TBX3 and Its Isoform TBX3+2a Are Functionally Distinctive in Inhibition of Senescence and Are Overexpressed in a Subset of Breast Cancer Cell Lines
Abstract
TBX3 is a transcription factor of the T-box gene family. Mutations of TBX3 cause ulnar-mammary syndrome (MIM 181450) in humans, an autosomal dominant disorder characterized by the absence or underdevelopment of the mammary glands and other congenital anomalies. It recently was found that TBX3 was able to immortalize mouse embryo fibroblast (MEF) cells. In addition, TBX2, a homologue of TBX3, is active in preventing senescence in rodent cells and was found to be amplified in some human breast cancers, suggesting TBX3 plays a role in breast cancer. This study examined the function of TBX3 and its isoform, TBX3 + 2a. TBX3 + 2a differs from TBX3 in the DNA binding domain with an extra 20 amino acids produced by alternative splicing. We first examined the tissue expression and alternative splicing patterns of these two isoforms. We found that TBX3 and TBX3 + 2a are widely expressed in humans and mice, and alternative splicing could be tissue specific and species specific. Overexpression of TBX3 is able to immortalize MEF cells, whereas TBX3 + 2a shows an acceleration of senescence, a functional difference that may be explained by the fact that these two isoforms may have different downstream targets. TBX3, but not TBX3 + 2a, is able to bind to the previously identified T-box binding site in a gel shift assay. A subset of human breast cancer cell lines overexpresses TBX3. Our results indicate that TBX3 and TBX3 + 2a are functionally distinctive in inhibition of senescence of MEF cells and may play a role in breast cancer.
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Synergistic activity of TBX3, c-Myc, and AKT has been revealed in rhabdomyosarcoma.
“In addition, synergistic activity of TBX3, c-Myc, and AKT has been revealed in rhabdomyosarcoma [31].”
From Overexpression of TBX3 suppresses tumorigenesis in experimental and human cholangiocarcinoma (2024) · cites this paper as [31]
The diverse behavior of TBX3 may be due to the expression of alternatively spliced isoforms and the cell/tissue context.
“This diverse behavior may be due to the expression of alternatively spliced isoforms [31] and the cell/tissue context.”
From Overexpression of TBX3 suppresses tumorigenesis in experimental and human cholangiocarcinoma (2024) · cites this paper as [31]
TBX3 cooperates with c-Myc to induce the transformation of sarcoma-initiating cells.
“Previously, it has been shown that TBX3 cooperates with c-Myc to induce the transformation of sarcoma-initiating cells [31].”
From Overexpression of TBX3 suppresses tumorigenesis in experimental and human cholangiocarcinoma (2024) · cites this paper as [31]
c-Myc is the critical effector of Akt/FBXW7ΔF-dependent cholangiocarcinogenesis.
“Interestingly, c-Myc is the critical effector of Akt/FBXW7ΔF-dependent cholangiocarcinogenesis [31].”
From Overexpression of TBX3 suppresses tumorigenesis in experimental and human cholangiocarcinoma (2024) · cites this paper as [31]
Human hepatoblastomas with an osteoid component are well-known in clinical practice.
“Intriguingly, human hepatoblastomas with an osteoid component are well-known in clinical practice [31]”
From Overexpression of TBX3 suppresses tumorigenesis in experimental and human cholangiocarcinoma (2024) · cites this paper as [31]
Cases of liver cirrhosis evolving into osteosarcomas have been previously described.
“and cases of liver cirrhosis evolving into osteosarcomas have been previously described [31].”
From Overexpression of TBX3 suppresses tumorigenesis in experimental and human cholangiocarcinoma (2024) · cites this paper as [31]
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“Enhanced expression of Tbx3 was confirmed by Northern and Western blotting (Fig. 1). The mRNA levels of Tbx3 and the longer isoform Tbx3 + 2a ( 30 ) were increased 2- to 10-fold in tumors with mutant h-catenin compared with tumors with wt h-catenin and normal liver (Fig. 1A).”
BackgroundInfluentialThe roles and regulation of TBX3 in development and disease
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- Authors
- Fan, W., Huang, X., Chen, C., Gray, J., & Huang, T.
- Affiliations
- University of California, Irvine (US)
- Lawrence Berkeley National Laboratory (US)
- Venue
- Cancer Research
- Published
- 2004-08-01
- Volume
- 64
- Issue
- 15
- Pages
- 5132-5139
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2098428050
- Cited by
- 136
- References
- 2
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 2 · 2023: 1 · 2022: 3 · 2021: 2 · 2020: 4 · 2019: 7 · 2018: 5 · 2017: 5 · 2016: 7 · 2015: 3 · 2014: 9 · 2013: 9 · 2012: 6
- FWCI
- 3.04
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of Oregon
- University of California, Irvine
- National Cancer Institute (P50CA058207)
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- TBX3, alternative splicing, cellular senescence, ulnar-mammary syndrome, breast cancer, T-box transcription factor, DNA-binding domain, cell immortalization, mouse embryonic fibroblasts, tissue-specific gene expression
- MeSH terms
- Animals, Breast Neoplasms, Embryo, Mammalian, Female, Fibroblasts, Humans, 3T3 Cells, Cellular Senescence, Alternative Splicing, Gene Expression Regulation, Developmental, Protein Isoforms, T-Box Domain Proteins, Electrophoretic Mobility Shift Assay, Mice
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