hmg/10.21.2403

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Abstract

Mutations in Tbx3 are responsible for ulnar-mammary syndrome (UMS), an autosomal dominant disorder affecting limb, tooth, hair, apocrine gland and genital development. Tbx3 is a member of a family of transcription factors that share a highly conserved DNA-binding domain known as the T-domain. UMS-causing mutations in Tbx3 have been found at numerous sites within the TBX3 gene, with many occurring downstream from the N-terminally located T-domain. The occurrence of mutations downstream of the DNA-binding domain raises the possibility that there exist important functional domains in C-terminal portions of the Tbx3 protein that affect its behavior as a transcription factor. To determine if and how such C-terminal mutations affect transcription we have mapped regions that confer transcriptional activity and nuclear localization and characterized the DNA binding properties of Tbx3. We find that Tbx3 binds the canonical Brachyury binding site as a monomer and represses transcription. We show that a key repression domain (RD1) resides in the Tbx3 C-terminus that can function as a portable repression domain. Most UMS-associated C-terminal mutants lack the RD1 and exhibit decreased or loss of transcriptional repression activity. In addition, we identify a domain responsible for nuclear localization of Tbx3 and show that two C-terminal mutants of Tbx3 have increased rates of protein decay. Finally, we show that Tbx3 can immortalize primary embryo fibroblasts and that the RD1 repression…

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Tbx3 shares a highly conserved DNA-binding domain and repression domain with Tbx2.
“It has been shown that Tbx3 shares a highly conserved DNA-binding domain and repression domain (RD) with Tbx2.19–21”
From Novel HDAC5-interacting motifs of Tbx3 are essential for the suppression of E-cadherin expression and for the promotion of metastasis in hepatocellular carcinoma (2018) · cites this paper as [21]
TBX3 functions predominantly as a transcriptional repressor.
“TBX3 functions predominantly as a transcriptional repressor.”
From The oncoprotein TBX3 is controlling severity in experimental arthritis (2019) · cites this paper as [17]

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Authors: Carlson, H.
Affiliations: Oregon Health & Science University (US)
Corresponding author: Carlson, H.
Venue: Human Molecular Genetics
Publisher: Oxford University Press (OUP)
Published: 2001-10-01
Volume: 10
Issue: 21
Pages: 2403-2413
ISSN: 0964-6906 (ISSN-L)
1460-2083
DOI: 10.1093/hmg/10.21.2403
OpenAlex: W2142480298
Cited by: 108
References: 24
Citations by year: 2025: 3 · 2024: 5 · 2023: 4 · 2022: 5 · 2021: 1 · 2020: 1 · 2019: 3 · 2018: 5 · 2017: 3 · 2016: 2 · 2015: 1 · 2014: 8 · 2013: 8 · 2012: 9
FWCI: 1.28
Type: journal article
Language: en
Open access: closed
Locations: Human Molecular Genetics (publishedVersion)
PubMed (publishedVersion)
Funders: Shriners Hospitals for Children
National Institutes of Health
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK048796, DK48796)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
Life Sciences › Biochemistry, Genetics and Molecular Biology › Developmental Biology › Congenital limb and hand anomalies
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
Keywords: TBX3, ulnar-mammary syndrome, transcriptional repression, repression domain, C-terminal mutations, nuclear localization, protein stability, cell immortalization, T-domain, transcription factor domains, autosomal dominant disorder
MeSH terms: Abnormalities, Multiple, Animals, Binding Sites, Breast, Cell Division, Cell Line, Cell Line, Transformed, DNA-Binding Proteins, Embryo, Mammalian, Female, Fibroblasts, Fungal Proteins, Gene Expression Regulation, Humans, Luciferases, Mutation, Promoter Regions, Genetic, Recombinant Fusion Proteins, Regulatory Sequences, Nucleic Acid, Syndrome, Transcription Factors, Transcription, Genetic, Transfection, Ulna, 3T3 Cells, Cellular Senescence, Limb Deformities, Congenital, T-Box Domain Proteins, Saccharomyces cerevisiae Proteins, Mice

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A dominant repression domain in Tbx3 mediates transcriptional repression and cell immortalization: relevance to mutations in Tbx3 that cause ulnar-mammary syndrome

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