Disease relevance of TBX2

• The TBX2 gene encoding a key developmental transcription factor is amplified in pancreatic cancer cell lines and preferentially amplified and overexpressed in BRCA1 and BRCA2 mutated breast tumors [1].
• The dorsoventral gradient of TBX2 expression disappeared before the ganglion cell layer (GCL) formed [2].
• T-box binding protein type two (TBX2) is an immediate early gene target in retinoic-acid-treated B16 murine melanoma cells [3].

High impact information on TBX2

• Senescence bypass screen identifies TBX2, which represses Cdkn2a (p19(ARF)) and is amplified in a subset of human breast cancers [4].
• We found TBX2 to be amplified in a subset of primary human breast cancers, indicating that it might contribute to breast cancer development [4].
• Functional dissection of the ET protein reveals a novel transcription-repression domain highly conserved among ET, human TBX3, and TBX2 [5].
• We also report that both the MSEu and MSEi are recognized by the brachyury-related transcription factor Tbx2, a member of the recently described T-box family, and that Tbx2 is expressed in melanocyte and melanoblast cell lines but not in melanoblast precursor cells [6].
• In the Hesr1-misexpressing heart, the boundaries of the AV canal are poorly defined, and the expression levels of specific markers of the AV myocardium, Bmp2 and Tbx2, are either very weak or undetectable [7].

Biological context of TBX2

• In addition to a role in development, TBX2 and TBX3 have been implicated in tumor development through downregulation of the alternative reading frame (ARF) tumor suppressor and an associated bypass of senescence [8].
• In the 17q arm, the ERBB2 oncogene was amplified in 20% of the cell lines, TBX2 in 50%, and BIRC5 in 58%, indicating increased involvement toward the q telomere of chromosome 17 [9].
• Here we show that although TBX1, TBX2 and the Xenopus T protein (Xbra) share only 50-60% identity within their DNA-binding domains they can bind the same DNA sequence in vitro [10].
• Most importantly, TBX2 represses while Xbra activates transcription of the same chimeric reporter plasmid [10].
• Identification, characterization, and localization to chromosome 17q21-22 of the human TBX2 homolog, member of a conserved developmental gene family [11].

Anatomical context of TBX2

• TBX2 expression and its induction by retinoic acid was also observed in normal human and nonmalignant mouse melanocytes [3].
• Northern blot analysis identified two major TBX2 expression fetal kidney and lung; and in adult kidney, lung, ovary, prostate, spleen, and testis [11].
• Here, we show that genetic deletion of SAFB1 in mouse embryonic fibroblasts (MEF) leads to spontaneous immortalization and altered expression of two proteins involved in immortalization and escape from senescence: low levels of p19(ARF) and high levels of TBX2 [12].
• Tension-induced reduction in connexin 43 expression in cranial sutures is linked to transcriptional regulation by TBX2 [13].
• Ectopic expression of Tbx3, a transcriptional repressor that belongs to the Tbx2/3/4/5 subfamily of T-box transcriptional regulators, in the forelimb results in a rostral shift in the position of the limb along the main body axis [14].

Associations of TBX2 with chemical compounds

• Increased TBX2 mRNA is seen within 2 h after addition of retinoic acid to B16 cells [3].
• Thromboxane B2 (TBX2) and leukotriene C4 (LTC4) were measured by radioimmunoassay (RIA), TNF alpha by enzyme-linked immunosorbent assay (ELISA) [15].

Regulatory relationships of TBX2

• Tbx2 is a transcriptional repressor implicated in several developmental processes and which has also been implicated in cancer through its ability to suppress senescence via repression of the p19(ARF) and p21(Cip1) (CDKN1A) promoters [16].

Other interactions of TBX2

• Whereas the core nucleotides required for interaction of the archetypal T-box protein Brachyury with a consensus T-site are conserved in the variant site, additional flanking nucleotides contribute to the specificity of TBX2 binding [17].
• Coduplication of MYC and TBX2 was common in the in situ and invasive lesions from the deleterious mutation carriers [18].
• TBX4, a human member of the Tbx2/3/4/5 subfamily, has been identified and characterized from a high-throughput genomic sequence [19].
• Support for this hypothesis comes from studies demonstrating that many of the amplified genes are over-expressed in breast cancer cell lines and tumors, and that the RPS6KB1, TBX2, and PPM1D genes from the region, that are amplified and over-expressed in breast tumors and cell lines, contribute to tumor formation and/or tumor progression [20].
• S6K, PAT1, and TBX2 were coamplified in about 10% of tumors, whereas RADS1C amplification was seen in only 3% of tumors [21].

References