Atlas of Genetics and Cytogenetics in Oncology and Haematology
TBX3 (T-box 3)
| Identity |
| Other names | TBX3-ISO |
| UMS | |
| XHL | |
| HGNC (Hugo) | TBX3 |
| LocusID (NCBI) | 6926 |
| Location | 12q24.1 |
| Location_base_pair | Starts at 115108059 and ends at 115121969 bp from pter ( according to hg19-Feb_2009) [Mapping] |
| Note | TBX3 is a member of the T-box transcription factor family, characterised by a conserved DNA-binding domain known as the T-box (Kispert and Herrmann, 1993; Bollag et al., 1994; Agulnik et al., 1996; reviewed in Papaioannou 2001). TBX3 belongs to the Tbx2 (also known as the Tbx2/3/4/5) subfamily, which includes the closely related genes Tbx2, Tbx3, Tbx4 and Tbx5 (Showell et al., 2004; Naiche et al., 2005). Tbx3 plays critical roles in the development of several organs such as the heart, limb and mammary gland (Davenport et al., 2003; Hoogaars et al., 2007). TBX3 is overexpressed in a range of cancers including breast, pancreatic and melanoma and has been directly implicated in tumourigenesis (Mahlamaki et al., 2002; Fan et al., 2004; Hoek et al., 2004). It has been reported to promote evasion of apoptosis, migration, invasion and tumour forming ability (Brummelkamp et al., 2002; Ito et al., 2005; Renard et al., 2007; Peres et al., 2010). |
| DNA/RNA |
| Note | 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). |
 | |
| 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. | |
| Description | The human TBX3 gene is found on the reverse strand of chromosome 12 and spans 13.9 kb. |
| Transcription | 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). |
| Pseudogene | No pseudogenes have been identified for TBX3 to date. |
| Protein |
| Note | 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). |
 | |
| 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. | |
| Description | 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). |
| Expression | 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). |
| Localisation | The TBX3 protein is predominantly nuclear. |
| Function | 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. |
| Homology | 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 |
| Germinal | 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 | Ulnar-mammary syndrome |
| Note | Results from congenital mutations in a single copy of the human TBX3 gene. |
| Disease | 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 | Breast cancer |
| Note | 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 | Pancreatic cancer |
| Note | 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 | Ovarian cancer |
| Note | 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 | Liver cancer |
| Note | 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-catenin's 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 | Glioblastoma |
| Note | 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 | Gastric cancer |
| Note | 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 | Uterine cervical cancer |
| Note | 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 | Melanoma |
| Note | 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 | Head and neck squamous cell cancer |
| Note | 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). |
| External links |
| Bibliography |
| The Brachyury gene encodes a novel DNA binding protein. |
| Kispert A, Herrmann BG. |
| EMBO J. 1993 Aug;12(8):3211-20. |
| PMID 8344258 |
| An ancient family of embryonically expressed mouse genes sharing a conserved protein motif with the T locus. |
| Bollag RJ, Siegfried Z, Cebra-Thomas JA, Garvey N, Davison EM, Silver LM. |
| Nat Genet. 1994 Jul;7(3):383-9. |
| PMID 7920656 |
| Cloning and mapping of a human gene (TBX2) sharing a highly conserved protein motif with the Drosophila omb gene. |
| Campbell C, Goodrich K, Casey G, Beatty B. |
| Genomics. 1995 Jul 20;28(2):255-60. |
| PMID 8530034 |
| Evolution of mouse T-box genes by tandem duplication and cluster dispersion. |
| Agulnik SI, Garvey N, Hancock S, Ruvinsky I, Chapman DL, Agulnik I, Bollag R, Papaioannou V, Silver LM. |
| Genetics. 1996 Sep;144(1):249-54. |
| PMID 8878690 |
| Clinical analysis of a large kindred with the Pallister ulnar-mammary syndrome. |
| Bamshad M, Root S, Carey JC. |
| Am J Med Genet. 1996 Nov 11;65(4):325-31. |
| PMID 8923944 |
| Mutations in human TBX3 alter limb, apocrine and genital development in ulnar-mammary syndrome. |
| Bamshad M, Lin RC, Law DJ, Watkins WC, Krakowiak PA, Moore ME, Franceschini P, Lala R, Holmes LB, Gebuhr TC, Bruneau BG, Schinzel A, Seidman JG, Seidman CE, Jorde LB. |
| Nat Genet. 1997 Jul;16(3):311-5. |
| PMID 9207801 |
| The spectrum of mutations in TBX3: Genotype/Phenotype relationship in ulnar-mammary syndrome. |
| Bamshad M, Le T, Watkins WS, Dixon ME, Kramer BE, Roeder AD, Carey JC, Root S, Schinzel A, Van Maldergem L, Gardner RJ, Lin RC, Seidman CE, Seidman JG, Wallerstein R, Moran E, Sutphen R, Campbell CE, Jorde LB. |
| Am J Hum Genet. 1999 Jun;64(6):1550-62. |
| PMID 10330342 |
| A dominant repression domain in Tbx3 mediates transcriptional repression and cell immortalization: relevance to mutations in Tbx3 that cause ulnar-mammary syndrome. |
| Carlson H, Ota S, Campbell CE, Hurlin PJ. |
| Hum Mol Genet. 2001 Oct 1;10(21):2403-13. |
| PMID 11689487 |
| TBX-3, the gene mutated in Ulnar-Mammary Syndrome, is a negative regulator of p19ARF and inhibits senescence. |
| Brummelkamp TR, Kortlever RM, Lingbeek M, Trettel F, MacDonald ME, van Lohuizen M, Bernards R. |
| J Biol Chem. 2002 Feb 22;277(8):6567-72. Epub 2001 Dec 17. |
| PMID 11748239 |
| The T-box repressors TBX2 and TBX3 specifically regulate the tumor suppressor gene p14ARF via a variant T-site in the initiator. |
| Lingbeek ME, Jacobs JJ, van Lohuizen M. |
| J Biol Chem. 2002 Jul 19;277(29):26120-7. Epub 2002 May 8. |
| PMID 12000749 |
| Frequent amplification of 8q24, 11q, 17q, and 20q-specific genes in pancreatic cancer. |
| Mahlamaki EH, Barlund M, Tanner M, Gorunova L, Hoglund M, Karhu R, Kallioniemi A. |
| Genes Chromosomes Cancer. 2002 Dec;35(4):353-8. |
| PMID 12378529 |
| Mammary gland, limb and yolk sac defects in mice lacking Tbx3, the gene mutated in human ulnar mammary syndrome. |
| Davenport TG, Jerome-Majewska LA, Papaioannou VE. |
| Development. 2003 May;130(10):2263-73. |
| PMID 12668638 |
| TBX3 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, Huang X, Chen C, Gray J, Huang T. |
| Cancer Res. 2004 Aug 1;64(15):5132-9. |
| PMID 15289316 |
| Met proto-oncogene and insulin-like growth factor binding protein 3 overexpression correlates with metastatic ability in well-differentiated pancreatic endocrine neoplasms. |
| Hansel DE, Rahman A, House M, Ashfaq R, Berg K, Yeo CJ, Maitra A. |
| Clin Cancer Res. 2004 Sep 15;10(18 Pt 1):6152-8. |
| PMID 15448002 |
| Expression profiling reveals novel pathways in the transformation of melanocytes to melanomas. |
| Hoek K, Rimm DL, Williams KR, Zhao H, Ariyan S, Lin A, Kluger HM, Berger AJ, Cheng E, Trombetta ES, Wu T, Niinobe M, Yoshikawa K, Hannigan GE, Halaban R. |
| Cancer Res. 2004 Aug 1;64(15):5270-82. |
| PMID 15289333 |
| T-box genes in early embryogenesis. |
| Showell C, Binder O, Conlon FL. |
| Dev Dyn. 2004 Jan;229(1):201-18. (REVIEW) |
| PMID 14699590 |
| Tbx3 expression is related to apoptosis and cell proliferation in rat bladder both hyperplastic epithelial cells and carcinoma cells. |
| Ito A, Asamoto M, Hokaiwado N, Takahashi S, Shirai T. |
| Cancer Lett. 2005 Feb 28;219(1):105-12. |
| PMID 15694670 |
| T-box genes in vertebrate development. |
| Naiche LA, Harrelson Z, Kelly RG, Papaioannou VE. |
| Annu Rev Genet. 2005;39:219-39. (REVIEW) |
| PMID 16285859 |
| Increased expression of cSHMT, Tbx3 and utrophin in plasma of ovarian and breast cancer patients. |
| Lomnytska M, Dubrovska A, Hellman U, Volodko N, Souchelnytskyi S. |
| Int J Cancer. 2006 Jan 15;118(2):412-21. |
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| Gene expressions and copy numbers associated with metastatic phenotypes of uterine cervical cancer. |
| Lyng H, Brovig RS, Svendsrud DH, Holm R, Kaalhus O, Knutstad K, Oksefjell H, Sundfor K, Kristensen GB, Stokke T. |
| BMC Genomics. 2006 Oct 20;7:268. |
| PMID 17054779 |
| Chemical genomic screening for methylation-silenced genes in gastric cancer cell lines using 5-aza-2'-deoxycytidine treatment and oligonucleotide microarray. |
| Yamashita S, Tsujino Y, Moriguchi K, Tatematsu M, Ushijima T. |
| Cancer Sci. 2006 Jan;97(1):64-71. |
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| T-box factors determine cardiac design. |
| Hoogaars WM, Barnett P, Moorman AF, Christoffels VM. |
| Cell Mol Life Sci. 2007 Mar;64(6):646-60. (REVIEW) |
| PMID 17380306 |
| Tbx3 is a downstream target of the Wnt/beta-catenin pathway and a critical mediator of beta-catenin survival functions in liver cancer. |
| Renard CA, Labalette C, Armengol C, Cougot D, Wei Y, Cairo S, Pineau P, Neuveut C, de Reynies A, Dejean A, Perret C, Buendia MA. |
| Cancer Res. 2007 Feb 1;67(3):901-10. |
| PMID 17283120 |
| TBX3 and its splice variant TBX3 + exon 2a are functionally similar. |
| Hoogaars WM, Barnett P, Rodriguez M, Clout DE, Moorman AF, Goding CR, Christoffels VM. |
| Pigment Cell Melanoma Res. 2008 Jun;21(3):379-87. doi: 10.1111/j.1755-148X.2008.00461.x. Epub 2008 Apr 26. |
| PMID 18444963 |
| Tbx3 represses E-cadherin expression and enhances melanoma invasiveness. |
| Rodriguez M, Aladowicz E, Lanfrancone L, Goding CR. |
| Cancer Res. 2008 Oct 1;68(19):7872-81. doi: 10.1158/0008-5472.CAN-08-0301. |
| PMID 18829543 |
| DNA methylation in glioblastoma: impact on gene expression and clinical outcome. |
| Etcheverry A, Aubry M, de Tayrac M, Vauleon E, Boniface R, Guenot F, Saikali S, Hamlat A, Riffaud L, Menei P, Quillien V, Mosser J. |
| BMC Genomics. 2010 Dec 14;11:701. doi: 10.1186/1471-2164-11-701. |
| PMID 21156036 |
| The Highly Homologous T-Box Transcription Factors, TBX2 and TBX3, Have Distinct Roles in the Oncogenic Process. |
| Peres J, Davis E, Mowla S, Bennett DC, Li JA, Wansleben S, Prince S. |
| Genes Cancer. 2010 Mar;1(3):272-82. doi: 10.1177/1947601910365160. |
| PMID 21779450 |
| Tbx3 represses PTEN and is over-expressed in head and neck squamous cell carcinoma. |
| Burgucu D, Guney K, Sahinturk D, Ozbudak IH, Ozel D, Ozbilim G, Yavuzer U. |
| BMC Cancer. 2012 Oct 19;12:481. doi: 10.1186/1471-2407-12-481. |
| PMID 23082988 |
| Transcriptional profiling identifies upregulated genes following induction of epithelial-mesenchymal transition in squamous carcinoma cells. |
| Humtsoe JO, Koya E, Pham E, Aramoto T, Zuo J, Ishikawa T, Kramer RH. |
| Exp Cell Res. 2012 Feb 15;318(4):379-90. doi: 10.1016/j.yexcr.2011.11.011. Epub 2011 Nov 29. |
| PMID 22154512 |
| REVIEW articles | automatic search in PubMed |
| Last year publications | automatic search in PubMed |
| Contributor(s) |
| Written | 01-2013 | Reyna Deeya Ballim, Sharon Prince |
| Department of Human Biology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa, 7925 |
| Citation |
| This paper should be referenced as such : |
| Ballim RD, Prince S . TBX3 (T-box 3). Atlas Genet Cytogenet Oncol Haematol. January 2013 . URL : http://AtlasGeneticsOncology.org/Genes/TBX3ID42486ch12q24.html |
This paper is referenced by INIST as such : |
| © Atlas of Genetics and Cytogenetics in Oncology and Haematology | indexed on : Wed May 1 12:54:51 CEST 2013 |
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