TBX3

Last updated

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

Contents

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
Protein TBX3 PDB 1h6f.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases TBX3 , TBX3-ISO, UMS, XHL, T-box 3, T-box transcription factor 3
External IDs OMIM: 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 Mb Chr 5: 119.81 – 119.82 Mb
PubMed search [6] [7]
Wikidata
View/Edit Human View/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]

TBX3 can activate and/or repress its target genes by binding a T-element, or half T-element sites. [18] 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. [19] [20] Furthermore, in the cancer context, TBX3 directly represses the cell cycle regulators p19ARF/p14ARF, [21] p21WAF1 [22] and TBX2 [23] as well as E-cadherin [11] which encodes a cell adhesion molecule, to promote proliferation and migration. 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. [24]

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 [25] and Sox4 [26] to assist it binding to its target genes to regulate heart development [10] [27] [28] [29] [30] 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. [31] [32] 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. [33]

TBX3 has been functionally connected to the regulation of the Wnt signalling, thereby providing a novel explanation of how signalling pathways are orchestrated by tissue-specific transcription factors. [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] TBX3 has been implicated in the regulation of Wnt target genes by tissue-specific crosstalk with the protein BCL9. [34]

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, [38] rheumatoid arthritis [53] and cancer. [54]

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. [8] [55] 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. [21] [56] [57] [58]

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. [38] Genome wide association studies also causally 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. [53] [59] 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. [53]

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, tumor formation, angiogenesis and metastasis. [14] [32] [54] [60] [61] [62] 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 tumor relapse and drug resistance and thus this may be another mechanism by which TBX3 contributes to cancer formation and tumor aggressiveness. [63] The mechanisms by which TBX3 contributes to oncogenic processes involve, in part, its ability to inhibit the tumor suppressor pathways p14ARF/p53/p21WAF1/CIP1, [15] [31] [64] p16INK4a/pRb, p57KIP2, [65] PTEN, [24] E-cadherin [60] [61] and activating the angiogenesis-associated genes FGF2 and VEGF-A [66] and the EMT gene SNAI. [14] Some of the oncogenic signaling molecules identified that upregulate TBX3 include TGF-β, [23] [67] BRAF-MAPK, [68] c-Myc, [16] AKT, [69] and PLCᗴ/PKC. [70] The function of TBX3 is also regulated by phosphorylation by the p38-MAPK, AKT3 and cyclin A/CDK2 [16] and by protein co-factors, which include PRC2, [65] Histone Deacetylases 1, 2, 3 and 5 [31] and CAPERα. [33]

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. [71] [72] [73] In addition, TBX3 is overexpressed in fibrosarcoma cells and removing TBX3 from these cells led to a more aggressive phenotype. [74]

Notes

Related Research Articles

The epithelial–mesenchymal transition (EMT) is a process by which epithelial cells lose their cell polarity and cell–cell adhesion, and gain migratory and invasive properties to become mesenchymal stem cells; these are multipotent stromal cells that can differentiate into a variety of cell types. EMT is essential for numerous developmental processes including mesoderm formation and neural tube formation. EMT has also been shown to occur in wound healing, in organ fibrosis and in the initiation of metastasis in cancer progression.

<span class="mw-page-title-main">T-box transcription factor T</span> Protein-coding gene in the species Homo sapiens

T-box transcription factor T, also known as Brachyury protein, is encoded for in humans by the TBXT gene. Brachyury functions as a transcription factor within the T-box family of genes. Brachyury homologs have been found in all bilaterian animals that have been screened, as well as the freshwater cnidarian Hydra.

<span class="mw-page-title-main">PAX3</span> Paired box gene 3

The PAX3 gene encodes a member of the paired box or PAX family of transcription factors. The PAX family consists of nine human (PAX1-PAX9) and nine mouse (Pax1-Pax9) members arranged into four subfamilies. Human PAX3 and mouse Pax3 are present in a subfamily along with the highly homologous human PAX7 and mouse Pax7 genes. The human PAX3 gene is located in the 2q36.1 chromosomal region, and contains 10 exons within a 100 kb region.

<span class="mw-page-title-main">Mothers against decapentaplegic homolog 4</span> Mammalian protein found in Homo sapiens

SMAD4, also called SMAD family member 4, Mothers against decapentaplegic homolog 4, or DPC4 is a highly conserved protein present in all metazoans. It belongs to the SMAD family of transcription factor proteins, which act as mediators of TGF-β signal transduction. The TGFβ family of cytokines regulates critical processes during the lifecycle of metazoans, with important roles during embryo development, tissue homeostasis, regeneration, and immune regulation.

<span class="mw-page-title-main">FOXC2</span> Protein-coding gene in the species Homo sapiens

Forkhead box protein C2 (FOXC2) also known as forkhead-related protein FKHL14 (FKHL14), transcription factor FKH-14, or mesenchyme fork head protein 1 (MFH1) is a protein that in humans is encoded by the FOXC2 gene. FOXC2 is a member of the fork head box (FOX) family of transcription factors.

<span class="mw-page-title-main">T-box</span> Genes that affect limb and heart development

T-box refers to a group of transcription factors involved in embryonic limb and heart development. Every T-box protein has a relatively large DNA-binding domain, generally comprising about a third of the entire protein that is both necessary and sufficient for sequence-specific DNA binding. All members of the T-box gene family bind to the "T-box", a DNA consensus sequence of TCACACCT.

<span class="mw-page-title-main">TP63</span> Protein-coding gene in the species Homo sapiens

Tumor protein p63, typically referred to as p63, also known as transformation-related protein 63 is a protein that in humans is encoded by the TP63 gene.

<span class="mw-page-title-main">Forkhead box C1</span> Protein-coding gene in the species Homo sapiens

Forkhead box C1, also known as FOXC1, is a protein which in humans is encoded by the FOXC1 gene.

<i>TBX5</i> (gene) Protein-coding gene that affects limb development and heart and bone function

T-box transcription factor TBX5, is a protein that in humans is encoded by the TBX5 gene. Abnormalities in the TBX5 gene can result in altered limb development, Holt-Oram syndrome, Tetra-amelia syndrome, and cardiac and skeletal problems.

<span class="mw-page-title-main">SIM2</span> Protein-coding gene in the species Homo sapiens

Single-minded homolog 2 is a protein that in humans is encoded by the SIM2 gene. It plays a major role in the development of the central nervous system midline as well as the construction of the face and head.

<span class="mw-page-title-main">SNAI2</span> Protein

Zinc finger protein SNAI2 is a transcription factor that in humans is encoded by the SNAI2 gene. It promotes the differentiation and migration of certain cells and has roles in initiating gastrulation.

<span class="mw-page-title-main">SALL4</span> Protein-coding gene in the species Homo sapiens

Sal-like protein 4(SALL4) is a transcription factor encoded by a member of the Spalt-like (SALL) gene family, SALL4. The SALL genes were identified based on their sequence homology to Spalt, which is a homeotic gene originally cloned in Drosophila melanogaster that is important for terminal trunk structure formation in embryogenesis and imaginal disc development in the larval stages. There are four human SALL proteins with structural homology and playing diverse roles in embryonic development, kidney function, and cancer. The SALL4 gene encodes at least three isoforms, termed A, B, and C, through alternative splicing, with the A and B forms being the most studied. SALL4 can alter gene expression changes through its interaction with many co-factors and epigenetic complexes. It is also known as a key embryonic stem cell (ESC) factor.

<span class="mw-page-title-main">TBX2</span> Protein-coding gene in the species Homo sapiens

T-box transcription factor 2 Tbx2 is a transcription factor that is encoded by the Tbx2 gene on chromosome 17q21-22 in humans. This gene is a member of a phylogenetically conserved family of genes that share a common DNA-binding domain, the T-box. Tbx2 and Tbx3 are the only T-box transcription factors that act as transcriptional repressors rather than transcriptional activators, and are closely related in terms of development and tumorigenesis. This gene plays a significant role in embryonic and fetal development through control of gene expression, and also has implications in various cancers. Tbx2 is associated with numerous signaling pathways, BMP, TGFβ, Wnt, and FGF, which allow for patterning and proliferation during organogenesis in fetal development.

<span class="mw-page-title-main">KMT2D</span> Protein-coding gene in humans

Histone-lysine N-methyltransferase 2D (KMT2D), also known as MLL4 and sometimes MLL2 in humans and Mll4 in mice, is a major mammalian histone H3 lysine 4 (H3K4) mono-methyltransferase. It is part of a family of six Set1-like H3K4 methyltransferases that also contains KMT2A, KMT2B, KMT2C, KMT2F, and KMT2G.

<span class="mw-page-title-main">AGGF1</span> Protein-coding gene in the species Homo sapiens

Angiogenic factor with G patch and FHA domains 1 is a protein that in humans is encoded by the AGGF1 gene.

<span class="mw-page-title-main">TBX22</span> Protein-coding gene in the species Homo sapiens

T-box transcription factor TBX22 is a protein that in humans is encoded by the TBX22 gene.

<span class="mw-page-title-main">Cadherin-1</span> Human protein-coding gene

Cadherin-1 or Epithelial cadherin(E-cadherin), is a protein that in humans is encoded by the CDH1 gene. Mutations are correlated with gastric, breast, colorectal, thyroid, and ovarian cancers. CDH1 has also been designated as CD324. It is a tumor suppressor gene.

<span class="mw-page-title-main">FOXA1</span> Protein-coding gene in the species Homo sapiens

Forkhead box protein A1 (FOXA1), also known as hepatocyte nuclear factor 3-alpha (HNF-3A), is a protein that in humans is encoded by the FOXA1 gene.

mir-200

In molecular biology, the miR-200 microRNA is a short RNA molecule. MicroRNAs function to regulate the expression levels of other genes by binding and cleaving mRNAs or inhibiting translation. The miR-200 family contains miR-200a, miR-200b, miR-200c, miR-141, and miR-429. There is growing evidence to suggest that miR-200 microRNAs are involved in cancer metastasis.

<span class="mw-page-title-main">FOXJ1</span> Protein-coding gene in the species Homo sapiens

Forkhead box protein J1 is a protein that in humans is encoded by the FOXJ1 gene. It is a member of the Forkhead/winged helix (FOX) family of transcription factors that is involved in ciliogenesis. FOXJ1 is expressed in ciliated cells of the lung, choroid plexus, reproductive tract, embryonic kidney and pre-somite embryo stage.

References

  1. ↑ Li QY, Newbury-Ecob RA, Terrett JA, Wilson DI, Curtis AR, Yi CH, et al. (January 1997). "Holt-Oram syndrome is caused by mutations in TBX5, a member of the Brachyury (T) gene family". Nature Genetics. 15 (1): 21–29. doi:10.1038/ng0197-21. PMID   8988164. S2CID   22619598.
  2. ↑ "Entrez Gene: TBX3 T-box 3 (ulnar mammary syndrome)".
  3. ↑ Papaioannou VE (October 2014). "The T-box gene family: emerging roles in development, stem cells and cancer". Development. 141 (20): 3819–3833. doi:10.1242/dev.104471. PMC   4197708 . PMID   25294936.
  4. 1 2 3 GRCh38: Ensembl release 89: ENSG00000135111 – Ensembl, May 2017
  5. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000018604 – Ensembl, May 2017
  6. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  7. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  8. 1 2 3 Bamshad M, Lin RC, Law DJ, Watkins WC, Krakowiak PA, Moore ME, et al. (July 1997). "Mutations in human TBX3 alter limb, apocrine and genital development in ulnar-mammary syndrome". Nature Genetics. 16 (3): 311–315. doi:10.1038/ng0797-311. PMID   9207801. S2CID   2415047.
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  30. ↑ Stennard FA, Harvey RP (November 2005). "T-box transcription factors and their roles in regulatory hierarchies in the developing heart". Development. 132 (22): 4897–4910. doi: 10.1242/dev.02099 . PMID   16258075.
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