The T-box Repressors TBX2 and TBX3Specifically Regulate the Tumor Suppressor Genep14 via a Variant T-site in the Initiator
Open accessAbstract
The murine tumor suppressor p19(ARF) (p14(ARF) in humans) is thought to fulfill an important protective role in preventing primary cells from oncogenic transformation via its action in the p53 pathway. Several disease-implicated regulators of p19(ARF) are known to date, among which are the T-box genes TBX2, which resides on an amplicon in primary breast tumors, and TBX3, which is mutated in the human developmental disorder Ulnar-Mammary syndrome. Here we identify a variant T-site, matching 13 of 20 nucleotides of a consensus T-site, as the essential TBX2/TBX3-binding element in the human p14(ARF) promoter. Mutant analysis indicates that both the consensus T-box and a C-terminal conserved repression domain are essential for p14(ARF) repression. Whereas the core nucleotides required for interaction of the archetypal T-box protein Brachyury with a consensus T-site are conserved in the variant site, additional flanking nucleotides contribute to the specificity of TBX2 binding. This is illustrated by the inability of TBX1A or Xbra to activate via the variant p14(ARF) T-site. Importantly, this suggests a hitherto unsuspected level of specificity associated with T-box factors and corresponding recognition sites in regulating their target genes in vivo.
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p19ARF and p14ARF are tumor suppressor genes that stabilize p53 via inactivation of Mdm2 in response to oncogenic stresses.
“the tumor suppressor genes that stabilize p53 (Trp53) via inactivation of Mdm2 in response to a variety of oncogenic stresses (Honda and Yasuda, 1999;Brummelkamp et al., 2002;Lingbeek et al., 2002;Kim and Sharpless, 2006).”
From Tbx3 controls the fate of hepatic progenitor cells in liver development by suppressing <i>p19ARF</i> expression (2008) · cites this paper as Lingbeek et al., 2002
The opening background passage (page unavailable) identifies mouse p19ARF and human p14ARF as counterparts and says p19ARF is induced by oncogenic signaling and leads via MDM2 to stable, active p53. It does not explicitly say that ARF inactivates MDM2, so that specific mechanism is not established by our copy. (LLM, conf=0.82)
Experimental — accuracy not yet measuredTbx3 is a transcriptional repressor for p19ARF and p14ARF.
“Tbx3 is known as a transcriptional repressor for p19 ARF (Cdkn2a -Mouse Genome Informatics) and p14 ARF (the human ortholog of p19 ARF )”
From Tbx3 controls the fate of hepatic progenitor cells in liver development by suppressing <i>p19ARF</i> expression (2008) · cites this paper as Lingbeek et al., 2002
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Retracted
- Authors
- Lingbeek, M. E., Jacobs, J. J. L., & van Lohuizen, M.
- Affiliations
- The Netherlands Cancer Institute (NL)
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2002-07
- Volume
- 277
- Issue
- 29
- Pages
- 26120-26127
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W1965159397
- Cited by
- 160
- References
- 7
- Citations by year
- 2026: 1 · 2025: 4 · 2023: 2 · 2022: 2 · 2021: 7 · 2020: 3 · 2019: 5 · 2018: 4 · 2017: 2 · 2016: 9 · 2015: 5 · 2014: 9 · 2013: 11 · 2012: 10
- FWCI
- 4.42
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- KWF Kankerbestrijding
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- TBX2, TBX3, p14ARF, T-box transcription factor, promoter regulation, transcriptional repression, Brachyury, Xbra, p53 pathway, tumor suppressor, transcription factor binding specificity, ulnar-mammary syndrome
- MeSH terms
- Brachyury Protein, Animals, Base Sequence, Binding Sites, Cell Transformation, Neoplastic, DNA, Fetal Proteins, Humans, Molecular Sequence Data, Mutation, Promoter Regions, Genetic, 3T3 Cells, Sequence Deletion, Codon, Initiator, Dimerization, COS Cells, Genes, p16, T-Box Domain Proteins, Transcription Initiation Site, Tumor Suppressor Protein p14ARF, Mice
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