Affinage

TBX2

T-box transcription factor TBX2 · UniProt Q13207

Length
712 aa
Mass
75.1 kDa
Annotated
2026-06-10
100 papers in source corpus 43 papers cited in narrative 42 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TBX2 is a T-box transcription factor that functions principally as a sequence-specific transcriptional repressor controlling cell-fate decisions, proliferation, and senescence across cardiac, limb, lung, inner ear, and epithelial lineages (PMID:15042700, PMID:15459098, PMID:19423846, PMID:35508658). It binds variant T-box elements distinct from those engaged by activating T-box proteins—binding as a monomer to repress targets where Xbra activates—and requires both its core DNA-binding domain and dedicated N- and C-terminal repression domains for silencing (PMID:12000749, PMID:11111039, PMID:11867218). Repression is executed by recruiting chromatin-modifying machinery: TBX2 brings HDAC1 to the initiator regions of cell-cycle inhibitors p21/CDKN1A and to muscle-specific promoters (PMID:15781639, PMID:24470334), and through a conserved N-terminal HP1-binding motif it assembles an HP1/KAP1 complex that deposits H3K9me3 and recruits DNMT3B, G9A, EZH2, and SUZ12 to establish heritable heterochromatin (PMID:31253870). A central output is suppression of cell-cycle arrest and senescence programs: TBX2 represses the CDKN2A-encoded p19ARF/p14ARF and p21/p27 loci to bypass oncogene-induced senescence and drive proliferation, and its repressive activity is enhanced by interaction with hypophosphorylated Rb1 and by p38 MAPK phosphorylation of S336/S623/S675 following UV stress (PMID:11062467, PMID:12000749, PMID:14996726, PMID:23341776, PMID:20534814, PMID:18025091). In the heart, TBX2 cooperates with NKX2.5 to repress chamber-specific genes (Nppa, Cx40, Cx43) in the atrioventricular canal, suppressing fast-conduction gene expression and chamber differentiation (PMID:12023302, PMID:15042700, PMID:15459098, PMID:21266775). Developmentally, TBX2 acts as a node that tunes secreted signaling: it represses Grem1, Frzb/Shisa3, Dkk2, and Flrt3 to modulate BMP, WNT, SHH, and FGF outputs in limb, lung, ureter, and neural tissue (PMID:23633963, PMID:27720610, PMID:30478225, PMID:27913219), and is itself induced by BMP2/Smad signaling and restrained by retinoic acid and TGF-β1/TBX3 (PMID:11087629, PMID:19661464, PMID:22186728, PMID:25371204). TBX2 specifies inner hair cell identity in the cochlea, where it is necessary and sufficient for the IHC fate and epistatic to Insm1 (PMID:35508658, PMID:36494345). In cancers, TBX2 represses E-cadherin to drive EMT and metastasis, represses PTEN to activate PI3K/AKT, and acts as a dosage-sensitive core regulatory circuitry factor (PMID:22844464, PMID:26686089, PMID:30451831).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 2000 High

    Established TBX2 as an anti-senescence oncogene by showing it represses the ARF tumor suppressor to bypass oncogene-induced senescence, defining its first functional role in proliferation control.

    Evidence Senescence bypass genetic screen and promoter reporter assays in primary fibroblasts

    PMID:11062467

    Open questions at the time
    • Did not define the co-repressor machinery recruited
    • Endogenous target occupancy not yet shown
  2. 1998 High

    First demonstrated that TBX2 is a sequence-specific transcriptional repressor, binding melanocyte promoter elements with target selectivity (TRP-1 but not tyrosinase/MITF).

    Evidence EMSA, cotransfection reporter assays, and binding-site mutagenesis

    PMID:9710594

    Open questions at the time
    • No co-repressor identified
    • Mechanism of promoter selectivity unresolved
  3. 2002 High

    Defined the molecular basis of TBX2 repression: it binds a variant T-box element and requires both the core T-box domain and discrete N- and C-terminal repression domains, distinguishing it from activating T-box proteins.

    Evidence In vitro binding, GAL4-fusion and deletion reporter assays in human and mouse promoters

    PMID:11111039 PMID:11867218 PMID:12000749

    Open questions at the time
    • Repression domains' interacting partners not identified
    • Monomeric binding mode structurally uncharacterized
  4. 2002 High

    Showed TBX2 functions combinatorially in vivo, forming a complex with NKX2.5 on the ANF promoter to restrict chamber gene expression in the atrioventricular canal.

    Evidence Transgenic T-box element mutation, co-IP, and reporter assays

    PMID:12023302

    Open questions at the time
    • Structural basis of TBX2-NKX2.5 cooperativity unknown
    • Genome-wide co-occupancy not mapped
  5. 2004 High

    Connected TBX2 repression to cell-cycle control and chamber morphogenesis by identifying p21/WAF1, Cx43, and chamber genes as direct targets repressed in proliferating and developing tissues.

    Evidence ChIP, in vitro binding, siRNA knockdown, transgenic mice, and null-mutant analysis

    PMID:14996726 PMID:15042700 PMID:15354864 PMID:15459098

    Open questions at the time
    • Co-repressor recruitment to these loci not yet shown
    • Relationship between developmental and oncogenic targets unclear
  6. 2005 High

    Identified the chromatin-modifying mechanism of repression, showing TBX2 recruits HDAC1 to the p21 initiator and that disrupting this recruitment induces senescence.

    Evidence Inducible dominant-negative TBX2, ChIP for HDAC1, and senescence assays in melanoma

    PMID:15781639

    Open questions at the time
    • Whether HDAC1 recruitment is direct or bridged not resolved
    • Other co-repressors at p21 not defined
  7. 2006 Medium

    Linked TBX2 to cell-cycle dynamics and a possible regulatory role in DNA replication by showing cell-cycle-coupled protein oscillation and S-phase localization to replication foci.

    Evidence Cell synchronization, Western blotting, immunofluorescence co-localization

    PMID:16730707

    Open questions at the time
    • Functional significance of replication-focus localization unknown
    • Mechanism controlling cell-cycle oscillation undefined
  8. 2007 High

    Established post-translational control of TBX2, showing p38 MAPK phosphorylates it on UV stress to boost protein levels, nuclear localization, and repressive activity.

    Evidence In vitro kinase assay, site-directed mutagenesis, immunofluorescence, and reporter assays

    PMID:18025091

    Open questions at the time
    • Phosphatase counter-regulation not addressed
    • Effect on genome-wide occupancy not tested
  9. 2010 Medium

    Showed TBX2 activity is tuned by protein interactions, with hypophosphorylated Rb1 binding adjacent to the T-box to enhance DNA binding and alter target selectivity.

    Evidence Reciprocal co-IP, domain mapping, and microarray in melanoma

    PMID:20534814

    Open questions at the time
    • Single-lab study
    • Direct structural interface not determined
  10. 2009 High

    Defined upstream control of cardiac TBX2 expression, showing a BMP/Smad-dependent enhancer drives AVC-restricted expression and that Tbx20 antagonizes it by sequestering Smad1/5.

    Evidence Single and double KO mice, Smad co-IP, and enhancer analysis

    PMID:11087629 PMID:19661464

    Open questions at the time
    • Smad partner specificity at the enhancer not fully resolved
  11. 2011 High

    Established TBX2 as the physiological repressor of fast-conduction gene expression and AVC fate, with loss causing accessory pathways and preexcitation, and demonstrated functional redundancy with TBX3 in a BMP2 feed-forward loop.

    Evidence Conditional myocardial KO with electrophysiology, lineage tracing, and TBX3 ChIP-seq

    PMID:19423846 PMID:21266775 PMID:22130515

    Open questions at the time
    • Quantitative division of labor between TBX2 and TBX3 unresolved
    • Pacemaker gene activation mechanism distinct from repression unclear
  12. 2011 High

    Defined a reciprocal TBX2–PML antagonism in senescence, in which PML/p130/E2F4 silences TBX2 while elevated TBX2 antagonizes PML pro-senescence function via direct interaction.

    Evidence ChIP, co-IP, knockdown, and senescence assays

    PMID:22002537

    Open questions at the time
    • Functional consequence of TBX2-PML binding on target loci undefined
  13. 2013 High

    Demonstrated that TBX2 controls organ growth and signaling through direct repression of cell-cycle inhibitors and secreted pathway antagonists, genetically separable target sets validated by rescue.

    Evidence Conditional KO, in vivo ChIP, and genetic epistasis in mouse lung and limb

    PMID:23341776 PMID:23633963

    Open questions at the time
    • Locus-specific co-repressor recruitment not mapped genome-wide
  14. 2018 High

    Generalized TBX2/TBX3 as Wnt-pathway effectors that fine-tune secreted antagonists across developmental contexts.

    Evidence Conditional double-KO, transcriptional profiling, and ChIP in mouse ureter and lung

    PMID:27720610 PMID:30478225

    Open questions at the time
    • Direct versus indirect contribution to each antagonist's regulation not fully separated
  15. 2019 High

    Resolved the full repressive complex, showing TBX2's N-terminal HP1-binding motif recruits KAP1, DNMT3B, G9A, EZH2, and SUZ12 to deposit H3K9me3 and silence target genes in cancer.

    Evidence HP1-motif mutagenesis, ChIP for H3K9me3 and complex components, co-IP, and knockdown

    PMID:31253870

    Open questions at the time
    • Whether this complex operates at developmental loci not tested
    • Order of complex assembly undefined
  16. 2022 High

    Established TBX2 as a master determinant of cochlear inner hair cell identity, necessary and sufficient for the IHC fate and epistatic to Insm1.

    Evidence Conditional KO, gain-of-function, and double-KO fate-mapping in mouse cochlea

    PMID:35508658 PMID:36494345

    Open questions at the time
    • Direct IHC-fate target genes not enumerated
    • Whether HP1/HDAC1 machinery mediates this fate decision unknown
  17. 2018 Medium

    Positioned TBX2 as an oncogenic driver in additional cancers, acting through E-cadherin/PTEN repression and as a dosage-sensitive core regulatory circuitry factor.

    Evidence ChIP, gain/loss-of-function, xenograft and super-enhancer mapping in breast cancer, RMS, and neuroblastoma

    PMID:22844464 PMID:26686089 PMID:30451831 PMID:33451831

    Open questions at the time
    • Whether oncogenic activity uses the same HP1/KAP1 complex unresolved
    • Cell-type specificity of target repertoire undefined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How TBX2 selects context-specific target gene sets and switches between repression and the apparent activation of some targets (e.g., WNT3A, pacemaker genes) remains unresolved.
  • No genome-wide structural model of variant T-box recognition
  • Mechanism of context-dependent activation versus repression unknown
  • Integration of phosphorylation, Rb1, and HP1/KAP1 inputs on target choice undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 10 GO:0003677 DNA binding 5 GO:0140096 catalytic activity, acting on a protein 1
Localization
GO:0005634 nucleus 2 GO:0000228 nuclear chromosome 1
Pathway
R-HSA-1266738 Developmental Biology 6 R-HSA-74160 Gene expression (Transcription) 6 R-HSA-1640170 Cell Cycle 4 R-HSA-4839726 Chromatin organization 3 R-HSA-8953897 Cellular responses to stimuli 2
Partners
HDAC1HP1KAP1MSX1MYOD1NKX2.5PMLRB1

Evidence

Reading pass · 42 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 TBX2 represses the Cdkn2a (p19ARF) promoter and attenuates E2F1-, Myc-, or HRAS-mediated induction of p19ARF, thereby bypassing senescence in primary fibroblasts. Senescence bypass genetic screen, promoter reporter assays, overexpression in primary Bmi1-deficient fibroblasts Nature genetics High 11062467
2002 TBX2 forms a complex with NKX2.5 on the TBE-NKE element of the ANF promoter and cooperatively represses ANF promoter activity in the atrioventricular canal (AVC), thereby restricting chamber-specific gene expression. Transgenic analysis with in vivo T-box element mutation, co-immunoprecipitation/protein complex analysis, promoter reporter assays Genes & development High 12023302
2004 Tbx2 is required to repress chamber differentiation genes (Nppa, Cx40, Cx43, Chisel) in the AVC; transgenic overexpression of Tbx2 in prechamber myocardium abolishes chamber formation and chamber-specific gene expression. Targeted null mutation in mice, transgenic overexpression, in vitro promoter reporter assays Developmental dynamics High 15042700 15459098
2002 TBX2 and TBX3 bind a variant T-site (13/20 nt match to consensus) in the human p14ARF promoter initiator region; both the core T-box DNA-binding domain and a C-terminal repression domain are essential for p14ARF repression. TBX1A and Xbra cannot activate via this variant site, indicating sequence specificity beyond the core T-box. Mutant promoter analysis, in vitro binding assays, co-transfection reporter assays, deletion/mutagenesis of T-box and C-terminal repression domain The Journal of biological chemistry High 12000749
2005 Tbx2 recruits histone deacetylase 1 (HDAC1) to the p21Cip1 (CDKN1A) initiator to repress p21 expression; dominant-negative Tbx2 displaces HDAC1, upregulates p21, and induces senescence in CDKN2A-null melanoma cells. Inducible dominant-negative Tbx2 expression, ChIP for HDAC1 at p21 promoter, Western blotting, senescence assays Cancer research High 15781639
2004 Tbx2 directly binds and represses the p21(WAF1) promoter in vitro and in vivo; siRNA-mediated knockdown of Tbx2 robustly activates p21 expression. In vitro DNA-binding assays, transfection reporter assays, chromatin immunoprecipitation (ChIP), siRNA knockdown Cancer research High 14996726
1998 Tbx2 binds the MSEu and MSEi elements of the TRP-1 promoter as a transcriptional repressor; mutations in either element that cause promoter derepression also diminish Tbx2 binding; TBX2 specifically represses TRP-1 but not tyrosinase, MITF, or GAPDH promoters in cotransfection assays. Electrophoretic mobility shift assay (EMSA), cotransfection reporter assays, mutagenesis of binding sites Molecular and cellular biology High 9710594
2000 TBX2 binds the palindromic T oligonucleotide as a monomer (unlike Xbra which binds as a dimer) and represses transcription of a chimeric reporter, whereas Xbra activates the same reporter; TBX2/DNA complexes are not stabilized by specific antibodies. In vitro DNA binding assays, cotransfection reporter assays, comparison with Xbra and TBX1 Gene Medium 11111039
2002 Murine Tbx2 contains two repression domains: one C-terminal domain conserved with Tbx3/ET, and a novel N-terminal domain upstream of the T-box; both domains independently repress transcription when fused to the GAL4 DNA-binding domain. The T-box itself can weakly activate transcription from its N-terminal end in a promoter-context-dependent manner. Deletion analysis, GAL4 fusion reporter assays, cotransfection Gene Medium 11867218
2000 The Tbx2 promoter contains a full consensus MITF recognition element (E-box); MITF binds the Tbx2 promoter in vitro and activates Tbx2 expression in an E-box-dependent manner in vivo, placing Tbx2 downstream of MITF in the melanocyte lineage. Promoter sequence analysis, in vitro binding (EMSA), in vivo cotransfection reporter assays, E-box mutagenesis The Journal of biological chemistry Medium 10770922
2000 BMP2 is necessary and sufficient to induce Tbx2 (and Tbx3) expression: BMP2 application induces Tbx2 in non-cardiogenic tissue, Noggin (BMP antagonist) down-regulates Tbx2, and Tbx2 expression is abolished in bmp2-null mouse embryos. BMP2 bead application in chick embryos, Noggin bead application, analysis of bmp2-null mouse embryos Developmental biology High 11087629
2006 Tbx2 protein expression is cell-cycle regulated: levels are low in G1, increase in mid-S phase, persist through G2, and dramatically decrease at the onset of mitosis. In S phase, Tbx2 localizes to a subset of late replication foci and to small DNA-associated nuclear foci distinct from telomeres, PML bodies, and Cajal bodies. Cell synchronization, Western blotting at cell-cycle stages, immunofluorescence co-localization with replication markers Experimental cell research Medium 16730707
2007 In response to UV irradiation, Tbx2 is phosphorylated by p38 MAPK at serine residues 336, 623, and 675; this phosphorylation increases Tbx2 protein levels, promotes nuclear localization, and enhances Tbx2-mediated repression of the p21 promoter. Site-directed mutagenesis, in vitro kinase assay, Western blotting, immunofluorescence, reporter assays The Journal of biological chemistry High 18025091
2009 Tbx20 suppresses Tbx2 expression in developing cardiac chambers by binding Smad1 and Smad5 and sequestering them from Smad4, thereby attenuating BMP/Smad-dependent activation of a Tbx2 enhancer; a BMP/Smad-dependent Tbx2 enhancer mediates AVC-restricted Tbx2 expression in vivo. Single and double knockout mouse embryos, transfection and co-localization studies in vitro, Tbx2 enhancer analysis, Smad co-IP Circulation research High 19661464
2011 Myocardium-specific inactivation of Tbx2 leads to ectopic expression of fast-conduction proteins (Cx40, Cx43, Scn5a) in AVC myocardium, formation of rapidly conducting accessory pathways, malformation of the annulus fibrosus, and ventricular preexcitation, establishing Tbx2 as the repressor of fast-conduction gene expression in AVC myocardium. Conditional Tbx2 knockout (myocardium-specific Cre), ECG analysis, immunohistochemistry, electrophysiology The Journal of clinical investigation High 21266775
2011 Tbx2 and Tbx3, acting in a functionally redundant manner, maintain AVC myocardial phenotype and trigger atrioventricular cushion formation through a regulatory feed-forward loop with Bmp2; ChIP-seq of Tbx3 shows direct interaction with and repression of chamber myocardial genes and activation of AVC pacemaker-like genes. Knockout and inducible overexpression mouse models, expression profiling, ChIP-sequencing of Tbx3 Cellular and molecular life sciences High 22130515
2009 Genetic lineage tracing using Tbx2Cre shows that Tbx2+ AVC cells contribute to the atrioventricular node (but not the AV bundle) and to the ventricular base. In Tbx2-deficient embryos, the left-sided AVC prematurely differentiates to chamber myocardium and proliferates at elevated rates, demonstrating that Tbx2 suppresses both differentiation and proliferation of primary myocardial cells. Genetic lineage tracing with Tbx2Cre knock-in allele, analysis of Tbx2-null embryos, cell proliferation assays Circulation research High 19423846
2013 Tbx2 directly binds the Cdkn1a (p21) and Cdkn1b (p27) loci in lung mesenchyme in vivo, repressing their expression; genetic deletion of both Cdkn1a and Cdkn1b largely rescues the lung hypoplasia of Tbx2-deficient mice. Conditional Tbx2 KO in mouse lung, ChIP in vivo, genetic epistasis (Tbx2/Cdkn1a/Cdkn1b triple mutants), gain-of-function overexpression PLoS genetics High 23341776
2013 Tbx2 directly represses Gremlin1 (Grem1) in the posterior limb mesenchyme, thereby allowing BMP signaling to terminate Fgf4/9/17 expression in the overlying epithelium; loss of Tbx2 prolongs Shh/Fgf4 signaling and causes digit duplication, while Tbx2 overexpression causes premature termination and digit loss. Tbx2-deficient hindlimbs, Tbx2 conditional overexpression, ChIP for Tbx2 at Grem1 locus, genetic interaction analysis PLoS genetics High 23633963
2010 Tbx2 specifically associates with active hypophosphorylated Rb1 (but not p107 or p130); the interaction maps to a domain immediately C-terminal to the T-box, enhances Tbx2 DNA binding and transcriptional repression, and affects Tbx2 target gene selectivity. Co-immunoprecipitation, domain mapping, microarray of melanoma cells expressing inducible dominant-negative Tbx2 with intact or mutated Rb1-interaction domain Molecular biology of the cell Medium 20534814
2011 PML represses TBX2 transcription in senescence by recruiting a p130/E2F4 repressor complex to the TBX2 promoter, establishing an inactive chromatin environment. TBX2 repression contributes actively to senescence, and elevated TBX2 antagonizes PML pro-senescence function through direct protein-protein interaction with PML. Gene expression profiling, ChIP, promoter reporter assays, TBX2 knockdown, co-immunoprecipitation of TBX2-PML The EMBO journal High 22002537
2019 TBX2 interacts with Heterochromatin Protein 1 (HP1) through a conserved HP1-binding motif in its N-terminus, which recruits KAP1 and associated proteins; this complex establishes H3K9me3 at the NDRG1 promoter, recruits DNMT3B, G9A, EZH2, and SUZ12, and represses EGR1-target genes to drive breast cancer proliferation. Mutation of the TBX2 HP1-binding domain abrogates the interaction and de-represses target genes. siRNA knockdown of TBX2/EGR1/HP1/KAP1, mutagenesis of HP1-binding motif, ChIP for H3K9me3 and complex components, co-immunoprecipitation Oncogene High 31253870
2015 TBX2 directly represses the PTEN tumor suppressor in rhabdomyosarcoma and normal skeletal muscle by binding to the PTEN promoter and recruiting HDAC1; depletion or dominant-negative inhibition of TBX2 upregulates PTEN and reduces phospho-AKT, linking TBX2 to the PI3K/AKT pathway. ChIP for TBX2 at PTEN promoter, exogenous TBX2 expression in normal muscle cells, TBX2 depletion in RMS cells, Western blotting for PTEN/phospho-AKT Oncogene High 26686089
2014 TBX2 interacts with myogenic regulatory factors MyoD and myogenin, inhibiting their activity; TBX2 recruits HDAC1 to muscle-specific gene promoters and to the p21 promoter, repressing muscle differentiation genes and promoting RMS cell proliferation. Co-immunoprecipitation of TBX2 with MyoD/myogenin, ChIP, siRNA knockdown, dominant-negative TBX2, xenograft assay International journal of cancer High 24470334
2012 TBX2 directly represses E-cadherin transcription (shown by ChIP and reporter assays) and induces EMT in mammary epithelial cells; inhibition of TBX2 reverses EMT markers and abolishes invasion and lung metastasis in xenograft models. Ectopic TBX2 expression in normal mammary cells, TBX2 knockdown in cancer lines, ChIP for TBX2 at E-cadherin promoter, reporter assays, xenograft metastasis assay PloS one High 22844464
2014 TBX2 represses CST6 (Cystatin 6) in a mechanism co-involving EGR1; this repression leads to uncontrolled Legumain (LGMN) activity maintaining breast cancer proliferation. Mutation of the CST6 Legumain-inhibitory domain abrogated its apoptotic effect, identifying the TBX2-CST6-LGMN axis as the key pathway. siRNA knockdown of TBX2, exogenous CST6 expression, CST6 domain mutagenesis, LGMN activity assays, siRNA knockdown of LGMN and GPI8 Oncotarget Medium 24742492
2017 TBX2 promotes transcription of the canonical WNT3A promoter in trans; blocking TBX2 in prostate cancer cells reduces WNT3A expression and invasion, and genetic rescue of WNT3A partially restores TBX2-induced metastatic capability, placing TBX2 upstream of WNT3A signaling. Dominant-negative TBX2 construct, WNT3A promoter reporter assay, WNT3A rescue experiment, WNT3A-neutralizing antibody, xenograft mouse models Cancer research Medium 28108510
2012 Retinoic acid (RA) directly downregulates Tbx2 expression through a functional retinoic acid response element (RARE) in the Tbx2 promoter; Tbx2 in turn activates Tgfb2 expression in OFT myocardium in culture, and the Tbx2-Tgfβ2 cascade is required for proper OFT epithelial-mesenchymal transition. RARE mutagenesis in Tbx2 promoter, organ culture with Tgfβ2 rescue, maternal RA administration in mice Development (Cambridge, England) Medium 22186728
2013 TBX2 and TBX3 directly repress the Wnt antagonists Frzb and Shisa3 in lung mesenchyme (shown by ChIP), and act downstream of Shh to maintain pro-proliferative canonical Wnt signaling; this function is genetically separable from their repression of Cdkn1a/Cdkn1b. Conditional double knockout (Tbx2/Tbx3) in mouse lung, genetic rescue experiments, ChIP for Tbx2/Tbx3 at Frzb and Shisa3 loci Developmental cell High 27720610
2006 In the developing hypothalamus, a BMP-Tbx2 pathway downregulates Shh expression; Tbx2 acts downstream of BMP signaling to repress Shh in floor plate-like cells, enabling their progression to a proliferating hypothalamic progenitor domain. In ovo Tbx2 manipulation in chick, BMP gain/loss of function, in vivo forced Shh maintenance assay Developmental cell Medium 17141161
2022 Tbx2 is both necessary and sufficient for inner hair cell (IHC) identity in the cochlea: ablation of Tbx2 in embryonic IHCs causes complete transdifferentiation into outer hair cells (OHCs), and ectopic expression of Tbx2 in OHCs converts them to IHCs. Tbx2 is epistatic to Insm1: in double-null cochleae only OHCs form, demonstrating that TBX2 is required for INSM1-deficient OHC-to-IHC transdifferentiation. Conditional Tbx2 knockout in IHCs, conditional Tbx2 overexpression in OHCs, Tbx2/Insm1 double knockout, cell fate marker analysis Nature High 35508658
2022 TBX2 specifies and maintains the inner hair cell/inner supporting cell compartment of the organ of Corti in a cell-autonomous manner; loss in prosensory progenitors prevents inner compartment specification, and hair cell-specific inactivation or misexpression causes transdifferentiation. TBX2 also represses FGF signaling to restrict neurogenesis to the anterior-ventral otocyst. Conditional Tbx2 deletion and misexpression in mouse cochlea, inner ear morphogenesis analysis, expression analysis of FGF signaling targets Nature communications High 36494345
2004 Tbx2 represses the Connexin43 (Cx43) promoter through two TCACAC T-box binding sites; in osteoblast-like cells, loss of Tbx2 de-represses the Cx43 promoter and increases Cx43 gap junctions with functional cell-cell communication. Transgenic mice with mutated Cx43 promoter binding sites show de-repression in limb bud regions. In vitro binding assays, transient transfection reporter assays, antisense Tbx2 stable knockdown in osteosarcoma cells, transgenic mouse analysis Calcified tissue international Medium 15354864
2018 TBX2 is a core regulatory circuitry (CRC) transcription factor in neuroblastoma that drives proliferation through activation of p21-DREAM-repressed FOXM1 target genes; combined MYCN/TBX2 knockdown enforces cell growth arrest, and super-enhancer-marked TBX2 on chromosome 17q is dosage-sensitive. Integrative epigenomics (H3K27ac super-enhancer mapping), combined MYCN/TBX2 knockdown, CDK7 and BET bromodomain inhibition Nature communications Medium 30451831
2014 TGF-β1 signaling represses TBX2 transcriptionally through TBX3: TGF-β1 upregulates TBX3, which in turn represses TBX2 gene expression; downregulation of TBX2 is implicated in the anti-proliferative function of the TGF-β1-TBX3 axis. TGF-β1 treatment, TBX3 knockdown/overexpression, TBX2 promoter reporter assays, cell proliferation assays The Journal of biological chemistry Medium 25371204
2006 In C. elegans, TBX-2 interacts with the SUMO-conjugating enzymes UBC-9 and GEI-17 in a yeast two-hybrid assay; ubc-9(RNAi) phenocopies tbx-2 mutants (loss of ABa-derived pharyngeal muscles) and alters subnuclear distribution of TBX-2::GFP, suggesting TBX-2 activity requires sumoylation. Yeast two-hybrid, TBX-2::GFP subcellular localization, RNAi knockdown, tbx-2 mutant analysis Developmental biology Low 16701625
2013 TBX2 and TBX3 interact with HPV16 L2 capsid protein (confirmed by co-immunoprecipitation and immunofluorescence); TBX2/3 repress transcription from the HPV long control region (LCR), and L2 enhances this repression; TBX2 directly interacts with the LCR shown by ChIP. Yeast two-hybrid, co-immunoprecipitation, immunofluorescence, promoter-reporter gene assays, ChIP Journal of virology Medium 23388722
2013 Tbx2 and Msx1 physically interact in mouse C3H10T1/2 cells; they antagonistically regulate Bmp4 expression during tooth development, with Tbx2 repressing mesenchymal Bmp4. Partial rescue of the Msx1-null bud-stage tooth arrest in Msx1/Tbx2 compound mutants confirms functional antagonism between these two factors. Co-immunoprecipitation of Tbx2 and Msx1, Tbx2 knockdown in C3H10T1/2 cells, genetic rescue in Msx1(-/-);Tbx2(+/-) compound mutants Development (Cambridge, England) Medium 23720046
2018 TBX2 and TBX3 act as effectors of canonical WNT signaling in ureteric mesenchyme; they directly repress the WNT antagonists Dkk2 and Shisa2, the BMP antagonist Bmper, and Cxcl12 (shown by ChIP), thereby maintaining BMP4 and WNT signaling for smooth muscle cell differentiation. Conditional Tbx2/Tbx3 double-KO in mouse ureter, transcriptional profiling, ChIP for TBX2/TBX3 at Dkk2, Shisa2, Bmper, Cxcl12 loci, activated β-catenin mouse line Development (Cambridge, England) High 30478225
2016 Tbx2 (in Xenopus) directly binds the T-box element in the Flrt3 promoter and represses its transcription, thereby attenuating FGF8/ERK signaling; this repression of FGF signaling is required for anterior neural specification downstream of BMP signaling. Tbx2 overexpression and morpholino knockdown in Xenopus, Flrt3 promoter reporter assay with T-box element mutation, ERK phosphorylation assay, rescue with Flrt3 or FGF inhibitor Developmental biology Medium 27913219
2018 TBX2 binds to the miR-200c-3p promoter and represses its transcription, leading to increased SOX2 and N-MYC expression; this TBX2/miR-200c-3p/SOX2/N-MYC axis promotes neuroendocrine prostate cancer transdifferentiation both intracellularly and via exosome-mediated intercellular signaling. Differential miR expression profiling with TBX2 genetic modulation, ChIP for TBX2 at miR-200c-3p promoter, miR-200c-3p rescue experiments, exosome isolation and transfer Cancers Medium 34638504
2013 In Ciona notochord, Tbx2/3 expression requires Brachyury (Ci-Bra) binding at multiple sites in a Ci-Tbx2/3 CRM; Tbx2/3 functions primarily in convergent extension of the notochord; microarray screens identified Ci-Tbx2/3 downstream targets including caspases, Noto4, and MLKL. Notochord CRM analysis with Brachyury binding site mutagenesis, dominant-negative Tbx2/3 expression, microarray Development (Cambridge, England) Medium 23674602

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 Senescence bypass screen identifies TBX2, which represses Cdkn2a (p19(ARF)) and is amplified in a subset of human breast cancers. Nature genetics 318 11062467
2002 Cooperative action of Tbx2 and Nkx2.5 inhibits ANF expression in the atrioventricular canal: implications for cardiac chamber formation. Genes & development 292 12023302
2004 Tbx2 is essential for patterning the atrioventricular canal and for morphogenesis of the outflow tract during heart development. Development (Cambridge, England) 231 15459098
2004 T-box transcription factor Tbx2 represses differentiation and formation of the cardiac chambers. Developmental dynamics : an official publication of the American Association of Anatomists 205 15042700
2005 Tbx2 is overexpressed and plays an important role in maintaining proliferation and suppression of senescence in melanomas. Cancer research 183 15781639
2000 Expression of chick Tbx-2, Tbx-3, and Tbx-5 genes during early heart development: evidence for BMP2 induction of Tbx2. Developmental biology 171 11087629
2005 Tbx20 is essential for cardiac chamber differentiation and repression of Tbx2. Development (Cambridge, England) 160 15901664
1998 Brachyury-related transcription factor Tbx2 and repression of the melanocyte-specific TRP-1 promoter. Molecular and cellular biology 149 9710594
1998 Involvement of T-box genes Tbx2-Tbx5 in vertebrate limb specification and development. Development (Cambridge, England) 144 9609833
1998 Expression of T-box genes Tbx2-Tbx5 during chick organogenesis. Mechanisms of development 140 9651516
2002 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 135 12000749
2004 Tbx2 directly represses the expression of the p21(WAF1) cyclin-dependent kinase inhibitor. Cancer research 134 14996726
2009 The Tbx2+ primary myocardium of the atrioventricular canal forms the atrioventricular node and the base of the left ventricle. Circulation research 132 19423846
2011 Tbx2 and Tbx3 induce atrioventricular myocardial development and endocardial cushion formation. Cellular and molecular life sciences : CMLS 114 22130515
2006 Regional morphogenesis in the hypothalamus: a BMP-Tbx2 pathway coordinates fate and proliferation through Shh downregulation. Developmental cell 111 17141161
2010 The T-box transcription factor Tbx2: its role in development and possible implication in cancer. IUBMB life 106 19960541
2007 Hesr1 and Hesr2 regulate atrioventricular boundary formation in the developing heart through the repression of Tbx2. Development (Cambridge, England) 103 17259303
2002 FGF signaling regulates expression of Tbx2, Erm, Pea3, and Pax3 in the early nasal region. Developmental biology 102 12086464
2009 Tbx20 interacts with smads to confine tbx2 expression to the atrioventricular canal. Circulation research 95 19661464
2000 The gene encoding the T-box factor Tbx2 is a target for the microphthalmia-associated transcription factor in melanocytes. The Journal of biological chemistry 88 10770922
2007 Tbx2 and Tbx3 regulate the dynamics of cell proliferation during heart remodeling. PloS one 85 17460765
2018 TBX2 is a neuroblastoma core regulatory circuitry component enhancing MYCN/FOXM1 reactivation of DREAM targets. Nature communications 84 30451831
2004 The role of Tbx2 and Tbx3 in mammary development and tumorigenesis. Journal of mammary gland biology and neoplasia 81 15300007
2010 The Highly Homologous T-Box Transcription Factors, TBX2 and TBX3, Have Distinct Roles in the Oncogenic Process. Genes & cancer 77 21779450
2000 Differential DNA binding and transcription modulation by three T-box proteins, T, TBX1 and TBX2. Gene 75 11111039
2011 Defective Tbx2-dependent patterning of the atrioventricular canal myocardium causes accessory pathway formation in mice. The Journal of clinical investigation 74 21266775
2005 Tbx3, the ulnar-mammary syndrome gene, and Tbx2 interact in mammary gland development through a p19Arf/p53-independent pathway. Developmental dynamics : an official publication of the American Association of Anatomists 71 16222716
2002 TBX2 is preferentially amplified in BRCA1- and BRCA2-related breast tumors. Cancer research 69 12097257
2000 Conserved and divergent expression of T-box genes Tbx2-Tbx5 in Xenopus. Mechanisms of development 68 10704879
2022 Tbx2 is a master regulator of inner versus outer hair cell differentiation. Nature 65 35508658
2013 Tbx2 controls lung growth by direct repression of the cell cycle inhibitor genes Cdkn1a and Cdkn1b. PLoS genetics 64 23341776
2011 Wnt signaling regulates atrioventricular canal formation upstream of BMP and Tbx2. Birth defects research. Part A, Clinical and molecular teratology 62 21567896
2011 Identification of a Tbx1/Tbx2/Tbx3 genetic pathway governing pharyngeal and arterial pole morphogenesis. Human molecular genetics 62 22116936
2018 Functional variants in TBX2 are associated with a syndromic cardiovascular and skeletal developmental disorder. Human molecular genetics 60 29726930
2013 The T-box transcription factors TBX2 and TBX3 in mammary gland development and breast cancer. Journal of mammary gland biology and neoplasia 60 23624936
1995 Cloning and mapping of a human gene (TBX2) sharing a highly conserved protein motif with the Drosophila omb gene. Genomics 60 8530034
2017 Bone Metastasis of Prostate Cancer Can Be Therapeutically Targeted at the TBX2-WNT Signaling Axis. Cancer research 59 28108510
2016 Tbx2 and Tbx3 Act Downstream of Shh to Maintain Canonical Wnt Signaling during Branching Morphogenesis of the Murine Lung. Developmental cell 57 27720610
2002 Murine Tbx2 contains domains that activate and repress gene transcription. Gene 57 11867218
2011 Microdeletion of 17q22q23.2 encompassing TBX2 and TBX4 in a patient with congenital microcephaly, thyroid duct cyst, sensorineural hearing loss, and pulmonary hypertension. American journal of medical genetics. Part A 55 21271665
2010 TBX2 and TBX3: the special value for anticancer drug targets. Biochimica et biophysica acta 55 20624445
2006 The T-box factor TBX-2 and the SUMO conjugating enzyme UBC-9 are required for ABa-derived pharyngeal muscle in C. elegans. Developmental biology 54 16701625
2012 The T box transcription factor TBX2 promotes epithelial-mesenchymal transition and invasion of normal and malignant breast epithelial cells. PloS one 52 22844464
2013 Tbx2 terminates shh/fgf signaling in the developing mouse limb bud by direct repression of gremlin1. PLoS genetics 48 23633963
2008 Conservation of linkage and evolution of developmental function within the Tbx2/3/4/5 subfamily of T-box genes: implications for the origin of vertebrate limbs. Development genes and evolution 48 18815807
2010 Expression of PSCA, PIWIL1 and TBX2 and its correlation with HPV16 infection in formalin-fixed, paraffin-embedded cervical squamous cell carcinoma specimens. Archives of virology 45 20229117
2006 Characterization of a novel ectodermal signaling center regulating Tbx2 and Shh in the vertebrate limb. Developmental biology 45 17300775
2007 Ectopic Tbx2 expression results in polyploidy and cisplatin resistance. Oncogene 44 17700536
2003 Coquillette, a sea urchin T-box gene of the Tbx2 subfamily, is expressed asymmetrically along the oral-aboral axis of the embryo and is involved in skeletogenesis. Mechanisms of development 43 12782273
2004 ERBB2, TBX2, RPS6KB1, and MYC alterations in breast tissues of BRCA1 and BRCA2 mutation carriers. Genes, chromosomes & cancer 42 15236312
2014 Stratification based on methylation of TBX2 and TBX3 into three molecular grades predicts progression in patients with pTa-bladder cancer. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 41 25394776
2019 TBX2 interacts with heterochromatin protein 1 to recruit a novel repression complex to EGR1-targeted promoters to drive the proliferation of breast cancer cells. Oncogene 40 31253870
2012 Ectopic retinoic acid signaling affects outflow tract cushion development through suppression of the myocardial Tbx2-Tgfβ2 pathway. Development (Cambridge, England) 40 22186728
2014 TBX2 represses CST6 resulting in uncontrolled legumain activity to sustain breast cancer proliferation: a novel cancer-selective target pathway with therapeutic opportunities. Oncotarget 39 24742492
2014 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 39 25371204
2006 Cell cycle regulation of the T-box transcription factor tbx2. Experimental cell research 39 16730707
1995 Identification, characterization, and localization to chromosome 17q21-22 of the human TBX2 homolog, member of a conserved developmental gene family. Mammalian genome : official journal of the International Mammalian Genome Society 39 8597636
2021 Regulation of otocyst patterning by Tbx2 and Tbx3 is required for inner ear morphogenesis in the mouse. Development (Cambridge, England) 38 33795231
2003 Distinct expression patterns of the two T-box homologues Brachyury and Tbx2/3 in the placozoan Trichoplax adhaerens. Development genes and evolution 38 13680223
2010 Expression of PSCA, PIWIL1, and TBX2 in endometrial adenocarcinoma. Onkologie 37 20502058
2007 UV-mediated regulation of the anti-senescence factor Tbx2. The Journal of biological chemistry 37 18025091
2006 Role of T-box gene tbx-2 for anterior foregut muscle development in C. elegans. Developmental biology 36 17005176
2009 Tbx2 misexpression impairs deployment of second heart field derived progenitor cells to the arterial pole of the embryonic heart. Developmental biology 35 19563797
2009 Expression and requirement of T-box transcription factors Tbx2 and Tbx3 during secondary palate development in the mouse. Developmental biology 35 19769959
2004 TBX2/TBX3 transcriptional factor homologue controls olfactory adaptation in Caenorhabditis elegans. Journal of neurobiology 35 14750151
2022 TBX2 specifies and maintains inner hair and supporting cell fate in the Organ of Corti. Nature communications 34 36494345
2011 Physical and functional interaction between PML and TBX2 in the establishment of cellular senescence. The EMBO journal 33 22002537
2002 Conserved expression control and shared activity between cognate T-box genes Tbx2 and Tbx3 in connection with Sonic hedgehog signaling during Xenopus eye development. Development, growth & differentiation 33 12175361
2022 Development and transdifferentiation into inner hair cells require Tbx2. National science review 32 36687561
2015 TBX2 represses PTEN in rhabdomyosarcoma and skeletal muscle. Oncogene 32 26686089
2013 Tbx2/3 is an essential mediator within the Brachyury gene network during Ciona notochord development. Development (Cambridge, England) 32 23674602
2009 Loss of Tbx2 delays optic vesicle invagination leading to small optic cups. Developmental biology 32 19576202
2008 Expression of Tbx2 and Tbx3 in the developing hypothalamic-pituitary axis. Gene expression patterns : GEP 32 18534921
2014 TBX2 blocks myogenesis and promotes proliferation in rhabdomyosarcoma cells. International journal of cancer 30 24470334
2013 A novel role for the anti-senescence factor TBX2 in DNA repair and cisplatin resistance. Cell death & disease 30 24113180
2018 EGR1 interacts with TBX2 and functions as a tumor suppressor in rhabdomyosarcoma. Oncotarget 29 29719592
2013 Msx1 and Tbx2 antagonistically regulate Bmp4 expression during the bud-to-cap stage transition in tooth development. Development (Cambridge, England) 29 23720046
2010 The retinoblastoma protein modulates Tbx2 functional specificity. Molecular biology of the cell 29 20534814
2004 Tbx2 represses expression of Connexin43 in osteoblastic-like cells. Calcified tissue international 29 15354864
2018 TBX2 and TBX3 act downstream of canonical WNT signaling in patterning and differentiation of the mouse ureteric mesenchyme. Development (Cambridge, England) 28 30478225
2006 Developmental expression patterns of Tbx1, Tbx2, Tbx5, and Tbx20 in Xenopus tropicalis. Developmental dynamics : an official publication of the American Association of Anatomists 28 16477648
2013 The transcription factors TBX2 and TBX3 interact with human papillomavirus 16 (HPV16) L2 and repress the long control region of HPVs. Journal of virology 23 23388722
2011 Role of Tbx2 in defining the territory of the pronephric nephron. Development (Cambridge, England) 23 21205791
2009 Expression of TBX2 promotes anchorage-independent growth and survival in the p53-negative SW13 adrenocortical carcinoma. Cancer letters 22 19216023
2019 Epigenetic Suppression of the T-box Subfamily 2 (TBX2) in Human Non-Small Cell Lung Cancer. International journal of molecular sciences 21 30866410
2013 Brachyury, Tbx2/3 and sall expression during embryogenesis of the indirectly developing polychaete Hydroides elegans. The International journal of developmental biology 21 23585355
1999 Expression of Xenopus T-box transcription factor, tbx2 in Xenopus embryo. Development genes and evolution 21 10552304
2012 TBX2 expression is regulated by PAX3 in the melanocyte lineage. Pigment cell & melanoma research 20 23020925
2011 Dynamic expression of Tbx2 subfamily genes in development of the mouse reproductive system. Developmental dynamics : an official publication of the American Association of Anatomists 20 22223620
2021 TBX2 Drives Neuroendocrine Prostate Cancer through Exosome-Mediated Repression of miR-200c-3p. Cancers 19 34638504
2011 Heart chamber size in zebrafish is regulated redundantly by duplicated tbx2 genes. Developmental dynamics : an official publication of the American Association of Anatomists 19 21448936
2010 TBX2 gene duplication associated with complex heart defect and skeletal malformations. American journal of medical genetics. Part A 19 20635360
2018 Identification of TBX2 and TBX3 variants in patients with conotruncal heart defects by target sequencing. Human genomics 18 30223900
2018 TBX2 overexpression promotes proliferation and invasion through epithelial-mesenchymal transition and ERK signaling pathway. Experimental and therapeutic medicine 18 30651856
2016 Tbx2 regulates anterior neural specification by repressing FGF signaling pathway. Developmental biology 18 27913219
2014 The orthologous Tbx transcription factors Omb and TBX2 induce epithelial cell migration and extrusion in vivo without involvement of matrix metalloproteinases. Oncotarget 18 25344916
2005 T-box and homeobox genes from the ctenophore Pleurobrachia pileus: comparison of Brachyury, Tbx2/3 and Tlx in basal metazoans and bilaterians. FEBS letters 18 16122738
2017 TBX2 over-expression promotes nasopharyngeal cancer cell proliferation and invasion. Oncotarget 17 28881763
2010 Generation of mice with a conditional null allele for Tbx2. Genesis (New York, N.Y. : 2000) 17 20095052
2005 Expression pattern of the Brachyury and Tbx2 homologues from the sponge Suberites domuncula. Biology of the cell 17 15850455

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