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== Role in stem cells ==
== Role in stem cells ==
Embryonic stem cells (ESCs) and adult stem cells, are undifferentiated cells which when they divide have the potential to either remain a stem cell or to differentiate into other specialised cells <sup>56,57</sup>. ESCs are pluripotent cells derived from the inner cell mass (ICM) of the blastocyst and give rise to a plethora of mature cell types that make up the body. Adult stem cells are multipotent progenitor cells found in numerous adult tissues and, as part of the body repair system, they can develop into more than one cell type but they are more limited than ESCs <sup>58–61</sup>. TBX3 is highly expressed in mouse ESCs (mESCs) and appears to have a dual role in these cells. Firstly it can enhance and maintain stem cell pluripotency by preventing differentiation and enhancing self-renewal and secondly it can maintain the pluripotency and differentiation potential of mESCS <sup>15,62–65</sup>. Induced pluripotent stem cells (iPSCs) are ESC-like cells that can generate scalable quantities of relevant tissue and are of major interest for their application in personalized regenerative medicine, drug screening, and for our understanding of the cell signalling networks that regulate embryonic development and disease. In vitro studies have shown that Tbx3 is an important factor that, together with KLF4, SOX2, OCT4, Nanog, LIN-28A and C-MYC, can reprogram somatic cells to form iPS cells <sup>66</sup>.
[[Embryonic stem cell|Embryonic stem cells]] (ESCs) and adult stem cells, are undifferentiated cells which when they divide have the potential to either remain a stem cell or to differentiate into other specialized cells. Adult stem cells are multipotent progenitor cells found in numerous adult tissues and, as part of the body repair system, they can develop into more than one cell type but they are more limited than ESCs. <ref>{{Cite journal|last=Gilbert|first=Penney M.|last2=Corbel|first2=Stephane|last3=Doyonnas|first3=Regis|last4=Havenstrite|first4=Karen|last5=Magnusson|first5=Klas E. G.|last6=Blau|first6=Helen M.|date=2012-02-10|title=A single cell bioengineering approach to elucidate mechanisms of adult stem cell self-renewal|url=http://dx.doi.org/10.1039/c2ib00148a|journal=Integrative Biology|volume=4|issue=4|pages=360–367|doi=10.1039/c2ib00148a|issn=1757-9708}}</ref> TBX3 is highly expressed in mouse ESCs (mESCs) and appears to have a dual role in these cells. Firstly it can enhance and maintain stem cell pluripotency by preventing differentiation and enhancing self-renewal and secondly it can maintain the pluripotency and differentiation potential of mESCS. <ref>{{Cite journal|last=Lu|first=Rui|last2=Yang|first2=Acong|last3=Jin|first3=Ying|date=2010-12-28|title=Dual Functions of T-Box 3 (Tbx3) in the Control of Self-renewal and Extraembryonic Endoderm Differentiation in Mouse Embryonic Stem Cells|url=http://dx.doi.org/10.1074/jbc.m110.202150|journal=Journal of Biological Chemistry|volume=286|issue=10|pages=8425–8436|doi=10.1074/jbc.m110.202150|issn=0021-9258}}</ref><ref>{{Cite journal|last=Russell|first=Ronan|last2=Ilg|first2=Marcus|last3=Lin|first3=Qiong|last4=Wu|first4=Guangming|last5=Lechel|first5=André|last6=Bergmann|first6=Wendy|last7=Eiseler|first7=Tim|last8=Linta|first8=Leonhard|last9=Kumar P.|first9=Pavan|date=2015-12|title=A Dynamic Role of TBX3 in the Pluripotency Circuitry|url=http://dx.doi.org/10.1016/j.stemcr.2015.11.003|journal=Stem Cell Reports|volume=5|issue=6|pages=1155–1170|doi=10.1016/j.stemcr.2015.11.003|issn=2213-6711}}</ref> Induced pluripotent stem cells (iPSCs) are ESC-like cells that can generate scalable quantities of relevant tissue and are of major interest for their application in personalized regenerative medicine, drug screening, and for our understanding of the cell signaling networks that regulate embryonic development and disease. In vitro studies have shown that Tbx3 is an important factor that, together with KLF4, SOX2, OCT4, Nanog, LIN-28A and C-MYC, can reprogram somatic cells to form iPS cells. <ref>{{Cite journal|last=Han|first=Jianyong|last2=Yuan|first2=Ping|last3=Yang|first3=Henry|last4=Zhang|first4=Jinqiu|last5=Soh|first5=Boon Seng|last6=Li|first6=Pin|last7=Lim|first7=Siew Lan|last8=Cao|first8=Suying|last9=Tay|first9=Junliang|date=2010-02|title=Tbx3 improves the germ-line competency of induced pluripotent stem cells|url=http://dx.doi.org/10.1038/nature08735|journal=Nature|volume=463|issue=7284|pages=1096–1100|doi=10.1038/nature08735|issn=0028-0836}}</ref>


== Clinical significance ==
== Clinical significance ==


TBX3 has been implicated in human diseases including the ulnar mammary syndrome <ref>{{Cite journal|last=Frank|first=Deborah U.|last2=Emechebe|first2=Uchenna|last3=Thomas|first3=Kirk R.|last4=Moon|first4=Anne M.|date=2013-07-02|editor-last=Dettman|editor-first=Robert|title=Mouse Tbx3 Mutants Suggest Novel Molecular Mechanisms for Ulnar-Mammary Syndrome|url=https://dx.plos.org/10.1371/journal.pone.0067841|journal=PLoS ONE|language=en|volume=8|issue=7|pages=e67841|doi=10.1371/journal.pone.0067841|issn=1932-6203|pmc=PMC3699485|pmid=23844108}}</ref>, obesity <ref>{{Cite journal|last=Quarta|first=Carmelo|last2=Fisette|first2=Alexandre|last3=Xu|first3=Yanjun|last4=Colldén|first4=Gustav|last5=Legutko|first5=Beata|last6=Tseng|first6=Yu-Ting|last7=Reim|first7=Alexander|last8=Wierer|first8=Michael|last9=De Rosa|first9=Maria Caterina|date=2019-01-28|title=Functional identity of hypothalamic melanocortin neurons depends on Tbx3|url=http://dx.doi.org/10.1038/s42255-018-0028-1|journal=Nature Metabolism|volume=1|issue=2|pages=222–235|doi=10.1038/s42255-018-0028-1|issn=2522-5812}}</ref>, rheumatoid arthritis <ref>{{Cite journal|last=Sardar|first=Samra|last2=Kerr|first2=Alish|last3=Vaartjes|first3=Daniëlle|last4=Moltved|first4=Emilie Riis|last5=Karosiene|first5=Edita|last6=Gupta|first6=Ramneek|last7=Andersson|first7=Åsa|date=2019-01-10|title=The oncoprotein TBX3 is controlling severity in experimental arthritis|url=http://dx.doi.org/10.1186/s13075-018-1797-3|journal=Arthritis Research & Therapy|volume=21|issue=1|doi=10.1186/s13075-018-1797-3|issn=1478-6362}}</ref> and cancer. <ref>{{Cite journal|last=Willmer|first=Tarryn|last2=Cooper|first2=Aretha|last3=Peres|first3=Jade|last4=Omar|first4=Rehana|last5=Prince|first5=Sharon|date=2017|title=The T-Box transcription factor 3 in development and cancer|url=https://www.jstage.jst.go.jp/article/bst/11/3/11_2017.01043/_article|journal=BioScience Trends|language=en|volume=11|issue=3|pages=254–266|doi=10.5582/bst.2017.01043|issn=1881-7815}}</ref>
TBX3 has been implicated in human diseases including the ulnar mammary syndrome, obesity, rheumatoid arthritis and cancer <sup>42,67–69</sup>.


In humans, heterozygous mutations of TBX3 lead to the autosomal dominant developmental disorder, ulnar mammary syndrome (UMS), which is characterized by a number of clinical features including mammary and apocrine gland hypoplasia, upper limb defects, malformations of areola, dental structures, heart and genitalia <sup>2,70</sup>. Several UMS causing mutations in the TBX3 gene have been reported which include 5 nonsense, 8 frameshift (due to deletion, duplication and insertion), 3 missense and 2 splice site mutations. Missense mutations within the T-domain, or the loss of RD1 result in aberrant transcripts and truncated proteins of TBX3. These mutations lead to reduced DNA binding, transcriptional control and splicing regulation of TBX3 and the loss of function and are associated with the most severe phenotype of UMS <sup>16,71–73</sup>.
In humans, heterozygous mutations of TBX3 lead to the autosomal dominant developmental disorder, ulnar mammary syndrome (UMS), which is characterized by a number of clinical features including mammary and apocrine gland hypoplasia, upper limb defects, malformations of areola, dental structures, heart and genitalia <sup>2,70</sup>. Several UMS causing mutations in the TBX3 gene have been reported which include 5 nonsense, 8 frameshift (due to deletion, duplication and insertion), 3 missense and 2 splice site mutations. Missense mutations within the T-domain, or the loss of RD1 result in aberrant transcripts and truncated proteins of TBX3. These mutations lead to reduced DNA binding, transcriptional control and splicing regulation of TBX3 and the loss of function and are associated with the most severe phenotype of UMS <sup>16,71–73</sup>.

Revision as of 18:17, 30 July 2019

T-box transcription factor TBX3 is a protein that in humans is encoded by the TBX3 gene.[1][2]

T-box 3 (TBX3) is a member of the T-box gene family of transcription factors which all share a highly conserved DNA binding domain known as the T-box. The T-box gene family consists of 17 members in mouse and humans that are grouped into five subfamilies, namely Brachyury (T), T-brain (Tbr1), TBX1, TBX2, and TBX6. Tbx3 is a member of the Tbx2 subfamily which includes Tbx2, Tbx4 and Tbx5.[3] The human TBX3 gene maps to chromosome 12 at position 12q23-24.1 and consists of 7 exons which encodes a 723 amino acid protein (ENSEMBL assembly release GRCh38.p12).

TBX3
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesTBX3, TBX3-ISO, UMS, XHL, T-box 3, T-box transcription factor 3
External IDsOMIM: 601621; MGI: 98495; HomoloGene: 4371; GeneCards: TBX3; OMA:TBX3 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

6926

21386

Ensembl

ENSG00000135111

ENSMUSG00000018604

UniProt

O15119

P70324

RefSeq (mRNA)

NM_016569
NM_005996

NM_011535
NM_198052

RefSeq (protein)

NP_005987
NP_057653

NP_035665
NP_932169

Location (UCSC)Chr 12: 114.67 – 114.68 MbChr 5: 119.81 – 119.82 Mb
PubMed search[6][7]
Wikidata
View/Edit HumanView/Edit Mouse

Transcript splicing

Alternative processing and splicing results in at least 4 distinct TBX3 isoforms with TBX3 and TBX3+2a being the predominant isoforms. TBX3+2a results from alternative splicing of the second intron which leads to the addition of the +2a exon and consequently this isoform has an additional 20 amino acids within the T-box DNA binding domain.[8][9] The functions of TBX3 and TBX3+2a may vary slightly across different cell types. [9][10][11][12][13][14]

Structure and function

TBX3 has domains which are important for its transcription factor function which include a DNA-binding domain (DBD) also called the T-box, a nuclear localization signal, two repression domains (R2 and R1) and an activation domain (A).[15] The T-box recognizes a palindromic DNA sequence (T(G/C)ACACCT AGGTGTGAAATT) known as the T-element, or half sites within this sequence called half T-elements, although it can also recognize variations within the consensus T-element sequences. While there are 29 predicted phosphorylation sites in the TBX3 protein only the SP190, SP692 and S720 have been fully characterized. The kinases involved are cyclin A-CDK2 at either SP190 or SP354, p38 mitogen-activated protein (MAP) kinase at SP692 in embryonic kidney cells and AKT3 at S720 in melanoma. These modifications act in a context dependent manner to promote TBX3 protein stability, nuclear localization and transcriptional activity.[16][17][18]

TBX3 can activate and/or repress its target genes by binding a T-element, or half T-element sites.[19] Indeed, Tbx3 binds highly conserved T-elements to activate the promoters of Eomes, T, Sox17 and Gata6, which are factors essential for mesoderm differentiation and extra embryonic endodermal.[20][21] Furthermore, in the cancer context, TBX3 directly represses the cell cycle regulators p19ARF/p14ARF, p21WAF1 and TBX2 as well as E-cadherin which encodes a cell adhesion molecule, to promote proliferation and migration.[11][22][23][24] TBX3 directly represses a region of the PTEN promoter which lacks putative T-elements, but which forms an important regulatory unit for PTEN transcriptional activators, thus raising the possibility that TBX3 may also repress some of its target genes through interfering with transcriptional activators.[25]

The function of TBX3 as either a transcriptional repressor or transcriptional activator is, in part, modulated by protein co-factors. For example, it can interact with other transcription factors such as Nkx2-5, Msx 1/2 [26] and Sox4 [27] to assist it binding to its target genes to regulate heart development [10][28][29][30][31] and it can interact with histone deacetylases (HDACs) 1, 2, 3 and 5 to repress p14ARF in breast cancer and with HDAC5 to repress E-cadherin to promote metastasis in hepatocellular carcinoma. [32][33] Lastly, TBX3 can also co-operate with other factors to inhibit the process of mRNA splicing by directly binding RNAs containing the core motif of a T-element. [10][11][12][13][14] Indeed, TBX3 interacts with Coactivator of AP1 and Estrogen Receptor (CAPERα) to repress the long non-coding RNA, Urothelial Cancer Associated 1 (UCA1), which leads to the bypass of senescence through the stabilization of p16INK4a mRNA. [34]

Role in development

During mouse embryonic development, Tbx3 is expressed in the inner cell mass of the blastocyst, in the extraembryonic mesoderm during gastrulation, and in the developing heart, limbs [35], musculoskeletal structures [36], mammary glands [37], nervous system [38], skin [39], eye [40], liver [41], pancreas [42], lungs [43] and genitalia. [8] Tbx3 null embryos show defects in, among other structures, the heart, mammary glands and limbs and they die in utero by embryonic day E16.5, most likely due to yolk sac and heart defects. These observations together with numerous other studies have illustrated that Tbx3 plays crucial roles in the development of the heart [44], mammary glands [45], limbs [46] and lungs. [47]

Role in stem cells

Embryonic stem cells (ESCs) and adult stem cells, are undifferentiated cells which when they divide have the potential to either remain a stem cell or to differentiate into other specialized cells. Adult stem cells are multipotent progenitor cells found in numerous adult tissues and, as part of the body repair system, they can develop into more than one cell type but they are more limited than ESCs. [48] TBX3 is highly expressed in mouse ESCs (mESCs) and appears to have a dual role in these cells. Firstly it can enhance and maintain stem cell pluripotency by preventing differentiation and enhancing self-renewal and secondly it can maintain the pluripotency and differentiation potential of mESCS. [49][50] Induced pluripotent stem cells (iPSCs) are ESC-like cells that can generate scalable quantities of relevant tissue and are of major interest for their application in personalized regenerative medicine, drug screening, and for our understanding of the cell signaling networks that regulate embryonic development and disease. In vitro studies have shown that Tbx3 is an important factor that, together with KLF4, SOX2, OCT4, Nanog, LIN-28A and C-MYC, can reprogram somatic cells to form iPS cells. [51]

Clinical significance

TBX3 has been implicated in human diseases including the ulnar mammary syndrome [52], obesity [53], rheumatoid arthritis [54] and cancer. [55]

In humans, heterozygous mutations of TBX3 lead to the autosomal dominant developmental disorder, ulnar mammary syndrome (UMS), which is characterized by a number of clinical features including mammary and apocrine gland hypoplasia, upper limb defects, malformations of areola, dental structures, heart and genitalia 2,70. Several UMS causing mutations in the TBX3 gene have been reported which include 5 nonsense, 8 frameshift (due to deletion, duplication and insertion), 3 missense and 2 splice site mutations. Missense mutations within the T-domain, or the loss of RD1 result in aberrant transcripts and truncated proteins of TBX3. These mutations lead to reduced DNA binding, transcriptional control and splicing regulation of TBX3 and the loss of function and are associated with the most severe phenotype of UMS 16,71–73.

Tbx3 is expressed in heterogenous populations of hypothalamic arcuate nucleus neurons which control energy homeostasis by regulating appetite and energy expenditure and the ablation of TBX3 function in these neurons was shown to cause obesity in mouse models. Importantly, Tbx3 was shown to be a key player in driving the functional heterogeneity of hypothalamic neurons and this function was conserved in mice, drosophila and humans 42. Genome wide association studies also casually linked TBX3 to rheumatoid arthritis (RA) susceptibility and a recent study identified Tbx3 as a candidate gene for RA in collagen-induced arthritis (CIA) mouse models 68,74. The severity of RA directly correlated with TBX3 serum levels in the CIA mouse models. Furthermore, Tbx3 was shown to repress B lymphocyte proliferation and to activate the humoral immune response which is associated with chronic inflammation of the synovium leading to RA. Tbx3 may thus be an important player in regulating the immune system and could be used as a biomarker for the diagnosis of RA severity 68.

TBX3 is overexpressed in a wide range of carcinomas (breast, pancreatic, melanoma, liver, lung, gastric, ovarian, bladder and head and neck cancers) and sarcomas (chondrosarcoma, fibrosarcoma, liposarcoma, rhabdomyosarcoma and synovial sarcoma) and there is compelling evidence that it contributes to several hallmarks of cancer. Indeed, TBX3 can bypass cellular senescence, apoptosis and anoikis as well as promote uncontrolled cell proliferation, tumour formation, angiogenesis and metastasis 8,27,69,75–77. Furthermore, TBX3 contributes to the expansion of cancer stem cells (CSCs) and is a key player in regulating pluripotency-related genes in these cells. CSCs contribute to tumour relapse and drug resistance and thus this may be another mechanism by which TBX3 contributes to cancer formation and tumour aggressiveness 96. The mechanisms by which TBX3 contributes to oncogenic processes involve, in part, its ability to inhibit the tumour suppressor pathways p14ARF/p53/p21WAF1/CIP1, p16INK4a/pRb, p57KIP2, PTEN and E-cadherin 9,19,26,78–82 and activating the angiogenesis-associated genes FGF2 and VEGF-A and the EMT gene SNAI 7,8,83. Some of the oncogenic signalling molecules identified that upregulate TBX3 include TGF-β, BRAF-MAPK, c-Myc, AKT and PLCᗴ/PKC 12,18,84–87 The function of TBX3 is also regulated by phosphorylation by the p38-MAPK, AKT3 and cyclin A/CDK2 10 and by protein co-factors, which include PRC2, Histone Deacetylases 1, 2, 3 and 5 and CAPERα 26,28,78.

There is also evidence that TBX3 may function as a tumour suppressor. During oncogenesis, TBX3 is silenced by methylation in some cancers and this was associated with a poor overall survival, resistance to cancer therapy and a more invasive phenotype 88–97. In addition, TBX3 is overexpressed in fibrosarcoma cells and removing TBX3 from these cells led to a more aggressive phenotype 98.

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