Gene Summary

Gene:TBX2; T-box 2
Summary:This gene is a member of a phylogenetically conserved family of genes that share a common DNA-binding domain, the T-box. T-box genes encode transcription factors involved in the regulation of developmental processes. This gene product is the human homolog of mouse Tbx2, and shares strong sequence similarity with Drosophila omb protein. Expression studies indicate that this gene may have a potential role in tumorigenesis as an immortalizing agent. Transcript heterogeneity due to alternative polyadenylation has been noted for this gene. [provided by RefSeq, Jul 2008]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:T-box transcription factor TBX2
Source:NCBIAccessed: 11 March, 2017


What does this gene/protein do?
Show (27)
Pathways:What pathways are this gene/protein implicaed in?
Show (1)

Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 11 March 2017 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Cell Cycle
  • Chromosome 17
  • Promoter Regions
  • Transfection
  • Bladder Cancer
  • Biomarkers, Tumor
  • Cell Cycle Proteins
  • Chromatin Immunoprecipitation
  • Western Blotting
  • Melanocytes
  • Molecular Sequence Data
  • Protein Binding
  • TGFA
  • Cell Proliferation
  • Neoplasm Invasiveness
  • Transcription
  • Neoplastic Cell Transformation
  • Melanoma
  • Pancreatic Cancer
  • Epithelial Cells
  • Apoptosis
  • Immunohistochemistry
  • p38 Mitogen-Activated Protein Kinases
  • Transcription Factors
  • Base Sequence
  • FISH
  • Gene Amplification
  • Neoplasm Proteins
  • Signal Transduction
  • CDKN2A Protein
  • Gene Expression Profiling
  • COS Cells
  • Breast Cancer
  • Messenger RNA
  • Up-Regulation
  • Cancer Gene Expression Regulation
  • Young Adult
  • CDKN1A
  • Cell Aging
  • Oncogenes
Tag cloud generated 11 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: TBX2 (cancer-related)

Ashaie MA, Chowdhury EH
Cadherins: The Superfamily Critically Involved in Breast Cancer.
Curr Pharm Des. 2016; 22(5):616-38 [PubMed] Related Publications
Breast cancer, one of the leading causes of mortality and morbidity among females, is regulated in part by diverse classes of adhesion molecules one of which is known as cadherins. Located at adherens junctions, the members of this superfamily are responsible for upholding proper cell-cell adhesion. Cadherins possess diverse structures and functions and any alteration in their structures or functions causes impeding of normal mammary cells development and maintenance, thus leading to breast malignancy. E-, N-, P-, VE-, Proto-, desmosomal and FAT cadherins have been found to regulate breast cancer in positive as well as negative fashion, whereby both Ecadherin (CDH1) and N-cadherin (CDH2) contribute significantly towards transitioning from epithelial state to mesenchymal state (EMT) and enacting the abnormal cells to invade and metastasize nearby and distant tissues. Aberration in gene expression of cadherins can be either due to somatic or epigenetic silencing or via transcriptional factors. Besides other cadherins, E-cadherin which serves as hallmark of EMT is associated with several regulatory factors such as Snail, Slug, Twist, Zeb, KLF4, NFI, TBX2, SIX, b-Myb, COX-2, Arf6, FOXA2, GATA3 and SMAR1, which modulate E-cadherin gene transcription to promote or represses tumor invasion and colonization. Signaling molecules such as Notch, TGF-β, estrogen receptors, EGF and Wnt initiate numerous signaling cascades via these vital factors of cell programming, controlling expression of E-cadherin at transcriptional (mRNA) and protein level. Thus, interactions of cadherins with their roles in tumor suppression and oncogenic transformation can be beneficial in providing valuable insights for breast cancer diagnosis and therapeutics development.

Beukers W, Kandimalla R, Masius RG, et al.
Stratification based on methylation of TBX2 and TBX3 into three molecular grades predicts progression in patients with pTa-bladder cancer.
Mod Pathol. 2015; 28(4):515-22 [PubMed] Related Publications
The potential risk of recurrence and progression in patients with non-muscle-invasive bladder cancer necessitates followup by cystoscopy. The risk of progression to muscle-invasive bladder cancer is estimated based on the European Organisation of Research and Treatment of Cancer score, a combination of several clinicopathological variables. However, pathological assessment is not objective and reproducibility is insufficient. The use of molecular markers could contribute to the estimation of tumor aggressiveness. We recently demonstrated that methylation of GATA2, TBX2, TBX3, and ZIC4 genes could predict progression in Ta tumors. In this study, we aimed to validate the markers in a large patient set using DNA from formalin-fixed and paraffin-embedded tissue. PALGA: the Dutch Pathology Registry was used for patient selection. We included 192 patients with pTaG1/2 bladder cancer of whom 77 experienced progression. Methylation analysis was performed and log-rank analysis was used to calculate the predictive value of each methylation marker for developing progression over time. This analysis showed better progression-free survival in patients with low methylation rates compared with the patients with high methylation rates for all markers (P<0.001) during a followup of ten-years. The combined predictive effect of the methylation markers was analyzed with the Cox-regression method. In this analysis, TBX2, TBX3, and ZIC4 were independent predictors of progression. On the basis of methylation status of TBX2 and TBX3, patients were divided into three new molecular grade groups. Survival analysis showed that only 8% of patients in the low molecular grade group progressed within 5 years. This was 29 and 63% for the intermediate- and high-molecular grade groups. In conclusion, this new molecular-grade based on the combination of TBX2 and TBX3 methylation is an excellent marker for predicting progression to muscle-invasive bladder cancer in patients with primary pTaG1/2 bladder cancer.

Shen J, Lu J, Sui L, et al.
The orthologous Tbx transcription factors Omb and TBX2 induce epithelial cell migration and extrusion in vivo without involvement of matrix metalloproteinases.
Oncotarget. 2014; 5(23):11998-2015 [PubMed] Free Access to Full Article Related Publications
The transcription factors TBX2 and TBX3 are overexpressed in various human cancers. Here, we investigated the effect of overexpressing the orthologous Tbx genes Drosophila optomotor-blind (omb) and human TBX2 in the epithelium of the Drosophila wing imaginal disc and observed two types of cell motility. Omb/TBX2 overexpressing cells could move within the plane of the epithelium. Invasive cells migrated long-distance as single cells retaining or regaining normal cell shape and apico-basal polarity in spite of attenuated apical DE-cadherin concentration. Inappropriate levels of DE-cadherin were sufficient to drive cell migration in the wing disc epithelium. Omb/TBX2 overexpression and reduced DE-cadherin-dependent adhesion caused the formation of actin-rich lateral cell protrusions. Omb/TBX2 overexpressing cells could also delaminate basally, penetrating the basal lamina, however, without degradation of extracellular matrix. Expression of Timp, an inhibitor of matrix metalloproteases, blocked neither intraepithelial motility nor basal extrusion. Our results reveal an MMP-independent mechanism of cell invasion and suggest a conserved role of Tbx2-related proteins in cell invasion and metastasis-related processes.

D'Costa ZC, Higgins C, Ong CW, et al.
TBX2 represses CST6 resulting in uncontrolled legumain activity to sustain breast cancer proliferation: a novel cancer-selective target pathway with therapeutic opportunities.
Oncotarget. 2014; 5(6):1609-20 [PubMed] Free Access to Full Article Related Publications
TBX2 is an oncogenic transcription factor known to drive breast cancer proliferation. We have identified the cysteine protease inhibitor Cystatin 6 (CST6) as a consistently repressed TBX2 target gene, co-repressed through a mechanism involving Early Growth Response 1 (EGR1). Exogenous expression of CST6 in TBX2-expressing breast cancer cells resulted in significant apoptosis whilst non-tumorigenic breast cells remained unaffected. CST6 is an important tumor suppressor in multiple tissues, acting as a dual protease inhibitor of both papain-like cathepsins and asparaginyl endopeptidases (AEPs) such as Legumain (LGMN). Mutation of the CST6 LGMN-inhibitory domain completely abrogated its ability to induce apoptosis in TBX2-expressing breast cancer cells, whilst mutation of the cathepsin-inhibitory domain or treatment with a pan-cathepsin inhibitor had no effect, suggesting that LGMN is the key oncogenic driver enzyme. LGMN activity assays confirmed the observed growth inhibitory effects were consistent with CST6 inhibition of LGMN. Knockdown of LGMN and the only other known AEP enzyme (GPI8) by siRNA confirmed that LGMN was the enzyme responsible for maintaining breast cancer proliferation. CST6 did not require secretion or glycosylation to elicit its cell killing effects, suggesting an intracellular mode of action. Finally, we show that TBX2 and CST6 displayed reciprocal expression in a cohort of primary breast cancers with increased TBX2 expression associating with increased metastases. We have also noted that tumors with altered TBX2/CST6 expression show poor overall survival. This novel TBX2-CST6-LGMN signaling pathway, therefore, represents an exciting opportunity for the development of novel therapies to target TBX2 driven breast cancers.

Zhu B, Zhang M, Byrum SD, et al.
TBX2 blocks myogenesis and promotes proliferation in rhabdomyosarcoma cells.
Int J Cancer. 2014; 135(4):785-97 [PubMed] Free Access to Full Article Related Publications
Rhabdomyosarcomas (RMSs) are the most frequent soft tissue sarcomas in children that share many features of developing skeletal muscle. We have discovered that a T-box family member, TBX2, is highly upregulated in tumor cells of both major RMS subtypes. TBX2 is a repressor that is often overexpressed in cancer cells and is thought to function in bypassing cell growth control, including repression of p14 and p21. The cell cycle regulator p21 is required for the terminal differentiation of skeletal muscle cells and is silenced in RMS cells. We have found that TBX2 interacts with the myogenic regulatory factors MyoD and myogenin and inhibits the activity of these factors. TBX2 is expressed in primary myoblasts and C2C12 cells, but is strongly downregulated upon differentiation. TBX2 recruits the histone deacetylase HDAC1 and is a potent inhibitor of the expression of muscle-specific genes and the cell cycle regulators, p21 and p14. TBX2 promotes the proliferation of RMS cells and either depletions of TBX2 or dominant negative TBX2 upregulate p21- and muscle-specific genes. Significantly, depletion or interference with TBX2 completely inhibits tumor growth in a xenograft assay, highlighting the oncogenic role of TBX2 in RMS cells. Thus, the data demonstrate that elevated expression of TBX2 contributes to the pathology of RMS cells by promoting proliferation and repressing differentiation-specific gene expression. These results show that deregulated TBX2 serves as an oncogene in RMS, suggesting that TBX2 may serve as a new diagnostic marker or therapeutic target for RMS tumors.

Douglas NC, Papaioannou VE
The T-box transcription factors TBX2 and TBX3 in mammary gland development and breast cancer.
J Mammary Gland Biol Neoplasia. 2013; 18(2):143-7 [PubMed] Free Access to Full Article Related Publications
TBX2 and TBX3, closely related members of the T-box family of transcription factor genes, are expressed in mammary tissue in both humans and mice. Ulnar mammary syndrome (UMS), an autosomal dominant disorder caused by mutations in TBX3, underscores the importance of TBX3 in human breast development, while abnormal mammary gland development in Tbx2 or Tbx3 mutant mice provides models for experimental investigation. In addition to their roles in mammary development, aberrant expression of TBX2 and TBX3 is associated with breast cancer. TBX2 is preferentially amplified in BRCA1/2-associated breast cancers and TBX3 overexpression has been associated with advanced stage disease and estrogen-receptor-positive breast tumors. The regulation of Tbx2 and Tbx3 and the downstream targets of these genes in development and disease are not as yet fully elucidated. However, it is clear that the two genes play unique, context-dependent roles both in mammary gland development and in mammary tumorigenesis.

Burgucu D, Guney K, Sahinturk D, et al.
Tbx3 represses PTEN and is over-expressed in head and neck squamous cell carcinoma.
BMC Cancer. 2012; 12:481 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Despite advances in diagnostic and treatment strategies, head and neck squamous cell cancer (HNSCC) constitutes one of the worst cancer types in terms of prognosis. PTEN is one of the tumour suppressors whose expression and/or activity have been found to be reduced in HNSCC, with rather low rates of mutations within the PTEN gene (6-8%). We reasoned that low expression levels of PTEN might be due to a transcriptional repression governed by an oncogene. Tbx2 and Tbx3, both of which are transcriptional repressors, have been found to be amplified or over-expressed in various cancer types. Thus, we hypothesize that Tbx3 may be over expressed in HNSCC and may repress PTEN, thus leading to cancer formation and/or progression.
METHODS: Using immunohistochemistry and quantitative PCR (qPCR), protein and mRNA levels of PTEN and Tbx3 were identified in samples excised from cancerous and adjacent normal tissues from 33 patients who were diagnosed with HNSCC. In addition, HeLa and HEK cell lines were transfected with a Tbx3 expressing plasmid and endogenous PTEN mRNA and protein levels were determined via qPCR and flow cytometry. Transcription assays were performed to demonstrate effects of Tbx3 on PTEN promoter activity. Mann-Whitney, Spearman's Correlation and Wilcoxon signed-rank tests were used to analyze the data.
RESULTS: We demonstrate that in HNSCC samples, Tbx3 mRNA levels are increased with respect to their normal tissue counterparts (p<0.001), whereas PTEN mRNA levels are significantly reduced in cancer tissues. Moreover, Tbx3 protein is also increased in HNSCC tissue sections. Over-expression of Tbx3 in HeLa and HEK cell lines causes reduction in endogenous PTEN mRNA and protein levels. In addition, transcription activity assays reveal that Tbx3 is capable of repressing both the basal and induced promoter activity of PTEN.
CONCLUSIONS: We show that Tbx3 is up-regulated in tissue samples of HNSCC patients and that Tbx3 represses PTEN transcription. Thus, our data not only reveals a new mechanism that may be important in cancer formation, but also suggests that Tbx3 can be used as a potential biomarker in cancer.

Liu F, Cao J, Lv J, et al.
TBX2 expression is regulated by PAX3 in the melanocyte lineage.
Pigment Cell Melanoma Res. 2013; 26(1):67-77 [PubMed] Free Access to Full Article Related Publications
The paired box homeotic gene 3 (PAX3) is a crucial regulator for the maintenance of melanocytic progenitor cells and has a poorly defined role in melanoma. To understand how PAX3 affects melanocyte and melanoma proliferation, we identified potential PAX3 downstream targets through gene expression profiling. Here, we identify T-box 2 (TBX2), a key developmental regulator of cell identity and an antisenescence factor in melanoma, as a directly regulated PAX3 target. We also found that TBX2 is involved in the survival of melanoma cells and is overexpressed in some melanoma specimens. The identification of TBX2 as a target for PAX3 provides a key insight into how PAX3 may contribute to melanoma evolution and may provide opportunities for prosenescence therapeutic intervention aimed at disrupting the ability of PAX3 to regulate TBX2.

Wang B, Lindley LE, Fernandez-Vega V, et al.
The T box transcription factor TBX2 promotes epithelial-mesenchymal transition and invasion of normal and malignant breast epithelial cells.
PLoS One. 2012; 7(7):e41355 [PubMed] Free Access to Full Article Related Publications
The T box transcription factor TBX2, a master regulator of organogenesis, is aberrantly amplified in aggressive human epithelial cancers. While it has been shown that overexpression of TBX2 can bypass senescence, a failsafe mechanism against cancer, its potential role in tumor invasion has remained obscure. Here we demonstrate that TBX2 is a strong cell-autonomous inducer of the epithelial-mesenchymal transition (EMT), a latent morphogenetic program that is key to tumor progression from noninvasive to invasive malignant states. Ectopic expression of TBX2 in normal HC11 and MCF10A mammary epithelial cells was sufficient to induce morphological, molecular, and behavioral changes characteristic of EMT. These changes included loss of epithelial adhesion and polarity gene (E-cadherin, ß-catenin, ZO1) expression, and abnormal gain of mesenchymal markers (N-cadherin, Vimentin), as well as increased cell motility and invasion. Conversely, abrogation of endogenous TBX2 overexpression in the malignant human breast carcinoma cell lines MDA-MB-435 and MDA-MB-157 led to a restitution of epithelial characteristics with reciprocal loss of mesenchymal markers. Importantly, TBX2 inhibition abolished tumor cell invasion and the capacity to form lung metastases in a Xenograft mouse model. Meta-analysis of gene expression in over one thousand primary human breast tumors further showed that high TBX2 expression was significantly associated with reduced metastasis-free survival in patients, and with tumor subtypes enriched in EMT gene signatures, consistent with a role of TBX2 in oncogenic EMT. ChIP analysis and cell-based reporter assays further revealed that TBX2 directly represses transcription of E-cadherin, a tumor suppressor gene, whose loss is crucial for malignant tumor progression. Collectively, our results uncover an unanticipated link between TBX2 deregulation in cancer and the acquisition of EMT and invasive features of epithelial tumor cells.

Luo Y, Ellis LZ, Dallaglio K, et al.
Side population cells from human melanoma tumors reveal diverse mechanisms for chemoresistance.
J Invest Dermatol. 2012; 132(10):2440-50 [PubMed] Free Access to Full Article Related Publications
Side population (SP) cells are identified as cells capable of excluding the fluorescent Hoechst dye and anticancer drugs, and it represents hematopoietic stem cells and chemoresistant cells from several solid tumors. In this study, we confirmed the presence of SP cells in tumors from melanoma patients. Melanoma SP cells overexpressed ATP-binding-cassette (ABC) transporters, ABCB1 and ABCB5. We generated a direct in vivo xenograft model, and demonstrated that SP cells were resistant to paclitaxel, a substrate of ABCB1, both in vitro and in vivo. However, melanoma SP cells were also resistant to temozolomide, which is not a substrate for ABC transporters, through IL-8 upregulation. In addition, gene profiling studies identified three signaling pathways (NF-κB, α6-β4-integrin, and IL-1) as differentially upregulated in melanoma SP cells, and there was a significant increase of PCDHB11 and decrease of FUK and TBX2 in these cells. Therefore, we provide evidence that SP is an enriched source of chemoresistant cells in human melanomas, and suggest that the selected genes and signaling pathways of SP cells may be a potential target for effective melanoma therapies. To our knowledge, this is a previously unreported study to isolate SP cells from melanoma patients and to investigate the gene expression profiling of these cells.

Kandimalla R, van Tilborg AA, Kompier LC, et al.
Genome-wide analysis of CpG island methylation in bladder cancer identified TBX2, TBX3, GATA2, and ZIC4 as pTa-specific prognostic markers.
Eur Urol. 2012; 61(6):1245-56 [PubMed] Related Publications
BACKGROUND: DNA methylation markers could serve as useful biomarkers, both as markers for progression and for urine-based diagnostic assays.
OBJECTIVE: Identify bladder cancer (BCa)-specific methylated DNA sequences for predicting pTa-specific progression and detecting BCa in voided urine.
DESIGN, SETTING, AND PARTICIPANTS: Genome-wide methylation analysis was performed on 44 bladder tumours using the Agilent 244K Human CpG Island Microarray (Agilent Technologies, Santa Clara, CA, USA). Validation was done using a custom Illumina 384-plex assay (Illumina, San Diego, CA, USA) in a retrospective group of 77 independent tumours. Markers for progression were identified in pTa (n = 24) tumours and validated retrospectively in an independent series of 41 pTa tumours by the SNaPshot method (Applied Biosystems, Foster City, CA, USA).
MEASUREMENTS: The percentage of methylation in tumour and urine samples was used to identify markers for detection and related to the end point of progression to muscle-invasive disease with Kaplan-Meier models and multivariate analysis.
RESULTS AND LIMITATIONS: In the validation set, methylation of the T-box 2 (TBX2), T-box 3 (TBX3), GATA binding protein 2 (GATA2), and Zic family member 4 (ZIC4) genes was associated with progression to muscle-invasive disease in pTa tumours (p = 0.003). Methylation of TBX2 alone showed a sensitivity of 100%, a specificity of 80%, a positive predictive value of 78%, and a negative predictive value of 100%, with an area under the curve of 0.96 (p<0.0001) for predicting progression. Multivariate analysis showed that methylation of TBX3 and GATA2 are independent predictors of progression when compared to clinicopathologic variables (p = 0.04 and p = 0.03, respectively). The predictive accuracy improved by 23% by adding methylation of TBX2, TBX3, and GATA2 to the European Organisation for Research and Treatment of Cancer risk scores. We further identified and validated 110 CpG islands (CGIs) that are differentially methylated between tumour cells and control urine. The limitation of this study is the small number of patients analysed for testing and validating the prognostic markers.
CONCLUSIONS: We have identified four methylation markers that predict progression in pTa tumours, thereby allowing stratification of patients for personalised follow-up. In addition, we identified CGIs that will enable detection of bladder tumours in voided urine.

Begum S, Papaioannou VE
Dynamic expression of Tbx2 and Tbx3 in developing mouse pancreas.
Gene Expr Patterns. 2011; 11(8):476-83 [PubMed] Free Access to Full Article Related Publications
Tbx2 and Tbx3 are closely related members of the T-box family of transcription factors that are important regulators during normal development as well as major contributors to human developmental syndromes when mutated. Although there is evidence for the involvement of Tbx2 and Tbx3 in pancreatic cancer, so far there are no reports characterizing the normal expression pattern of these genes in the pancreas. In this study, we examined spatial and temporal expression of Tbx2 and Tbx3 in mouse pancreas during development and in the adult using in situ hybridization and immunohistochemistry. Our results show that Tbx2 and Tbx3 are both expressed in the pancreatic mesenchyme throughout development beginning at embryonic day (E) 9.5. In addition, Tbx2 is expressed in pancreatic vasculature during development and in epithelial-derived endocrine and ductal cells during late fetal stages, postnatal development and in adult pancreas. In contrast, Tbx3 is expressed in exocrine tissue in the postnatal and adult pancreas. Further our results demonstrate that Tbx2 and Tbx3 are expressed in tumor-derived endocrine and exocrine cell lines, respectively. These dynamic changes in the expression pattern of these transcription factors lay the foundation for investigation of potential roles in pancreas development.

Taneja P, Maglic D, Kai F, et al.
Critical roles of DMP1 in human epidermal growth factor receptor 2/neu-Arf-p53 signaling and breast cancer development.
Cancer Res. 2010; 70(22):9084-94 [PubMed] Free Access to Full Article Related Publications
Human epidermal growth factor receptor 2 (HER2) overexpression stimulates cell growth in p53-mutated cells while it inhibits cell proliferation in those with wild-type p53, but the molecular mechanism is unknown. The Dmp1 promoter was activated by HER2/neu through the phosphatidylinositol-3'-kinase-Akt-NF-κB pathway, which in turn stimulated Arf transcription. Binding of p65 and p52 subunits of NF-κB was shown to the Dmp1 promoter and that of Dmp1 to the Arf promoter on HER2/neu overexpression. Both Dmp1 and p53 were induced in premalignant lesions from mouse mammary tumor virus-neu mice, and mammary tumorigenesis was significantly accelerated in both Dmp1+/- and Dmp1-/- mice. Selective deletion of Dmp1 and/or overexpression of Tbx2/Pokemon was found in >50% of wild-type HER2/neu carcinomas, although the involvement of Arf, Mdm2, or p53 was rare. Tumors from Dmp1+/-, Dmp1-/-, and wild-type neu mice with hemizygous Dmp1 deletion showed significant downregulation of Arf and p21Cip1/WAF1, showing p53 inactivity and more aggressive phenotypes than tumors without Dmp1 deletion. Notably, endogenous hDMP1 mRNA decreased when HER2 was depleted in human breast cancer cells. Our study shows the pivotal roles of Dmp1 in HER2/neu-p53 signaling and breast carcinogenesis.

Vance KW, Shaw HM, Rodriguez M, et al.
The retinoblastoma protein modulates Tbx2 functional specificity.
Mol Biol Cell. 2010; 21(15):2770-9 [PubMed] Free Access to Full Article Related Publications
Tbx2 is a member of a large family of transcription factors defined by homology to the T-box DNA-binding domain. Tbx2 plays a key role in embryonic development, and in cancer through its capacity to suppress senescence and promote invasiveness. Despite its importance, little is known of how Tbx2 is regulated or how it achieves target gene specificity. Here we show that Tbx2 specifically associates with active hypophosphorylated retinoblastoma protein (Rb1), a known regulator of many transcription factors involved in cell cycle progression and cellular differentiation, but not with the Rb1-related proteins p107 or p130. The interaction with Rb1 maps to a domain immediately carboxy-terminal to the T-box and enhances Tbx2 DNA binding and transcriptional repression. Microarray analysis of melanoma cells expressing inducible dominant-negative Tbx2, comprising the T-box and either an intact or mutated Rb1 interaction domain, shows that Tbx2 regulates the expression of many genes involved in cell cycle control and that a mutation which disrupts the Rb1-Tbx2 interaction also affects Tbx2 target gene selectivity. Taken together, the data show that Rb1 is an important determinant of Tbx2 functional specificity.

Liu WK, Jiang XY, Zhang ZX
Expression of PSCA, PIWIL1, and TBX2 in endometrial adenocarcinoma.
Onkologie. 2010; 33(5):241-5 [PubMed] Related Publications
BACKGROUND: Endometrial cancer is the 4th most common gynecological cancer. The expression of prostate stem cell antigen (PSCA), piwi-like 1 (PIWIL1), and T-box 2 (TBX2) in endometrial cancer remains to be elucidated.
MATERIAL AND METHODS: The expression of PSCA, PIWIL1, and TBX2 was examined using the streptavidin-peroxidase method in 64 endometrial endometrioid adenocarcinoma (EAC) and paired normal endometrium (NE) samples from the Shaanxi Province in China.
RESULTS: Positive expression rates of PSCA, PIWIL1, and TBX2 were 75% (48/64), 25% (16/64), and 56% (36/64), respectively in EACs, but 5% (3/64), 6% (4/64), and 2% (1/64), respectively in NEs. The difference was statistically significant (p < 0.05). PSCA was positively correlated with TBX2 (p = 0.003) but not PIWIL1 (p = 0.188). PIWIL1 was positively correlated with TBX2 (p = 0.003). PSCA was positively correlated with age, tumor grade, and lymph node metastasis (p < 0.05). TBX2 had an association with lymph node metastasis (p = 0.014). PIWIL1 was not associated with clinicopathological features (p > 0.05).
CONCLUSIONS: We report the first analysis of PSCA, PIWIL1, and TBX2 expression in EAC. Our findings suggest that PSCA and TBX2 might be candidate targets for cancer therapy, and have helped us further understand the carcinogenesis of endometrial cancer.

Redmond KL, Crawford NT, Farmer H, et al.
T-box 2 represses NDRG1 through an EGR1-dependent mechanism to drive the proliferation of breast cancer cells.
Oncogene. 2010; 29(22):3252-62 [PubMed] Related Publications
T-box 2 (TBX2) is a transcription factor involved in mammary development and is known to be overexpressed in a subset of aggressive breast cancers. TBX2 has previously been shown to repress growth control genes such as p14(ARF) and p21(WAF1/cip1). In this study we show that TBX2 drives proliferation in breast cancer cells and this is abrogated after TBX2 small interfering RNA (siRNA) knockdown or after the expression of a dominant-negative TBX2 protein. Using microarray analysis we identified a large cohort of novel TBX2-repressed target genes including the breast tumour suppressor NDRG1 (N-myc downregulated gene 1). We show that TBX2 targets NDRG1 through a previously undescribed mechanism involving the recruitment of early growth response 1 (EGR1). We show EGR1 is required for the ability of TBX2 to repress NDRG1 and drive cell proliferation. We show that TBX2 interacts with EGR1 and that TBX2 requires EGR1 to target the NDRG1 proximal promoter. Abrogation of either TBX2 or EGR1 expression is accompanied by the upregulation of cell senescence and apoptotic markers. NDRG1 can recapitulate these effects when transfected into TBX2-expressing cells. Together, these data identify a novel mechanism for TBX2-driven oncogenesis and highlight the importance of NDRG1 as a growth control gene in breast tissue.

Liu WK, Jiang XY, Zhang ZX
Expression of PSCA, PIWIL1 and TBX2 and its correlation with HPV16 infection in formalin-fixed, paraffin-embedded cervical squamous cell carcinoma specimens.
Arch Virol. 2010; 155(5):657-63 [PubMed] Related Publications
The purpose of our study was to investigate the expression of prostate stem cell antigen (PSCA), piwi-like 1 (PIWIL1) and T-box 2 (TBX2) and its correlation with HPV16 infection in cervical squamous cell carcinoma (CSCC). HPV16 was detected by amplifying the HPV16 E7 gene by the polymerase chain reaction (PCR) method, and the expression of PSCA, PIWIL1, TBX2 and HPV16 E7 in 59 CSCCs and matched adjacent normal cervix (MANC) was examined by the streptavidin-peroxidase (SP) method. Fifty-two CSCCs and MANC specimens that were positive for the E7 gene and the E7 protein were identified as infected with HPV16 and included in present study. The rate of infection with HPV16 in CSCC was 52% (27/52), but that in matched adjacent normal cervix (MANC) samples was 4% (2/52). Infection with HPV16 was found to be statistically more frequent in CSCC (P = 0.000). The expression rates of PSCA, PIWIL1 and TBX2 in MANC were 6% (3/52), 8% (4/52) and 2% (1/52), respectively, but those in CSCC were 62% (32/52), 75% (39/52) and 52% (27/52), respectively. Higher expression rates of PSCA, PIWIL1 and TBX2 were observed in CSCC than in MANC (P = 0.000). HPV16 had a statistical positive correlation with PSCA, PIWIL1 and TBX2 in CSCC (P < 0.05). The increased expression of PSCA, PIWIL1 and TBX2 had no correlation with the patient's age or histological grade P > 0.05). The elevated expression of PSCA and PIWIL1 was associated with invasion of CSCC (P < 0.05). Up-regulated expression of TBX2 had a positive association with lymph node metastasis (P = 0.014). These findings demonstrate for the first time the expression of PSCA, PIWIL1 and TBX2 in CSCC. Their correlation with HPV16 might provide new basic information for investigating the molecular mechanism of HPV and help us to deepen our understanding of the interaction between HPV16 and host cells the carcinogenesis of CSCC.

Abrahams A, Parker MI, Prince S
The T-box transcription factor Tbx2: its role in development and possible implication in cancer.
IUBMB Life. 2010; 62(2):92-102 [PubMed] Related Publications
Tbx2 is a member of the T-box family of transcription factors that are crucial in embryonic development. Recent studies suggest that T-box factors may also play a role in controlling cell cycle progression and in the genesis of cancer. Tbx2 has been implicated in several developmental processes such as coordinating cell fate, patterning and morphogenesis of a wide range of tissues and organs including limbs, kidneys, lungs, mammary glands, heart, and craniofacial structures. Importantly, Tbx2 is overexpressed in several cancers including melanoma, small cell lung carcinoma, breast, pancreatic, liver, and bladder cancers and can suppress senescence, a cellular process, which serves as a barrier to cancer development. This review presents a state of the art overview of the role and regulation of Tbx2 in early embryonic development and in cancer.

Dimova I, Orsetti B, Negre V, et al.
Genomic markers for ovarian cancer at chromosomes 1, 8 and 17 revealed by array CGH analysis.
Tumori. 2009 May-Jun; 95(3):357-66 [PubMed] Related Publications
AIMS AND BACKGROUND: The literature data show that the most frequently affected chromosomes in ovarian carcinogenesis are 1, 8 and 17. In the present study we aimed to define more precisely at a high resolution the genomic imbalances of these chromosomes in ovarian cancer and to determine genomic markers separating tumors of different histological types and stages.
METHODS: Array comparative genomic hybridization (CGH) with a resolution of approximately 0.8 Mb was applied in 28 primary ovarian tumors. We identified regions of highly frequent gains or losses (affecting more than 40% of ovarian cancers) and determined sites showing alterations of elevated amplitude (amplifications or homozygous deletions). Doing this we also identified at least two adjacent changed clones.
RESULTS: We determined anomalies strongly associated with the disease such as deletions at 8p21-23, 17p12-13, 1p35-36 or amplifications at 1q23, 17q12, 17q23.2, 8q13.2, 8q24. We defined more precisely the gains in 17q12-q24, finding as strong candidates for ovarian tumorigenesis the genes LASP1 (17q12), TGF11 (17q21.32), MUL (17q23.2), TBX2 (17q23.2), AXIN2 (17q24.3) and GRB2 (17q25.1). Of particular note was gain of 8q13.2, which occurred at a high frequency in ovarian cancer, especially in serous and late-stage tumors. We found that gains of 1q32-1q43, 8p11-p12, 8q11.23, 8q13.2, and 8q24.21-8q24.22 and losses of 1p36.21, 8p23.1-8p21.1 and 8q21.2 were associated with serous histology, whereas losses of 1q23 and 1q32-43 and gains of 17q11.2-12 and 17q25 were associated with mucinous histology. Gains of 1q23, 8q24, 17q23.2, 17q24.2 and losses of 1p35-36, 8p, 17p, and 17q were specific for late-stage ovarian cancers.
CONCLUSIONS: Our study has identified potential genomic markers of interest on chromosomes 1, 8 and 17 in ovarian cancer. Tumors showed a wide variety in the patterns of alteration, suggesting that alternative mechanisms of genomic instability may play a role in this tumor type.

Duo S, Tiao-Dong T, Lei Z, et al.
Expression and clinical significance of tbx2 in pancreatic cancer.
Asian Pac J Cancer Prev. 2009 Jan-Mar; 10(1):118-22 [PubMed] Related Publications
TBX2 is one of the family of genes encoding developmental transcription factors, characterized by a 200 amino acid DNA binding domain (T-box), found to be related to malignant phenotypes of mammary cancer. However, the role of TBX2 in pancreatic cancer progression remains unclear. Therefore, the present study was conducted to investigate the expression and clinical significance of TBX2 in pancreatic cancer. Immunohistochemistry was carried out on paraffin-embedded sections of pancreatic cancer and normal pancreatic tissues. In addition, semiquantitative RT-PCR and Western blots were carried out to analyze mRNA and protein expression of Tbx2 in 6 pairs of freshly resected pancreatic cancer and their adjacent nontumorous tissue. TBX2 expression was significantly increased in pancreatic cancer tissue (29/48 or 60.4%). The expression level of Tbx2 had a significant positive relationship with tumor differentiation degree, higher TNM stage and distant metastasis. Also, mRNA and protein expression of Tbx2 were found to be at higher levels in almost all cancer tissues compared to adjacent tissues. In conclusion, Tbx2 protein might play an important role in the process of the development and metastasis of pancreatic cancers and high-level Tbx2 expression might be related to malignant potential.

Kelemen LE, Wang X, Fredericksen ZS, et al.
Genetic variation in the chromosome 17q23 amplicon and breast cancer risk.
Cancer Epidemiol Biomarkers Prev. 2009; 18(6):1864-8 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Gene amplification leading to overexpression is a common event in breast tumors that is linked to tumor development and progression. The 17q23 region is amplified in >40% of breast tumors and contains several candidate oncogenes. Because common genetic variation in several oncogenes has been associated with cancer risk, we assessed the relevance of common variants in the 17q23 candidate oncogenes to breast cancer.
METHODS: We investigated 60 polymorphisms in the TUBD1, SEPT4, PRKCA, TBX2, TBX4, TEX14, TLK2, YPEL2, and PPM1E genes from this amplicon for association with breast cancer risk among 798 Caucasian breast cancer cases and 843 unaffected Caucasian controls from the Mayo Clinic.
RESULTS: Eight polymorphisms in PRKCA, TBX4, TLK2, and YPEL2 displayed significant dose-response associations with breast cancer risk (P(trend) < 0.05). Of these, PRKCA rs7342847 and TLK2 rs2245092 and rs733025 were also associated with hormone receptor-positive breast cancer: PRKCA rs7342847 (odds ratio, 0.7; 95% confidence interval, 0.6-0.9; P(trend) = 0.002) and TLK2 rs733025 and rs2245092 (both: odds ratio, 0.8; 95% confidence interval, 0.7-1.0; P(trend) = 0.03). Interactions between SEPT4 rs758377 and TEX14 rs302864 (P(interaction) = 0.0003) and between TLK2 rs733025 and YPEL2 rs16943468 (P(interaction) = 0.05) for risk of breast cancer were also observed.
CONCLUSION: These findings suggest that single polymorphisms and combinations of polymorphisms within candidate oncogenes from the 17q23 amplicon may influence risk of breast cancer overall and possibly specific molecular subtypes of breast tumors. The findings are discussed within the context of the results from two independent data sets.

Rodriguez M, Aladowicz E, Lanfrancone L, Goding CR
Tbx3 represses E-cadherin expression and enhances melanoma invasiveness.
Cancer Res. 2008; 68(19):7872-81 [PubMed] Related Publications
The T-box transcription factors Tbx2 and Tbx3 are overexpressed in many cancers and in melanoma promote proliferation by actively suppressing senescence. Whether they also contribute to tumor progression via other mechanisms is not known. Here, we identify a novel role for these factors, providing evidence that Tbx3, and potentially Tbx2, directly repress the expression of E-cadherin, a keratinocyte-melanoma adhesion molecule whose loss is required for the acquisition of an invasive phenotype. Overexpression of Tbx2 and Tbx3 in melanoma cells down-regulates endogenous E-cadherin expression, whereas depletion of Tbx3, but not Tbx2, increases E-cadherin mRNA and protein levels and decreases melanoma invasiveness in vitro. Consistent with these observations, in melanoma tissue, Tbx3 and E-cadherin expression are inversely correlated. Depletion of Tbx3 also leads to substantial up-regulation of Tbx2. The results suggest that Tbx2 and Tbx3 may play a dual role during the radial to vertical growth phase transition by both inhibiting senescence via repression of p21(CIP1) expression, and enhancing melanoma invasiveness by decreasing E-cadherin levels.

Taghavi P, Verhoeven E, Jacobs JJ, et al.
In vitro genetic screen identifies a cooperative role for LPA signaling and c-Myc in cell transformation.
Oncogene. 2008; 27(54):6806-16 [PubMed] Related Publications
c-Myc drives uncontrolled cell proliferation in various human cancers. However, in mouse embryo fibroblasts (MEFs), c-Myc also induces apoptosis by activating the p19Arf tumor suppressor pathway. Tbx2, a transcriptional repressor of p19Arf, can collaborate with c-Myc by suppressing apoptosis. MEFs overexpressing c-Myc and Tbx2 are immortal but not transformed. We have performed an unbiased genetic screen, which identified 12 oncogenes that collaborate with c-Myc and Tbx2 to transform MEFs in vitro. One of them encodes the LPA2 receptor for the lipid growth factor lysophosphatidic acid (LPA). We find that LPA1 and LPA4, but not LPA3, can reproduce the transforming effect of LPA2. Using pharmacological inhibitors, we show that the in vitro cell transformation induced by LPA receptors is dependent on the Gi-linked ERK and PI3K signaling pathways. The transforming ability of LPA1, LPA2 and LPA4 was confirmed by tumor formation assays in vivo and correlated with prolonged ERK1/2 activation in response to LPA. Our results reveal a direct role for LPA receptor signaling in cell transformation and tumorigenesis in conjunction with c-Myc and reduced p19Arf expression.

Bennett DC
How to make a melanoma: what do we know of the primary clonal events?
Pigment Cell Melanoma Res. 2008; 21(1):27-38 [PubMed] Related Publications
Rapid advances have been made in our knowledge of the commonest genetic and epigenetic alterations found in human sporadic melanomas. Valuable recent contributions came from analyses of gene copy number by comparative genome hybridization, and from large-scale gene expression profiling. All of the commonest affected genes encode regulatory components. Loci with established importance in melanoma, like CDKN2A, BRAF and PTEN, have been joined by some less familiar genes including transcription factor sequences TBX2 and STK11 (LKB). This knowledge is reviewed in relation to the cellular signaling pathways affected by these molecules, their biological outcomes, and the implications as to what changes are required overall to generate a melanoma. The data support a model in which genesis of melanoma requires changes that (1) initiate clonal expansion, (2) overcome cell senescence, and (3) reduce apoptosis.

Abrahams A, Mowla S, Parker MI, et al.
UV-mediated regulation of the anti-senescence factor Tbx2.
J Biol Chem. 2008; 283(4):2223-30 [PubMed] Related Publications
Several lines of evidence have implicated members of the developmentally important T-box gene family in cell cycle regulation and in cancer. Importantly, the highly related T-box factors Tbx2 and Tbx3 can suppress senescence through repressing the cyclin-dependent kinase inhibitors p19(ARF) and p21(WAF1/CIP1/SDII). Furthermore, Tbx2 is up-regulated in several cancers, including melanomas where it was shown to function as an anti-senescence factor, suggesting that this may be one of the mechanisms by which T-box proteins contribute to the oncogenic process. However, very little is known about whether Tbx2 is regulated by p21-mediated stress-induced senescence signaling pathways. In this study, using the MCF-7 breast cancer cell line known to overexpress Tbx2, we show that in response to stress induced by ultraviolet irradiation the Tbx2 protein is specifically phosphorylated by the p38 mitogen-activated protein kinase. Using site-directed mutagenesis and in vitro kinase assays, we have identified serine residues 336, 623, and 675 in the Tbx2 protein as the p38 target sites and show that these sites are phosphorylated in vivo. Importantly, we show by Western blotting, immunofluorescence, and reporter assays that this phosphorylation leads to increased Tbx2 protein levels, predominant nuclear localization of the protein, and an increase in the ability of Tbx2 to repress the p21(WAF1/CIP1/SDII) promoter. These results show for the first time that the ability of Tbx2 to repress the p21 gene is enhanced in response to a stress-induced senescence pathway, which leads to a better understanding of the regulation of the anti-senescence function of Tbx2.

Davis E, Teng H, Bilican B, et al.
Ectopic Tbx2 expression results in polyploidy and cisplatin resistance.
Oncogene. 2008; 27(7):976-84 [PubMed] Related Publications
T-box factors play critical roles in embryonic development and have been implicated in cell cycle regulation and cancer. For example, Tbx2 can suppress senescence through a mechanism involving the repression of the cyclin-dependent kinase inhibitors, p19(ARF) and p21(WAF1/CIP1/SDII), and the Tbx2 gene is deregulated in melanoma, breast and pancreatic cancers. In this study, several transformed human lung fibroblast cell lines were shown to downregulate Tbx2. To further investigate the role of Tbx2 in oncogenesis we therefore stably reexpressed Tbx2 in one such cell line. Compared to their parental cells, the resulting Tbx2-expressing cells are larger, with binucleate and lobular nuclei containing double the number of chromosomes. Moreover, these cells had an increase in frequency of several features of genomic instability such as chromosome missegregation, chromosomal rearrangements and polyploidy. While grossly abnormal, these cells still divide and give rise to cells that are resistant to the chemotherapeutic drug cisplatin. Furthermore, this is shown to be neither species nor cell type dependent, as ectopically expressing Tbx2 in a murine melanoma cell line also induce mitotic defects and polyploidy. These results have important implications for our understanding of the role of Tbx2 in tumorigenesis because polyploidy frequently precedes aneuploidy, which is associated with high malignancy and poor prognosis.

Teng H, Davis E, Abrahams A, et al.
A role for Tbx2 in the regulation of the alpha2(1) collagen gene in human fibroblasts.
J Cell Biochem. 2007; 102(3):618-25 [PubMed] Related Publications
The T-box gene family encodes highly conserved transcription factors that play important roles in embryonic development and have been implicated in carcinogenesis. One member of the family, Tbx2, is generally regarded as a transcriptional repressor but appears to be capable of functioning as an activator depending on the cellular context. This study shows that Tbx2 is expressed in normal human fibroblasts but is drastically reduced in several transformed fibroblast cell lines. This pattern of Tbx2 expression correlated with that observed for the human alpha2(1) collagen gene (COL1A2). Interestingly, stable expression of transfected Tbx2 in transformed fibroblast cell lines further reduces expression of the human endogenous COL1A2 gene. This ability of Tbx2 to repress the human COL1A2 gene was confirmed in luciferase reporter assays and shown to be independent of the consensus T-box binding element.

Bandyopadhyay S, Zhan R, Chaudhuri A, et al.
Interaction of KAI1 on tumor cells with DARC on vascular endothelium leads to metastasis suppression.
Nat Med. 2006; 12(8):933-8 [PubMed] Related Publications
CD82, also known as KAI1, was recently identified as a prostate cancer metastasis suppressor gene on human chromosome 11p1.2 (ref. 1). The product of CD82 is KAI1, a 40- to 75-kDa tetraspanin cell-surface protein also known as the leukocyte cell-surface marker CD82 (refs. 1,2). Downregulation of KAI1 has been found to be clinically associated with metastatic progression in a variety of cancers, whereas overexpression of CD82 specifically suppresses tumor metastasis in various animal models. To define the mechanism of action of KAI1, we used a yeast two-hybrid screen and identified an endothelial cell-surface protein, DARC (also known as gp-Fy), as an interacting partner of KAI1. Our results indicate that the cancer cells expressing KAI1 attach to vascular endothelial cells through direct interaction between KAI1 and DARC, and that this interaction leads to inhibition of tumor cell proliferation and induction of senescence by modulating the expression of TBX2 and p21. Furthermore, the metastasis-suppression activity of KAI1 was significantly compromised in DARC knockout mice, whereas KAI1 completely abrogated pulmonary metastasis in wild-type and heterozygous littermates. These results provide direct evidence that DARC is essential for the function of CD82 as a suppressor of metastasis.

Vance KW, Carreira S, Brosch G, Goding CR
Tbx2 is overexpressed and plays an important role in maintaining proliferation and suppression of senescence in melanomas.
Cancer Res. 2005; 65(6):2260-8 [PubMed] Related Publications
The INK4a and ARF genes found at the CDKN2A locus are key effectors of cellular senescence that is believed to act as a powerful anticancer mechanism. Accordingly, mutations in these genes are present in a wide variety of spontaneous human cancers and CDKN2A germ line mutations are found in familial melanoma. 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. Overexpression of Tbx2 and the related factor Tbx3, which is also overexpressed in breast cancer and melanomas, can suppress senescence in defined experimental systems through repression of ARF expression. However, it is not known how Tbx2 mediates its repressive effect nor whether endogenous Tbx2 or Tbx3 perform a similar antisenescence function in transformed cells. This is a particularly important question because the loss of CDKN2A in many human cancers would, in principle, bypass the requirement for Tbx2/3-mediated repression of ARF in suppressing senescence. We show here that Tbx2 is overexpressed in melanoma cell lines and that Tbx2 targets histone deacetylase 1 to the p21Cip1 (CDKN1A) initiator. Strikingly, expression of an inducible dominant-negative Tbx2 (dnTbx2) leads to displacement of histone deacetylase 1, up-regulation of p21(Cip1) expression, and the induction of replicative senescence in CDKN2A-null B16 melanoma cells. In human melanoma cells, expression of dnTbx2 leads to severely reduced growth and induction of senescence-associated heterochromatin foci. The results suggest that the activity of endogenous Tbx2 is critically required to maintain proliferation and suppress senescence in melanomas.

Chen JR, Chatterjee B, Meyer R, et al.
Tbx2 represses expression of Connexin43 in osteoblastic-like cells.
Calcif Tissue Int. 2004; 74(6):561-73 [PubMed] Related Publications
Tbx2 belongs to a family of developmental transcription regulatory factors. We evaluated whether the gap junction protein Connexin43 (Cx43), an important regulator of osteoblast function and bone development, may be a downstream target gene regulated by Tbx2. The Cx43 promoter contains direct repeats of the consensus T-box binding motif, TCACAC, and moreover, Tbx2 and Cx43 show overlapping expression domains in precursors to bone and in osteoblasts. In vitro analysis showed that the Cx43 promoter contains two Tbx2 binding sites, and this binding was dependent on the TCACAC consensus sequence. Transient transfection analysis with a Cx43 promoter-driven lacZ reporter construct revealed negative regulation mediated by these two Tbx2 binding sites in osteoblast-like cells. Thus, downregulation of Tbx2 led to de-repression of wild-type Cx43 promoter activity, whereas a promoter construct with mutated binding sites showed no de-repression. In stably transfected osteosarcoma cells in which expression of the endogenous Tbx2 gene was downregulated with a Tbx2 antisense construct, a marked de-repression of the endogenous Cx43 gene was observed. This was accompanied by a marked increase in the abundance of Cx43 gap junctions and increased functional gap junction-mediated cell-cell communication. Analysis of lacZ expression in transgenic mice containing the mutated Cx43 promoter-driven lacZ construct further suggested de-repression of the Cx43 promoter in limb buds, a region destined to give rise to long bones of the limbs. Taken together, these findings indicate that the promoter of Cx43 is repressible by Tbx2, both in cultured osteoblast-like cells in vitro and likely in the developing embryo.

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