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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)
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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)
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