TBX3 (T-box 3)

2013-01-01   Reyna Deeya Ballim , Sharon Prince 

Department of Human Biology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa, 7925





Tbx2 and Tbx3 both belong to the Tbx2 subfamily of T-box factors (Agulnik et al., 1996). Phylogenetic analysis suggests that this subfamily originated from a single ancestral gene which was duplicated by unequal crossing over to form a two-gene cluster (Tbx2/3 and Tbx4/5) and at some point in the vertebrate lineage, duplicated again to form four separate genes with Tbx2 and Tbx4 linked on chromosome 11, and Tbx3 and Tbx5 on chromosome 5 (chromosomes 17q23 and 12q24 respectively in humans; Figure 1A) (Campbell et al., 1995; Agulnik et al., 1996; Bamshad et al., 1997). Due to the original duplication event, Tbx2 and Tbx3 form a closely related gene pair while Tbx4 and Tbx5 are more closely related to each other (Agulnik et al., 1996).
Atlas Image
Figure 1: A) Drawing of gene duplication. B) Drawing of TBX3 mRNA. (A) Model describing evolution of Tbx 2/3/4/5 gene family (based on Agulnick et al, 1996). (B) Schematic representation of human TBX3 mRNA depicting relative size and position of exons. In the TBX3 + 2a isoform, exon +2a is included in the mRNA through alternative splicing of the second intron.


The human TBX3 gene is found on the reverse strand of chromosome 12 and spans 13.9 kb.


Four TBX3 transcripts have been identified but only two encode for full length functional proteins viz TBX3 and TBX3 + 2a (Figure 1B). The TBX3 mRNA is 4.7 kb and contains 7 exons encoding a protein of 723 amino acids. Alternative splicing of the intronic region between exons 2 and 3 gives rise to the TBX3 + 2a transcript which contains an extra 60 bp sequence designated exon 2a leading to the production of a 743 amino acid protein (Bamshad et al., 1999). TBX3 and TBX3 + 2a isoforms are widely expressed in mouse and human tissues with TBX3 generally observed to be the dominant isoform and the ratio between the two being both tissue and species dependent (Fan et al., 2004).


No pseudogenes have been identified for TBX3 to date.



The TBX3 + 2a transcript yields a protein with an extra 20 amino acids in the middle of the T-box DNA binding domain, giving rise to speculation that it may affect the DNA-binding ability of the protein (Bamshad et al., 1999). While the work of Fan et al. (2004) has provided evidence supporting this hypothesis, subsequent studies have shown no functional difference between the TBX3 and TBX3 + 2a proteins (Hoogaars et al., 2008; Rodriguez et al., 2008).
Atlas Image
Figure 2. Schematic representation of the human TBX3 protein. The domains depicted above are: T-box, DNA binding domain (pink); R, repression domain; A, putative activation domain. The amino and carboxy termini of the protein are labelled N and C respectively.


The T-box DNA binding domain is found in the N-terminal half of the TBX3 protein extending from amino acids 104 - 285 and in the TBX3 + 2a isoform, the additional 20 amino acids are inserted into the middle of the T-box at position 219 (Figure 2). TBX3 has two repression domains, one in the N-terminus and one in the C-terminus of the protein, as well as a putative activation domain located in the C-terminal end of the protein (Figure 2) (Carlson et al., 2001).


In humans, TBX3 is expressed in a number of organs, including foetal heart, liver, spleen, lung and kidney, and in adult prostate, lung, placenta, ovary, spleen, heart, kidney, testis, small intestine, adrenal gland, thyroid, breast, bladder, uterus, liver and salivary gland (Bamshad et al., 1999).


The TBX3 protein is predominantly nuclear.


TBX3 has been described to function as a transcriptional repressor and to date was shown to directly repress p14, p21, E-cadherin and phosphatase and TENsin homolog (PTEN) (Lingbeek et al., 2002; Hoogaars et al., 2008; Rodriguez et al., 2008; Burgucu et al., 2012). While in vitro assays have suggested that TBX3 is capable of transcriptional activation, it has not yet been shown to activate any physiologically relevant target genes.


Human TBX3 shares 98% amino acid identity with mouse Tbx3 and homologs have been identified in mammals, reptiles, fish and amphibians, as well as invertebrates such as tunicates (Bamshad et al., 1997).



Mutations in human TBX3 have been linked with ulnar-mammary syndrome and those described to date include frame shift, premature termination and missense mutations (Bamshad et al., 1997; Bamshad et al.,1999).

Implicated in

Entity name
Ulnar-mammary syndrome
Results from congenital mutations in a single copy of the human TBX3 gene.
Characterised by posterior limb abnormalities, such as malformed ulna and posterior digits, hypoplasia and/or dysfunction of the mammary and apocrine glands, absent axillary hair, abnormal dentition, delayed puberty in males and genital anomalies (Bamshad et al., 1996; Bamshad et al., 1997).
Entity name
Breast cancer
Breast cancer lines screened by real time PCR analysis displayed increased expression of TBX3 in 15 of 28 cell lines tested (Fan et al., 2004). When TBX3 expression was examined by immunohistochemistry in breast tumour tissues, the results showed that levels of TBX3 protein were higher in tumour tissue compared to adjacent normal tissue, with increased cytoplasmic localisation.
Entity name
Pancreatic cancer
Microarray analyses comparing non-metastatic and metastatic pancreatic endocrine neoplasms revealed that TBX3 expression is upregulated in the latter tumour type (Hansel et al., 2004).
Entity name
Ovarian cancer
Using 2D gel electrophoresis and matrix-assisted laser desorption/ionization (MALDI) time of flight (TOF) mass spectrometry, a truncated form of TBX3 was detected in blood plasma from ovarian cancer patients (Lomnytska et al., 2006).
Entity name
Liver cancer
Increased TBX3 expression was shown to correlate with a mutant active form of β-catenin in both human and mouse hepatocellular carcinomas (HCCs) and human hepatoblastomas. Renard et al. (2007) demonstrated TBX3 to be involved in β-catenins activation of cell proliferation in the human hepatoma cell line HepG2. Using in vitro assays they showed that expression of mutant β-catenin upregulated TBX3 expression and that this was due to direct binding of active β-catenin together with its co-activator T-cell factor (Tcf) to a Tcf-binding element in the TBX3 promoter (Renard et al., 2007).
Entity name
Genome-wide DNA methylation profiling of 55 glioblastoma tissue samples compared to non-neoplastic brains revealed that methylation of TBX3 correlated with decreased overall survival, identifying it as a potential independent prognostic marker (Etcheverry et al., 2010).
Entity name
Gastric cancer
Genome-wide screening identified TBX3 to be epigenetically silenced in the gastric cancer cell line AGS and the TBX3 gene was shown to be methylated in 7 out of 10 primary gastric cancers (Yamashita et al., 2006).
Entity name
Uterine cervical cancer
TBX3 expression was shown to be downregulated in microarray analyses comparing lymph node positive to lymph node negative cervical tumours. A significant correlation was observed between low TBX3 expression and the metastatic phenotype. In addition, multivariate analysis identified TBX3 as a potential independent prognostic marker for this cancer (Lyng et al., 2006).
Entity name
In 2004, Hoek et al. showed that compared to normal melanocytes TBX3 expression was upregulated in at least 4 of 6 melanoma cell lines tested and Rodriguez et al. (2008) later demonstrated increased TBX3 protein levels in 6 out of 12 melanoma cell lines. Furthermore, TBX3 was shown to contribute to melanoma formation, migration and invasion by a process involving its ability to repress the cell adhesion molecule E-cadherin (Rodriguez et al., 2008; Peres et al., 2010).
Entity name
Head and neck squamous cell cancer
TBX3 is upregulated in head and neck squamous cell carcinoma (HNSCC) cell lines and tissues (Humtsoe et al., 2011; Burgucu et al., 2012). The study by Humtsoe et al. shows that TBX3 expression is specifically upregulated in HNSCC cells which display characteristics of epithelial to mesenchymal transition (EMT). Interestingly, however they show that TBX3 promotes cell survival and to a lesser extent, cell invasion in these cells (Humtsoe et al., 2011). This is consistent with the results of Burgucu et al. (2012) which demonstrate that TBX3 represses the tumour suppressor, phosphatase and TENsin homolog (PTEN).


Pubmed IDLast YearTitleAuthors
88786901996Evolution of mouse T-box genes by tandem duplication and cluster dispersion.Agulnik SI et al
103303421999The spectrum of mutations in TBX3: Genotype/Phenotype relationship in ulnar-mammary syndrome.Bamshad M et al
89239441996Clinical analysis of a large kindred with the Pallister ulnar-mammary syndrome.Bamshad M et al
79206561994An ancient family of embryonically expressed mouse genes sharing a conserved protein motif with the T locus.Bollag RJ et al
117482392002TBX-3, the gene mutated in Ulnar-Mammary Syndrome, is a negative regulator of p19ARF and inhibits senescence.Brummelkamp TR et al
230829882012Tbx3 represses PTEN and is over-expressed in head and neck squamous cell carcinoma.Burgucu D et al
85300341995Cloning and mapping of a human gene (TBX2) sharing a highly conserved protein motif with the Drosophila omb gene.Campbell C et al
116894872001A dominant repression domain in Tbx3 mediates transcriptional repression and cell immortalization: relevance to mutations in Tbx3 that cause ulnar-mammary syndrome.Carlson H et al
126686382003Mammary gland, limb and yolk sac defects in mice lacking Tbx3, the gene mutated in human ulnar mammary syndrome.Davenport TG et al
211560362010DNA methylation in glioblastoma: impact on gene expression and clinical outcome.Etcheverry A et al
152893162004TBX3 and its isoform TBX3+2a are functionally distinctive in inhibition of senescence and are overexpressed in a subset of breast cancer cell lines.Fan W et al
154480022004Met proto-oncogene and insulin-like growth factor binding protein 3 overexpression correlates with metastatic ability in well-differentiated pancreatic endocrine neoplasms.Hansel DE et al
152893332004Expression profiling reveals novel pathways in the transformation of melanocytes to melanomas.Hoek K et al
184449632008TBX3 and its splice variant TBX3 + exon 2a are functionally similar.Hoogaars WM et al
221545122012Transcriptional profiling identifies upregulated genes following induction of epithelial-mesenchymal transition in squamous carcinoma cells.Humtsoe JO et al
156946702005Tbx3 expression is related to apoptosis and cell proliferation in rat bladder both hyperplastic epithelial cells and carcinoma cells.Ito A et al
83442581993The Brachyury gene encodes a novel DNA binding protein.Kispert A et al
120007492002The T-box repressors TBX2 and TBX3 specifically regulate the tumor suppressor gene p14ARF via a variant T-site in the initiator.Lingbeek ME et al
160499732006Increased expression of cSHMT, Tbx3 and utrophin in plasma of ovarian and breast cancer patients.Lomnytska M et al
170547792006Gene expressions and copy numbers associated with metastatic phenotypes of uterine cervical cancer.Lyng H et al
123785292002Frequent amplification of 8q24, 11q, 17q, and 20q-specific genes in pancreatic cancer.Mahlamäki EH et al
162858592005T-box genes in vertebrate development.Naiche LA et al
217794502010The Highly Homologous T-Box Transcription Factors, TBX2 and TBX3, Have Distinct Roles in the Oncogenic Process.Peres J et al
172831202007Tbx3 is a downstream target of the Wnt/beta-catenin pathway and a critical mediator of beta-catenin survival functions in liver cancer.Renard CA et al
188295432008Tbx3 represses E-cadherin expression and enhances melanoma invasiveness.Rodriguez M et al
146995902004T-box genes in early embryogenesis.Showell C et al
163679232006Chemical genomic screening for methylation-silenced genes in gastric cancer cell lines using 5-aza-2'-deoxycytidine treatment and oligonucleotide microarray.Yamashita S et al

Other Information

Locus ID:

NCBI: 6926
MIM: 601621
HGNC: 11602
Ensembl: ENSG00000135111


dbSNP: 6926
ClinVar: 6926
TCGA: ENSG00000135111


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Signaling pathways regulating pluripotency of stem cellsKEGGhsa04550
Signaling pathways regulating pluripotency of stem cellsKEGGko04550


Pubmed IDYearTitleCitations
194304792009Genome-wide association study of blood pressure and hypertension.542
200620602010Genome-wide association study of PR interval.185
232665562013Identification of Genetic Susceptibility Loci for Colorectal Tumors in a Genome-Wide Meta-analysis.172
210982632010Estrogen expands breast cancer stem-like cells through paracrine FGF/Tbx3 signaling.120
165569162006Isl1Cre reveals a common Bmp pathway in heart and limb development.116
172349702007Molecular pathway for the localized formation of the sinoatrial node.97
199131212009Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.85
201339102010Development of the pacemaker tissues of the heart.74
188295432008Tbx3 represses E-cadherin expression and enhances melanoma invasiveness.61
120007492002The T-box repressors TBX2 and TBX3 specifically regulate the tumor suppressor gene p14ARF via a variant T-site in the initiator.52


Reyna Deeya Ballim ; Sharon Prince

TBX3 (T-box 3)

Atlas Genet Cytogenet Oncol Haematol. 2013-01-01

Online version: http://atlasgeneticsoncology.org/gene/42486/tbx3