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Atlas of Genetics and Cytogenetics in Oncology and Haematology INIST-CNRS OPEN ACCESS JOURNAL Gene Section Review TBX3 (T-box 3) Reyna Deeya Ballim, Sharon Prince Department of Human Biology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa, 7925 (RDB, SP) Published in Atlas Database: January 2013 Online updated version : http://AtlasGeneticsOncology.org/Genes/TBX3ID42486ch12q24.html DOI: 10.4267/2042/51044 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2013 Atlas of Genetics and Cytogenetics in Oncology and Haematology 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). Identity Other names: TBX3-ISO, UMS, XHL HGNC (Hugo): TBX3 Location: 12q24.1 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). 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). 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 Atlas Genet Cytogenet Oncol Haematol. 2013; 17(7) Pseudogene No pseudogenes have been identified for TBX3 to date. 473 TBX3 (T-box 3) Ballim RD, Prince S 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. 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). 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). 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. Description Function The T-box DNA binding domain is found in the Nterminal 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 Atlas Genet Cytogenet Oncol Haematol. 2013; 17(7) 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). 474 TBX3 (T-box 3) Ballim RD, Prince S 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. that TBX3 expression is upregulated in the latter tumour type (Hansel et al., 2004). 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. 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). 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). Liver cancer Mutations 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). 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 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). Glioblastoma Note Genome-wide DNA methylation profiling of 55 glioblastoma tissue samples compared to nonneoplastic brains revealed that methylation of TBX3 correlated with decreased overall survival, identifying it as a potential independent prognostic marker (Etcheverry et al., 2010). Breast cancer Gastric 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. 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). 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 Pancreatic cancer Note Microarray analyses comparing non-metastatic and metastatic pancreatic endocrine neoplasms revealed Atlas Genet Cytogenet Oncol Haematol. 2013; 17(7) 475 TBX3 (T-box 3) Ballim RD, Prince S Moran E, Sutphen R, Campbell CE, Jorde LB. The spectrum of mutations in TBX3: Genotype/Phenotype relationship in ulnarmammary syndrome. Am J Hum Genet. 1999 Jun;64(6):155062 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). Carlson H, Ota S, Campbell CE, Hurlin PJ. A dominant repression domain in Tbx3 mediates transcriptional repression and cell immortalization: relevance to mutations in Tbx3 that cause ulnar-mammary syndrome. Hum Mol Genet. 2001 Oct 1;10(21):2403-13 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). Brummelkamp TR, Kortlever RM, Lingbeek M, Trettel F, MacDonald ME, van Lohuizen M, Bernards R. TBX-3, the gene mutated in Ulnar-Mammary Syndrome, is a negative regulator of p19ARF and inhibits senescence. J Biol Chem. 2002 Feb 22;277(8):6567-72 Lingbeek ME, Jacobs JJ, van Lohuizen M. The T-box repressors TBX2 and TBX3 specifically regulate the tumor suppressor gene p14ARF via a variant T-site in the initiator. J Biol Chem. 2002 Jul 19;277(29):26120-7 Mahlamäki EH, Bärlund M, Tanner M, Gorunova L, Höglund M, Karhu R, Kallioniemi A. Frequent amplification of 8q24, 11q, 17q, and 20q-specific genes in pancreatic cancer. Genes Chromosomes Cancer. 2002 Dec;35(4):353-8 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). Davenport TG, Jerome-Majewska LA, Papaioannou VE. Mammary gland, limb and yolk sac defects in mice lacking Tbx3, the gene mutated in human ulnar mammary syndrome. Development. 2003 May;130(10):2263-73 Fan W, Huang X, Chen C, Gray J, Huang T. TBX3 and its isoform TBX3+2a are functionally distinctive in inhibition of senescence and are overexpressed in a subset of breast cancer cell lines. Cancer Res. 2004 Aug 1;64(15):5132-9 Hansel DE, Rahman A, House M, Ashfaq R, Berg K, Yeo CJ, Maitra A. Met proto-oncogene and insulin-like growth factor binding protein 3 overexpression correlates with metastatic ability in well-differentiated pancreatic endocrine neoplasms. Clin Cancer Res. 2004 Sep 15;10(18 Pt 1):6152-8 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. Expression profiling reveals novel pathways in the transformation of melanocytes to melanomas. Cancer Res. 2004 Aug 1;64(15):5270-82 References Kispert A, Herrmann BG. The Brachyury gene encodes a novel DNA binding protein. EMBO J. 1993 Aug;12(8):3211-20 Bollag RJ, Siegfried Z, Cebra-Thomas JA, Garvey N, Davison EM, Silver LM. An ancient family of embryonically expressed mouse genes sharing a conserved protein motif with the T locus. Nat Genet. 1994 Jul;7(3):383-9 Showell C, Binder O, Conlon FL. T-box genes in early embryogenesis. Dev Dyn. 2004 Jan;229(1):201-18 Ito A, Asamoto M, Hokaiwado N, Takahashi S, Shirai T. Tbx3 expression is related to apoptosis and cell proliferation in rat bladder both hyperplastic epithelial cells and carcinoma cells. Cancer Lett. 2005 Feb 28;219(1):105-12 Campbell C, Goodrich K, Casey G, Beatty B. Cloning and mapping of a human gene (TBX2) sharing a highly conserved protein motif with the Drosophila omb gene. Genomics. 1995 Jul 20;28(2):255-60 Naiche LA, Harrelson Z, Kelly RG, Papaioannou VE. T-box genes in vertebrate development. Annu Rev Genet. 2005;39:219-39 Agulnik SI, Garvey N, Hancock S, Ruvinsky I, Chapman DL, Agulnik I, Bollag R, Papaioannou V, Silver LM. Evolution of mouse T-box genes by tandem duplication and cluster dispersion. Genetics. 1996 Sep;144(1):249-54 Lomnytska M, Dubrovska A, Hellman U, Volodko N, Souchelnytskyi S. Increased expression of cSHMT, Tbx3 and utrophin in plasma of ovarian and breast cancer patients. Int J Cancer. 2006 Jan 15;118(2):412-21 Bamshad M, Root S, Carey JC. Clinical analysis of a large kindred with the Pallister ulnar-mammary syndrome. Am J Med Genet. 1996 Nov 11;65(4):325-31 Lyng H, Brøvig RS, Svendsrud DH, Holm R, Kaalhus O, Knutstad K, Oksefjell H, Sundfør K, Kristensen GB, Stokke T. Gene expressions and copy numbers associated with metastatic phenotypes of uterine cervical cancer. BMC Genomics. 2006 Oct 20;7:268 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. Mutations in human TBX3 alter limb, apocrine and genital development in ulnar-mammary syndrome. Nat Genet. 1997 Jul;16(3):311-5 Yamashita S, Tsujino Y, Moriguchi K, Tatematsu M, Ushijima T. Chemical genomic screening for methylation-silenced genes in gastric cancer cell lines using 5-aza-2'-deoxycytidine treatment and oligonucleotide microarray. Cancer Sci. 2006 Jan;97(1):64-71 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, Atlas Genet Cytogenet Oncol Haematol. 2013; 17(7) 476 TBX3 (T-box 3) Ballim RD, Prince S Hoogaars WM, Barnett P, Moorman AF, Christoffels VM. T-box factors determine cardiac design. Cell Mol Life Sci. 2007 Mar;64(6):646-60 Peres J, Davis E, Mowla S, Bennett DC, Li JA, Wansleben S, Prince S. The Highly Homologous T-Box Transcription Factors, TBX2 and TBX3, Have Distinct Roles in the Oncogenic Process. Genes Cancer. 2010 Mar;1(3):272-82 Renard CA, Labalette C, Armengol C, Cougot D, Wei Y, Cairo S, Pineau P, Neuveut C, de Reyniès A, Dejean A, Perret C, Buendia MA. Tbx3 is a downstream target of the Wnt/betacatenin pathway and a critical mediator of beta-catenin survival functions in liver cancer. Cancer Res. 2007 Feb 1;67(3):901-10 Burgucu D, Guney K, Sahinturk D, Ozbudak IH, Ozel D, Ozbilim G, Yavuzer U. Tbx3 represses PTEN and is overexpressed in head and neck squamous cell carcinoma. BMC Cancer. 2012 Oct 19;12:481 Hoogaars WM, Barnett P, Rodriguez M, Clout DE, Moorman AF, Goding CR, Christoffels VM. TBX3 and its splice variant TBX3 + exon 2a are functionally similar. Pigment Cell Melanoma Res. 2008 Jun;21(3):379-87 Humtsoe JO, Koya E, Pham E, Aramoto T, Zuo J, Ishikawa T, Kramer RH. Transcriptional profiling identifies upregulated genes following induction of epithelial-mesenchymal transition in squamous carcinoma cells. Exp Cell Res. 2012 Feb 15;318(4):379-90 Rodriguez M, Aladowicz E, Lanfrancone L, Goding CR. Tbx3 represses E-cadherin expression and enhances melanoma invasiveness. Cancer Res. 2008 Oct 1;68(19):7872-81 This article should be referenced as such: Ballim RD, Prince S. TBX3 (T-box 3). Atlas Genet Cytogenet Oncol Haematol. 2013; 17(7):473-477. 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. DNA methylation in glioblastoma: impact on gene expression and clinical outcome. BMC Genomics. 2010 Dec 14;11:701 Atlas Genet Cytogenet Oncol Haematol. 2013; 17(7) 477