TBX-3, the Gene Mutated in Ulnar-Mammary Syndrome, Is a Negative Regulator of p19 and Inhibits Senescence
Open accessAbstract
Prolonged culturing of rodent cells in vitro activates p19(ARF) (named p14(ARF) in man), resulting in a p53-dependent proliferation arrest known as senescence. The p19(ARF)-Mdm2-p53 pathway also serves to protect primary cells against oncogenic transformation. We have used a genetic screen in mouse neuronal cells, conditionally immortalized by a temperature-sensitive mutant of SV40 large T antigen, to identify genes that allow bypass of senescence. Using retroviral cDNA expression libraries, we have identified TBX-3 as a potent inhibitor of senescence. TBX-3 is a T-box gene, which is found mutated in the human developmental disorder Ulnar-Mammary Syndrome. We have shown that TBX-3 potently represses expression of both mouse p19(ARF) and human p14(ARF). We have also shown here that point mutants of TBX-3, which are found in Ulnar-Mammary Syndrome, have lost the ability to inhibit senescence and fail to repress mouse p19(ARF) and human p14(ARF) expression. These data suggest that the hypoproliferative features of this genetic disorder may be caused, at least in part, by deregulated expression of p14(ARF).
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TBX3 functions primarily as a transcriptional repressor and initial reports suggested that it can promote proliferation by repressing the cell cycle regulators p14/p19ARF and p21.
“TBX3 functions primarily as a transcriptional repressor and initial reports suggested that it can promote proliferation by repressing the cell cycle regulators p14/p19ARF and p21 [60–62].”
From The oncoprotein TBX3 is controlling severity in experimental arthritis (2019) · cites this paper as [61]
The Results section ('TBX-3 Down-regulates p19 ARF'; page unavailable) reports TBX-3-mediated repression of the human p14 ARF promoter and reduced p19 ARF expression. The Discussion says TBX-3 drives proliferation and inhibits senescence, consistent with that part of the claim. The passages found do not show that TBX-3 represses p21, so this source does not support the claim in full. (LLM, conf=0.87)
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 Brummelkamp et al., 2002
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 Brummelkamp et al., 2002
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- Authors
- Brummelkamp, T. R., Kortlever, R. M., Lingbeek, M., Trettel, F., MacDonald, M. E., van Lohuizen, M., & Bernards, R.
- Affiliations
- The Netherlands Cancer Institute (NL)
- Massachusetts General Hospital (US)
- Corresponding author
- Bernards, René
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2002-02
- Volume
- 277
- Issue
- 8
- Pages
- 6567-6572
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W1986820083
- Cited by
- 154
- References
- 36
- Citations by year
- 2026: 1 · 2023: 2 · 2022: 5 · 2021: 8 · 2020: 2 · 2019: 3 · 2018: 1 · 2016: 7 · 2015: 3 · 2014: 11 · 2013: 13 · 2012: 11
- FWCI
- 6.00
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion, cc-by)
- Funders
- KWF Kankerbestrijding
- National Institutes of Health
- National Institute of Neurological Disorders and Stroke (NS32765, R01NS032765)
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- ulnar-mammary syndrome, p19ARF, p14ARF, cellular senescence, senescence bypass, p53, MDM2, T-box transcription factor, point mutations, neurons, oncogenic transformation
- MeSH terms
- Aging, Animals, Bone Diseases, Breast Diseases, Cell Line, Cells, Cultured, Chlorocebus aethiops, Corpus Striatum, Embryo, Mammalian, Female, Gene Expression Regulation, Humans, Mutation, Placenta, Pregnancy, Promoter Regions, Genetic, Retroviridae, Suppression, Genetic, Syndrome, Transfection, Gene Library, Genes, p53, COS Cells, Cyclin-Dependent Kinase Inhibitor p16, Genes, p16, T-Box Domain Proteins, Tumor Suppressor Protein p14ARF, Mice
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