Biology:TBX3

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Short description: Protein-coding gene in the species Homo sapiens

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).

A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example


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.[4][5] The functions of TBX3 and TBX3+2a may vary slightly across different cell types.[5][6][7][8][9][10]

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).[11] 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.[12][13]

TBX3 can activate and/or repress its target genes by binding a T-element, or half T-element sites.[14] 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.[15][16] Furthermore, in the cancer context, TBX3 directly represses the cell cycle regulators p19ARF/p14ARF,[17] p21WAF1 [18] and TBX2 [19] as well as E-cadherin [7] 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.[20]

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 [21] and Sox4 [22] to assist it binding to its target genes to regulate heart development [6][23][24][25][26] 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.[27][28] 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.[6][7][8][9][10] 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.[29]

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.[30]

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,[31] musculoskeletal structures,[32] mammary glands,[33] nervous system,[34] skin,[35] eye,[36] liver,[37] pancreas,[38] lungs [39] and genitalia.[4] 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,[40] mammary glands,[41] limbs [42] and lungs.[43] TBX3 has been implicated in the regulation of Wnt target genes by tissue-specific crosstalk with the protein BCL9.[30]

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.[44] 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.[45][46] 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.[47]

Clinical significance

TBX3 has been implicated in human diseases including the ulnar mammary syndrome,[48] obesity,[34] rheumatoid arthritis[49] and cancer.[50]

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.[4][51] 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.[17][52][53][54]

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.[34] 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.[49][55] 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.[49]

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.[10][28][50][56][57][58] 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.[59] The mechanisms by which TBX3 contributes to oncogenic processes involve, in part, its ability to inhibit the tumor suppressor pathways p14ARF/p53/p21WAF1/CIP1,[11][27][60] p16INK4a/pRb, p57KIP2,[61] PTEN,[20] E-cadherin[56][57] and activating the angiogenesis-associated genes FGF2 and VEGF-A[62] and the EMT gene SNAI.[10] Some of the oncogenic signaling molecules identified that upregulate TBX3 include TGF-β,[19][63] BRAF-MAPK,[64] c-Myc,[12] AKT,[65] and PLCᗴ/PKC.[66] The function of TBX3 is also regulated by phosphorylation by the p38-MAPK, AKT3 and cyclin A/CDK2[12] and by protein co-factors, which include PRC2,[61] Histone Deacetylases 1, 2, 3 and 5[27] and CAPERα.[29]

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.[67][68][69] In addition, TBX3 is overexpressed in fibrosarcoma cells and removing TBX3 from these cells led to a more aggressive phenotype.[70]

Notes

References

  1. ↑ "Holt-Oram syndrome is caused by mutations in TBX5, a member of the Brachyury (T) gene family". Nature Genetics 15 (1): 21–9. Jan 1997. doi:10.1038/ng0197-21. PMID 8988164. 
  2. ↑ "Entrez Gene: TBX3 T-box 3 (ulnar mammary syndrome)". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=6926. 
  3. ↑ "The T-box gene family: emerging roles in development, stem cells and cancer". Development 141 (20): 3819–33. October 2014. doi:10.1242/dev.104471. PMID 25294936. 
  4. ↑ 4.0 4.1 4.2 "Mutations in human TBX3 alter limb, apocrine and genital development in ulnar-mammary syndrome". Nature Genetics 16 (3): 311–5. July 1997. doi:10.1038/ng0797-311. PMID 9207801. 
  5. ↑ 5.0 5.1 "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 Research 64 (15): 5132–9. August 2004. doi:10.1158/0008-5472.CAN-04-0615. PMID 15289316. 
  6. ↑ 6.0 6.1 6.2 "TBX3 and its splice variant TBX3 + exon 2a are functionally similar". Pigment Cell & Melanoma Research 21 (3): 379–87. June 2008. doi:10.1111/j.1755-148X.2008.00461.x. PMID 18444963. 
  7. ↑ 7.0 7.1 7.2 "Tbx3 represses E-cadherin expression and enhances melanoma invasiveness". Cancer Research 68 (19): 7872–81. October 2008. doi:10.1158/0008-5472.CAN-08-0301. PMID 18829543. 
  8. ↑ 8.0 8.1 "Tbx3 isoforms are involved in pluripotency maintaining through distinct regulation of Nanog transcriptional activity". Biochemical and Biophysical Research Communications 444 (3): 411–4. February 2014. doi:10.1016/j.bbrc.2014.01.093. PMID 24472544. 
  9. ↑ 9.0 9.1 "The transcriptional regulator TBX3 promotes progression from non-invasive to invasive breast cancer". BMC Cancer 16 (1): 671. August 2016. doi:10.1186/s12885-016-2697-z. PMID 27553211. 
  10. ↑ 10.0 10.1 10.2 10.3 "TBX3 promotes progression of pre-invasive breast cancer cells by inducing EMT and directly up-regulating SLUG". The Journal of Pathology 248 (2): 191–203. June 2019. doi:10.1002/path.5245. PMID 30697731. 
  11. ↑ 11.0 11.1 "Tbx3 impinges on the p53 pathway to suppress apoptosis, facilitate cell transformation and block myogenic differentiation". Oncogene 21 (24): 3827–35. May 2002. doi:10.1038/sj.onc.1205476. PMID 12032820. 
  12. ↑ 12.0 12.1 12.2 "The T-Box factor TBX3 is important in S-phase and is regulated by c-Myc and cyclin A-CDK2". Cell Cycle 14 (19): 3173–83. 2015-10-02. doi:10.1080/15384101.2015.1080398. PMID 26266831. 
  13. ↑ "Tara up-regulates E-cadherin transcription by binding to the Trio RhoGEF and inhibiting Rac signaling". The Journal of Cell Biology 193 (2): 319–32. April 2011. doi:10.1083/jcb.201009100. PMID 21482718. 
  14. ↑ "The T-box family". Genome Biology 3 (6): REVIEWS3008. 2002. doi:10.1186/gb-2002-3-6-reviews3008. PMID 12093383. 
  15. ↑ "TBX3 Directs Cell-Fate Decision toward Mesendoderm". Stem Cell Reports 1 (3): 248–65. September 2013. doi:10.1016/j.stemcr.2013.08.002. PMID 24319661. 
  16. ↑ "Dual functions of T-box 3 (Tbx3) in the control of self-renewal and extraembryonic endoderm differentiation in mouse embryonic stem cells". The Journal of Biological Chemistry 286 (10): 8425–36. March 2011. doi:10.1074/jbc.M110.202150. PMID 21189255. 
  17. ↑ 17.0 17.1 "The T-box repressors TBX2 and TBX3 specifically regulate the tumor suppressor gene p14ARF via a variant T-site in the initiator". The Journal of Biological Chemistry 277 (29): 26120–7. July 2002. doi:10.1074/jbc.M200403200. PMID 12000749. 
  18. ↑ "The T-box transcription factor TBX3 drives proliferation by direct repression of the p21(WAF1) cyclin-dependent kinase inhibitor". Cell Division 11 (1): 6. March 2016. doi:10.1186/s13008-016-0019-0. PMID 27110270. 
  19. ↑ 19.0 19.1 "The anti-proliferative function of the TGF-β1 signaling pathway involves the repression of the oncogenic TBX2 by its homologue TBX3". The Journal of Biological Chemistry 289 (51): 35633–43. December 2014. doi:10.1074/jbc.M114.596411. PMID 25371204. 
  20. ↑ 20.0 20.1 "Tbx3 represses PTEN and is over-expressed in head and neck squamous cell carcinoma". BMC Cancer 12 (1): 481. October 2012. doi:10.1186/1471-2407-12-481. PMID 23082988. 
  21. ↑ "Msx1 and Msx2 are functional interacting partners of T-box factors in the regulation of Connexin43". Cardiovascular Research 78 (3): 485–93. June 2008. doi:10.1093/cvr/cvn049. PMID 18285513. 
  22. ↑ "Sox4 mediates Tbx3 transcriptional regulation of the gap junction protein Cx43". Cellular and Molecular Life Sciences 68 (23): 3949–61. December 2011. doi:10.1007/s00018-011-0693-7. PMID 21538160. 
  23. ↑ "Transcription factor Tbx3 is required for the specification of the atrioventricular conduction system". Circulation Research 102 (11): 1340–9. June 2008. doi:10.1161/circresaha.107.169565. PMID 18467625. 
  24. ↑ "Chamber formation and morphogenesis in the developing mammalian heart". Developmental Biology 223 (2): 266–78. July 2000. doi:10.1006/dbio.2000.9859. PMID 10882515. 
  25. ↑ "T-box transcription factor Tbx2 represses differentiation and formation of the cardiac chambers". Developmental Dynamics 229 (4): 763–70. April 2004. doi:10.1002/dvdy.10487. PMID 15042700. 
  26. ↑ "T-box transcription factors and their roles in regulatory hierarchies in the developing heart". Development 132 (22): 4897–910. November 2005. doi:10.1242/dev.02099. PMID 16258075. 
  27. ↑ 27.0 27.1 27.2 "TBX3 is overexpressed in breast cancer and represses p14 ARF by interacting with histone deacetylases". Cancer Research 68 (3): 693–9. February 2008. doi:10.1158/0008-5472.can-07-5012. PMID 18245468. 
  28. ↑ 28.0 28.1 "The special stemness functions of Tbx3 in stem cells and cancer development". Seminars in Cancer Biology 57: 105–110. September 2018. doi:10.1016/j.semcancer.2018.09.010. PMID 30268432. 
  29. ↑ 29.0 29.1 "Coordinated control of senescence by lncRNA and a novel T-box3 co-repressor complex". eLife 3. May 2014. doi:10.7554/elife.02805. PMID 24876127. 
  30. ↑ 30.0 30.1 Zimmerli, Dario; Borrelli, Costanza; Jauregi-Miguel, Amaia; Söderholm, Simon; Brütsch, Salome; Doumpas, Nikolaos; Reichmuth, Jan; Murphy-Seiler, Fabienne et al. (18 August 2020). "TBX3 acts as tissue-specific component of the Wnt/β-catenin transcriptional complex". eLife 9: e58123. doi:10.7554/eLife.58123. ISSN 2050-084X. PMID 32808927. 
  31. ↑ Tümpel, S (2002-10-15). "Regulation of Tbx3 Expression by Anteroposterior Signalling in Vertebrate Limb Development". Developmental Biology 250 (2): 251–262. doi:10.1016/s0012-1606(02)90762-1. ISSN 0012-1606. PMID 12376101. 
  32. ↑ "Giant intracranial epidural meningioma". Journal of Neurosurgery 35 (6): 748–50. December 1971. doi:10.3171/jns.1971.35.6.0748. PMID 5117227. 
  33. ↑ "Molecular interactions between Tbx3 and Bmp4 and a model for dorsoventral positioning of mammary gland development". Proceedings of the National Academy of Sciences of the United States of America 103 (45): 16788–93. November 2006. doi:10.1073/pnas.0604645103. PMID 17071745. Bibcode: 2006PNAS..10316788C. 
  34. ↑ 34.0 34.1 34.2 "Functional identity of hypothalamic melanocortin neurons depends on Tbx3". Nature Metabolism 1 (2): 222–235. 2019-01-28. doi:10.1038/s42255-018-0028-1. PMID 32694784. PMC 8291379. https://push-zb.helmholtz-muenchen.de/frontdoor.php?source_opus=55677. 
  35. ↑ "Tbx3-dependent amplifying stem cell progeny drives interfollicular epidermal expansion during pregnancy and regeneration". Nature Communications 8 (1): 508. September 2017. doi:10.1038/s41467-017-00433-7. PMID 28894084. Bibcode: 2017NatCo...8..508I. 
  36. ↑ "Tbx3 represses bmp4 expression and, with Pax6, is required and sufficient for retina formation". Development 143 (19): 3560–3572. October 2016. doi:10.1242/dev.130955. PMID 27578778. 
  37. ↑ "Tbx3 controls the fate of hepatic progenitor cells in liver development by suppressing p19ARF expression". Development 135 (9): 1589–95. May 2008. doi:10.1242/dev.016634. PMID 18356246. 
  38. ↑ "Dynamic expression of Tbx2 and Tbx3 in developing mouse pancreas". Gene Expression Patterns 11 (8): 476–83. December 2011. doi:10.1016/j.gep.2011.08.003. PMID 21867776. 
  39. ↑ "Wnt and FGF mediated epithelial-mesenchymal crosstalk during lung development". Developmental Dynamics 244 (3): 342–66. March 2015. doi:10.1002/dvdy.24234. PMID 25470458. 
  40. ↑ "Diverse functional networks of Tbx3 in development and disease". Wiley Interdisciplinary Reviews. Systems Biology and Medicine 4 (3): 273–83. 2012-02-14. doi:10.1002/wsbm.1162. PMID 22334480. 
  41. ↑ "The role of Tbx2 and Tbx3 in mammary development and tumorigenesis". Journal of Mammary Gland Biology and Neoplasia 9 (2): 109–18. April 2004. doi:10.1023/b:jomg.0000037156.64331.3f. PMID 15300007. 
  42. ↑ "The Roles of T-Box Genes in Vertebrate Limb Development". Current Topics in Developmental Biology (Elsevier) 122: 355–381. 2017. doi:10.1016/bs.ctdb.2016.08.009. ISBN 9780128013809. PMID 28057270. 
  43. ↑ "Tbx2 and Tbx3 Act Downstream of Shh to Maintain Canonical Wnt Signaling during Branching Morphogenesis of the Murine Lung". Developmental Cell 39 (2): 239–253. October 2016. doi:10.1016/j.devcel.2016.08.007. PMID 27720610. 
  44. ↑ "A single cell bioengineering approach to elucidate mechanisms of adult stem cell self-renewal". Integrative Biology 4 (4): 360–7. April 2012. doi:10.1039/c2ib00148a. PMID 22327505. 
  45. ↑ "Dual functions of T-box 3 (Tbx3) in the control of self-renewal and extraembryonic endoderm differentiation in mouse embryonic stem cells". The Journal of Biological Chemistry 286 (10): 8425–36. March 2011. doi:10.1074/jbc.m110.202150. PMID 21189255. 
  46. ↑ "A Dynamic Role of TBX3 in the Pluripotency Circuitry". Stem Cell Reports 5 (6): 1155–1170. December 2015. doi:10.1016/j.stemcr.2015.11.003. PMID 26651606. 
  47. ↑ "Tbx3 improves the germ-line competency of induced pluripotent stem cells". Nature 463 (7284): 1096–100. February 2010. doi:10.1038/nature08735. PMID 20139965. Bibcode: 2010Natur.463.1096H. 
  48. ↑ Dettman, Robert, ed (2013-07-02). "Mouse TBX3 mutants suggest novel molecular mechanisms for Ulnar-mammary syndrome". PLOS ONE 8 (7): e67841. doi:10.1371/journal.pone.0067841. PMID 23844108. Bibcode: 2013PLoSO...867841F. 
  49. ↑ 49.0 49.1 49.2 "The oncoprotein TBX3 is controlling severity in experimental arthritis". Arthritis Research & Therapy 21 (1): 16. January 2019. doi:10.1186/s13075-018-1797-3. PMID 30630509. 
  50. ↑ 50.0 50.1 "The T-Box transcription factor 3 in development and cancer". BioScience Trends 11 (3): 254–266. July 2017. doi:10.5582/bst.2017.01043. PMID 28579578. 
  51. ↑ "Ulnar Mammary syndrome and TBX3: expanding the phenotype". American Journal of Medical Genetics. Part A 149A (12): 2809–12. December 2009. doi:10.1002/ajmg.a.33096. PMID 19938096. 
  52. ↑ "Novel TBX3 mutation data in families with ulnar-mammary syndrome indicate a genotype-phenotype relationship: mutations that do not disrupt the T-domain are associated with less severe limb defects". European Journal of Medical Genetics 49 (2): 151–8. March 2006. doi:10.1016/j.ejmg.2005.04.021. PMID 16530712. 
  53. ↑ "A dominant repression domain in Tbx3 mediates transcriptional repression and cell immortalization: relevance to mutations in Tbx3 that cause ulnar-mammary syndrome". Human Molecular Genetics 10 (21): 2403–13. October 2001. doi:10.1093/hmg/10.21.2403. PMID 11689487. 
  54. ↑ "TBX3 regulates splicing in vivo: a novel molecular mechanism for Ulnar-mammary syndrome". PLOS Genetics 10 (3): e1004247. March 2014. doi:10.1371/journal.pgen.1004247. OCLC 908304248. PMID 24675841. 
  55. ↑ "Genome-wide association study of rheumatoid arthritis in the Spanish population: KLF12 as a risk locus for rheumatoid arthritis susceptibility". Arthritis and Rheumatism 58 (8): 2275–86. August 2008. doi:10.1002/art.23623. PMID 18668548. 
  56. ↑ 56.0 56.1 "T-box Transcription Factor Tbx3 Contributes to Human Hepatocellular Carcinoma Cell Migration and Invasion by Repressing E-Cadherin Expression". Oncology Research 26 (6): 959–966. July 2018. doi:10.3727/096504017x15145624664031. PMID 29295731. 
  57. ↑ 57.0 57.1 "Novel HDAC5-interacting motifs of Tbx3 are essential for the suppression of E-cadherin expression and for the promotion of metastasis in hepatocellular carcinoma". Signal Transduction and Targeted Therapy 3 (1): 22. 2018-08-24. doi:10.1038/s41392-018-0025-6. PMID 30151243. 
  58. ↑ "TBX3 gene in renal carcinoma and its clinical significance". Oncology Letters 15 (4): 4235–4240. April 2018. doi:10.3892/ol.2018.7841. PMID 29541189. 
  59. ↑ "The fundamental role of epigenetic events in cancer". Nature Reviews. Genetics 3 (6): 415–28. June 2002. doi:10.1038/nrg816. PMID 12042769. 
  60. ↑ "TBX-3, the gene mutated in Ulnar-Mammary Syndrome, is a negative regulator of p19ARF and inhibits senescence". The Journal of Biological Chemistry 277 (8): 6567–72. February 2002. doi:10.1074/jbc.m110492200. PMID 11748239. 
  61. ↑ 61.0 61.1 "KIP2 repression". Oncogene 37 (21): 2773–2792. May 2018. doi:10.1038/s41388-017-0090-2. PMID 29511350. 
  62. ↑ "Tbx3 fosters pancreatic cancer growth by increased angiogenesis and activin/nodal-dependent induction of stemness". Stem Cell Research 17 (2): 367–378. September 2016. doi:10.1016/j.scr.2016.08.007. PMID 27632063. 
  63. ↑ "The oncogenic TBX3 is a downstream target and mediator of the TGF-β1 signaling pathway". Molecular Biology of the Cell 24 (22): 3569–76. November 2013. doi:10.1091/mbc.e13-05-0273. PMID 24025717. 
  64. ↑ "Oncogenic B-RAF(V600E) signaling induces the T-Box3 transcriptional repressor to repress E-cadherin and enhance melanoma cell invasion". The Journal of Investigative Dermatology 133 (5): 1269–77. May 2013. doi:10.1038/jid.2012.421. PMID 23190890. 
  65. ↑ "The T-box transcription factor, TBX3, is a key substrate of AKT3 in melanomagenesis". Oncotarget 6 (3): 1821–33. January 2015. doi:10.18632/oncotarget.2782. PMID 25595898. 
  66. ↑ "A new PKCα/β/TBX3/E-cadherin pathway is involved in PLCε-regulated invasion and migration in human bladder cancer cells". Cellular Signalling 26 (3): 580–93. March 2014. doi:10.1016/j.cellsig.2013.11.015. PMID 24316392. 
  67. ↑ "Stratification based on methylation of TBX2 and TBX3 into three molecular grades predicts progression in patients with pTa-bladder cancer". Modern Pathology 28 (4): 515–22. April 2015. doi:10.1038/modpathol.2014.145. PMID 25394776. 
  68. ↑ "Genome-wide analysis of CpG island methylation in bladder cancer identified TBX2, TBX3, GATA2, and ZIC4 as pTa-specific prognostic markers". European Urology 61 (6): 1245–56. June 2012. doi:10.1016/j.eururo.2012.01.011. PMID 22284968. 
  69. ↑ "DNA methylation in glioblastoma: impact on gene expression and clinical outcome". BMC Genomics 11 (1): 701. December 2010. doi:10.1186/1471-2164-11-701. PMID 21156036. 
  70. ↑ "The T-box transcription factor 3 is a promising biomarker and a key regulator of the oncogenic phenotype of a diverse range of sarcoma subtypes". Oncogenesis 5 (2): e199. February 2016. doi:10.1038/oncsis.2016.11. PMID 26900951. 

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