Affinage

PAX3

Paired box protein Pax-3 · UniProt P23760

Length
479 aa
Mass
53.0 kDa
Annotated
2026-06-10
100 papers in source corpus 39 papers cited in narrative 39 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PAX3 is a developmental transcription factor that recognizes DNA through tandem paired and paired-type homeodomains and orchestrates skeletal myogenesis and neural crest specification (PMID:2022185, PMID:9094722, PMID:23509273). Its two DNA-binding modules act synergistically and independently of angular orientation, and binding induces conformational changes in target DNA; an intervening segment including the conserved octapeptide mediates homodimerization, and disease-causing splotch/Waardenburg syndrome type 1 mutations alter these DNA-binding and dimerization activities (PMID:8065927, PMID:7909605). The protein is functionally bipartite, with an N-terminal transcriptional inhibitory region and a C-terminal activation domain (PMID:7809114). In limb muscle progenitors PAX3 is required for the delamination, migration, and survival of dermomyotome-derived cells, acting in part by directly activating c-Met (MET) (PMID:7600971, PMID:8633043), and it drives the myogenic program by inducing MyoD, Myf5, and myogenin, including through a Six1/Eya2/Mox1 cascade and a direct Pax3→Dmrt2→Myf5 axis (PMID:9094722, PMID:11262400, PMID:20368965). Together with Pax7 it maintains a resident muscle progenitor pool whose loss leads to death or non-myogenic fate, while PAX3 also represses Pax7 during normal development (PMID:10079229, PMID:15843801). In neural crest, PAX3 acts downstream of Msx1 and cooperates with Zic1 to drive full neural crest commitment and Slug induction in a WNT-dependent manner (PMID:15691759, PMID:23509273), and it directly regulates the BMP inhibitor Sostdc1 in cranial crest (PMID:18483623). PAX3 transcriptional output is shaped by cofactors including the repressor hDaxx (acting through the homeodomain), the co-activator TAZ, and Ldb1, which is recruited to Pax3-bound elements to mediate chromatin looping and H3K4me1 deposition required for migratory myogenic progenitor specification (PMID:10393185, PMID:16300735, PMID:31127120). PAX3 abundance and activity are further controlled post-translationally by Taf1-mediated monoubiquitination and proteasomal degradation, by C-terminal acetylation at K437/K475 reversed by SIRT1, and post-transcriptionally by miR-27b and by alternative polyadenylation that tunes miR-206 sensitivity (PMID:21145483, PMID:21169561, PMID:19666532, PMID:31699935). The PAX3-FOXO1 fusion that defines alveolar rhabdomyosarcoma behaves as both a dominant-negative and gain-of-function variant of PAX3 (PMID:15520281); it reprograms the cis-regulatory landscape by inducing de novo super-enhancers, recruiting BRD4, and maintaining RNA polymerase pause release and enhancer accessibility at direct targets, and is stabilized by PLK1 (S503) and Aurora kinase A phosphorylation (PMID:28446439, PMID:36395771, PMID:25398439, PMID:31888889).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 1991 High

    Established the fundamental molecular identity of PAX3 as a sequence-specific DNA-binding protein, defining the structural basis for its later-characterized transcription factor functions.

    Evidence In vitro DNA binding assay showing recognition of the e5 sequence; identification of paired domain and paired-type homeodomain

    PMID:2022185

    Open questions at the time
    • Did not define in vivo target genes
    • Did not establish transcriptional activation vs repression
  2. 1994 High

    Resolved how PAX3 engages DNA and acts as a transcription factor by mapping separable inhibitory and activation domains and demonstrating synergistic, orientation-independent binding by both DNA-binding modules with DNA bending.

    Evidence Domain deletion/mutagenesis with reporter assays; gel shift and circular permutation analysis

    PMID:7809114 PMID:8065927

    Open questions at the time
    • Endogenous promoter targets not yet identified
    • Cofactors driving repression vs activation unknown
  3. 1994 High

    Connected PAX3 biochemistry to human and mouse disease by showing splotch and Waardenburg syndrome type 1 mutations impair DNA binding and disrupt octapeptide-mediated homodimerization.

    Evidence In vitro DNA binding and dimerization assays with disease-mutant proteins

    PMID:7909605

    Open questions at the time
    • Did not link specific binding defects to in vivo developmental phenotypes
    • Dimerization partners beyond homodimers unaddressed
  4. 1994 High

    Defined the in vivo developmental requirement for PAX3, showing it is specifically required for the migratory progenitor population that builds limb muscle but dispensable for trunk muscle.

    Evidence Histological analysis of splotch mouse null embryos

    PMID:7600971

    Open questions at the time
    • Direct molecular targets driving migration not identified here
    • Mechanism distinguishing limb from trunk requirement unresolved
  5. 1996 High

    Identified the first direct myogenic migration target by linking PAX3 loss to reduced c-Met and showing PAX3 can stimulate c-met via a promoter binding site, explaining the migration defect.

    Evidence Splotch embryo analysis, cell culture reporter assay, promoter binding-site identification

    PMID:8633043

    Open questions at the time
    • Direct in vivo occupancy not yet shown
    • Other migration targets uncharacterized
  6. 1997 High

    Established PAX3 as sufficient to initiate the myogenic program by showing ectopic expression induces MyoD, Myf5, and myogenin in normally non-myogenic tissues.

    Evidence Retroviral Pax-3 expression in avian embryonic tissues with gene expression readouts

    PMID:9094722

    Open questions at the time
    • Whether activation is direct or relayed through intermediates unresolved
    • Cofactor requirements not defined
  7. 1999 High

    Defined the first PAX3 cofactor relationships and a key regulatory output: hDaxx represses PAX3 via the homeodomain, and PAX3 represses Pax7 while supporting MyoD activation and progenitor survival.

    Evidence Reciprocal Co-IP, in vitro binding, reporter assays, antisense knockdown in explants, splotch mutant analysis

    PMID:10079229 PMID:10393185

    Open questions at the time
    • Mechanism of Pax7 repression (direct vs indirect) not defined
    • How PAX3-FKHR escapes hDaxx repression mechanistically unclear
  8. 2001 High

    Placed PAX3 atop a defined myogenic transcriptional cascade by showing it induces Six1, Eya2, and Mox1 before MyoD/myogenin and is necessary and sufficient for stem cell myogenesis.

    Evidence Gain- and dominant-negative loss-of-function in pluripotent stem cells with reporter and expression analysis

    PMID:11262400

    Open questions at the time
    • Direct vs indirect activation of Six1/Eya2 not distinguished
    • Mox2 interaction (#36) functional consequence not established
  9. 2004 High

    Clarified paralog functional specificity, showing Pax7 can replace Pax3 in neural and somite contexts but not in long-range muscle migration owing to inefficient c-Met activation, and that PAX3-FKHR carries mixed dominant-negative and gain-of-function activity.

    Evidence Pax7-for-Pax3 knock-in and PAX3:FKHR conditional knock-in mouse models

    PMID:15132998 PMID:15520281

    Open questions at the time
    • Molecular basis of paralog specificity beyond c-Met unresolved
    • Quantitative contribution of dominant-negative vs gain-of-function for the fusion not separated
  10. 2005 High

    Established PAX3/PAX7 as maintainers of the muscle progenitor pool and resolved distinct paralog roles in satellite cells, while extending PAX3 to neural crest induction via WNT/Slug.

    Evidence Pax3/Pax7 double-mutant mice with lineage tracing; dominant-negative satellite cell cultures; Xenopus morpholino/overexpression epistasis

    PMID:15691759 PMID:15843801 PMID:16380438

    Open questions at the time
    • Direct targets for progenitor maintenance not enumerated
    • Direct Slug/Snail occupancy by PAX3 not shown
  11. 2005 Medium

    Identified TAZ as a transcriptional co-activator of PAX3, broadening the cofactor repertoire to include positive regulators acting on melanocyte/pigment targets such as MITF.

    Evidence Yeast two-hybrid, Co-IP, co-localization, luciferase reporter on MITF promoter

    PMID:16300735

    Open questions at the time
    • Single-study interaction with limited mechanistic follow-up
    • In vivo developmental relevance not tested
  12. 2008 High

    Provided direct in vivo evidence of a PAX3 target in cranial neural crest, showing it directly regulates the BMP inhibitor Sostdc1 to control osteogenic competence.

    Evidence Cre-inducible mouse model, ChIP, reporter assay, loss-of-function

    PMID:18483623

    Open questions at the time
    • Whether persistent expression mirrors normal regulation unclear
    • Broader cranial crest target set undefined
  13. 2010 High

    Defined direct chromatin-level myogenic targets and a layered post-translational/post-transcriptional control network, establishing PAX3→Dmrt2→Myf5, Taf1-mediated monoubiquitination/degradation, SIRT1-reversible acetylation, and miR-27b 3'UTR targeting.

    Evidence Gel shift/ChIP/transgenic reporter (Dmrt2); Co-IP and ubiquitination assays (Taf1); lysine mutagenesis and SIRT1 knockdown (acetylation); 3'UTR reporter and in vivo antagomir (miR-27b)

    PMID:19666532 PMID:20368965 PMID:21145483 PMID:21169561

    Open questions at the time
    • Acetylation findings (#21) from a single lab
    • Integration of degradation, acetylation, and miRNA control across developmental stages not unified
  14. 2012 Medium

    Expanded PAX3 mechanism to chromatin-modifying recruitment and melanoma signaling, identifying Pax3/7BP as an adaptor to the Wdr5 H3K4 methyltransferase complex and PI3K→PAX3→Brn-2 and GSK-3β kinase regulation.

    Evidence Y2H/Co-IP/ChIP/HMT assay/shRNA (Pax3/7BP); PI3K inhibitor with ChIP/reporter (Brn-2); in vitro kinase and Co-IP (GSK-3β); Schwann cell overexpression; chick Co-IP (Meis2)

    PMID:22390724 PMID:22532290 PMID:22679108 PMID:22862948 PMID:22988297

    Open questions at the time
    • GSK-3β, Brn-2, Meis2 and Schwann cell findings each from single labs
    • Direct phosphosites for GSK-3β on PAX3 not mapped
  15. 2013 Medium

    Defined neoplastic and developmental mechanisms of the PAX3-FOXO1 fusion distinct from wild-type PAX3, including Hippo pathway suppression via RASSF4 and EGR1/p57Kip2-mediated differentiation block, and confirmed PAX3/Zic1 sufficiency for neural crest commitment.

    Evidence RNAi/overexpression with cell cycle and senescence assays (RASSF4); transgenic myoblasts (p57Kip2/EGR1); Xenopus overexpression and transplantation (Zic1)

    PMID:17986608 PMID:23509273 PMID:24334454

    Open questions at the time
    • RASSF4 and EGR1 mechanisms from single labs
    • Whether wild-type PAX3 shares any of these activities not fully excluded
  16. 2014 Medium

    Identified ETS1 as a direct PAX3 partner cooperatively activating MET in melanoma, reinforcing MET as a recurrent direct PAX3 target across lineages.

    Evidence Co-IP, promoter reporters, ChIP, siRNA, xenograft

    PMID:25531327

    Open questions at the time
    • Single-lab interaction
    • Generality beyond melanoma untested
  17. 2019 High

    Resolved how PAX3 reshapes 3D chromatin and how its levels are tuned, showing Ldb1-mediated looping and H3K4me1 at Pax3 sites and alternative polyadenylation/miR-206 control of PAX3 protein levels in muscle stem cells.

    Evidence Mass spectrometry, ChIP-seq, 4C-seq, conditional Ldb1 deletion (looping); 3'UTR reporters, U1 and miR-206 manipulation, in vivo muscle analysis (APA)

    PMID:31127120 PMID:31699935

    Open questions at the time
    • Recruitment determinants directing Ldb1 to a subset of sites unknown
    • How APA isoform choice is regulated upstream incompletely defined
  18. 2022 High

    Defined the dynamic transcriptional mechanism of PAX3-FOXO1, showing it continuously maintains enhancer accessibility and drives RNA polymerase pause release/elongation at direct targets via super-enhancers and BRD4, stabilized by PLK1 (S503) and Aurora kinase A.

    Evidence Auxin-inducible degron with CUT&RUN/ATAC-seq/nascent transcription (dynamics); ChIP-seq/ATAC-seq/BET inhibition (super-enhancers/BRD4); kinome screens, Co-IP, phospho/ubiquitination assays, xenografts (PLK1, Aurora A)

    PMID:25398439 PMID:28446439 PMID:31888889 PMID:36395771

    Open questions at the time
    • Aurora A finding from single lab
    • Direct vs indirect contribution to individual super-enhancer elements not fully parsed

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the array of PAX3 cofactors, post-translational modifications, and post-transcriptional controls are coordinated to switch PAX3 between progenitor maintenance, myogenic, neural crest, and oncogenic programs in a context-specific manner remains unresolved.
  • No unified model integrating Taf1, SIRT1, miRNA, and kinase inputs
  • Determinants directing cofactor choice (hDaxx vs TAZ vs Ldb1) at specific loci unknown
  • Structural basis for context-specific target selection undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 5 GO:0140110 transcription regulator activity 5
Localization
GO:0005634 nucleus 1
Pathway
R-HSA-1266738 Developmental Biology 5 R-HSA-1643685 Disease 4 R-HSA-4839726 Chromatin organization 3 R-HSA-74160 Gene expression (Transcription) 3
Partners
DAXXETS1FOXO1LDB1SOX10TAF1TAZZIC1

Evidence

Reading pass · 39 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1991 Pax-3 encodes a DNA binding protein that specifically recognizes the e5 sequence present upstream of the Drosophila even-skipped gene, and contains both a paired domain and a paired-type homeodomain. In vitro DNA binding assay; protein characterization The EMBO journal High 2022185
1994 Pax-3 contains a transcription inhibition activity in the first 90 N-terminal amino acids (including part of the paired domain) and a transcriptional activation activity in the C-terminus. Pax-3 activates transcription over a narrow range of protein concentration when promoter elements contain functional binding sites. Functional dissection by deletion/domain mutagenesis and transient transfection reporter assays Proceedings of the National Academy of Sciences of the United States of America High 7809114
1994 Pax-3 interacts with DNA through both its paired domain and homeodomain synergistically; the two domains bind independently of their angular orientation on DNA. Pax-3 binding causes conformational changes in DNA (demonstrated by circular permutation analysis), a property intrinsic to the paired domain. In vitro gel shift assay; circular permutation analysis; domain deletion constructs Nucleic acids research High 8065927
1994 Mutations in Pax-3 found in splotch (mouse) and Waardenburg syndrome type 1 (human) alleles alter DNA binding activity of both the paired domain and homeodomain. A segment between the two DNA-binding domains, including the conserved octapeptide, participates in protein homodimerization; a splotch allele mutation disrupts dimerization. In vitro DNA binding assays with mutant proteins; dimerization analysis Proceedings of the National Academy of Sciences of the United States of America High 7909605
1994 Loss-of-function Pax-3 in splotch mice eliminates a population of dermomyotome-derived cells that normally migrate to the limb, causing loss of limb muscles, demonstrating Pax-3 is required for limb but not trunk muscle development. Genetic loss-of-function (splotch mouse mutant); histological analysis of muscle development Development (Cambridge, England) High 7600971
1996 Pax3 directly regulates c-Met (MET) expression in limb muscle progenitors. c-Met expression is markedly reduced in the lateral dermomyotome of Pax3 (splotch) mutant embryos. Pax3 can stimulate c-met expression in cultured cells, and a potential Pax3 binding site was identified in the human c-MET promoter. Splotch mutant embryo analysis; cell culture transfection reporter assay; promoter binding site identification Proceedings of the National Academy of Sciences of the United States of America High 8633043
1997 Ectopic Pax-3 expression is sufficient to induce MyoD, Myf-5, and myogenin expression in paraxial and lateral plate mesoderm and in the neural tube in the absence of inducing tissues, demonstrating that Pax-3 can activate myogenic determination genes. Retroviral infection with Pax-3 in avian embryonic tissues in vitro; gene expression analysis Cell High 9094722
1999 Human Daxx (hDaxx) interacts with Pax3 in vivo and with DNA-bound Pax3 in vitro, mediated primarily through the homeodomain recognition helix with involvement of the octapeptide domain. hDaxx represses Pax3 transcriptional activity by ~80%. The Pax3-FKHR fusion protein is unresponsive to this repression despite physically interacting with hDaxx. Co-immunoprecipitation (in vivo); in vitro binding assay; transcriptional reporter assays; domain mutagenesis The EMBO journal High 10393185
1999 Disruption of Pax3 by antisense oligonucleotides impairs MyoD activation in cultured presomitic mesoderm and is accompanied by increased apoptosis. In Pax3 mutant embryos, Pax7 expression is upregulated and expands into dorsal neural tube and somites where Pax3 is normally expressed, demonstrating Pax3 represses Pax7 during normal development. Antisense oligonucleotide knockdown in explant culture; analysis of splotch mutant embryos; gene expression assays Development (Cambridge, England) High 10079229
2001 Pax3 is necessary and sufficient to induce skeletal myogenesis in pluripotent stem cells. Pax3 induces expression of Six1, Eya2, and Mox1 prior to inducing MyoD and myogenin. A dominant-negative Pax3 abolishes myogenesis and reduces Six1, Eya2, and endogenous Pax3 expression. Gain- and dominant-negative loss-of-function in pluripotent stem cell culture; reporter assays; gene expression analysis The Journal of biological chemistry High 11262400
2002 N-Myc-Max and c-Myc-Max activate the Pax-3 promoter through a noncanonical E-box site in the 5' promoter region. Pax-3 mRNA expression is cell cycle-regulated and mutation of the E-box site alters cell cycle-dependent expression. Transient transfection reporter assay; site-directed mutagenesis of Pax-3 promoter; cell cycle analysis The Journal of biological chemistry Medium 12095979
2004 Pax3:Fkhr knock-in acts as a dominant-negative on embryonic Pax3 and Pax7 function, and paradoxically activates the Pax3 target gene c-Met. Ectopic neuroprogenitor cell proliferation also occurs, establishing that PAX3-FKHR has both dominant-negative and gain-of-function activities relative to wild-type Pax3. Cre-mediated conditional knock-in into mouse Pax3 locus; genetic analysis Genes & development High 15520281
2004 Pax7 can substitute for Pax3 function in dorsal neural tube, neural crest, and somite development but not in muscles formed by long-range migration. The hypomorphic activity of Pax7 replacing Pax3 is due to defects in delamination, migration, and proliferation of muscle precursor cells with inefficient activation of c-Met in the hypaxial somite. Gene targeting knock-in (Pax3 replaced by Pax7) in mouse; genetic and cellular analysis Genes & development High 15132998
2005 Pax3 and Pax7 are required for maintenance of a resident muscle progenitor cell population in developing muscles. In the absence of both Pax3 and Pax7, further muscle development is arrested and cells either die or assume non-myogenic fates. Genetic double-mutant mouse analysis; GFP reporter targeted to Pax3 locus; lineage tracing Nature High 15843801
2005 Dominant-negative forms of both Pax3 and Pax7 repress MyoD but do not interfere with Myf5 expression in satellite cells. Pax3 cannot replace the antiapoptotic function of Pax7 in satellite cells, demonstrating distinct functions for the two paralogs. Dominant-negative constructs in satellite cell cultures; Pax7 mutant mouse analysis The Journal of cell biology High 16380438
2005 Msx1 and Pax3 are both required for neural crest formation in Xenopus. Pax3 acts downstream of Msx1; Pax3 combined with ZicR1 activates Slug in a WNT-dependent manner. WNT signals initiate Slug induction through Pax3 activity, and FGF8 induces neural crest through both Msx1 and Pax3 activities. Morpholino knockdown and overexpression in Xenopus; epistasis analysis Developmental cell High 15691759
2005 TAZ physically interacts with Pax3 (identified by yeast two-hybrid, confirmed by co-immunoprecipitation and nuclear co-localization) and functions as a transcriptional co-activator of Pax3, enhancing Pax3 transcriptional activity on the MITF promoter and artificial reporter constructs. Yeast two-hybrid screen; co-immunoprecipitation; co-localization; luciferase reporter assay Biochemical and biophysical research communications Medium 16300735
2008 Persistent Pax3 expression in cranial neural crest cells (via Cre-inducible system) causes cleft palate and defective osteogenesis. Pax3 directly regulates expression of Sostdc1, a soluble BMP signaling inhibitor, rendering cranial crest resistant to BMP-induced osteogenesis. Cre-inducible mouse model; ChIP; reporter assay; loss-of-function analysis The Journal of clinical investigation High 18483623
2009 microRNA-27b (miR-27b) directly targets the 3'-UTR of Pax3 mRNA and down-regulates Pax3 protein. In vivo overexpression of miR-27b in Pax3-positive cells leads to down-regulation of Pax3 and interference with progenitor cell migration and premature differentiation. Inhibition of miR-27b in adult satellite cells causes continued Pax3 expression, more proliferation, and delayed differentiation. Pax7 levels are not affected. 3'-UTR luciferase reporter assay; transgenic in vivo overexpression; miR-27b inhibitor transfection; in vivo antagomir injection Proceedings of the National Academy of Sciences of the United States of America High 19666532
2010 Pax3 binds to a conserved 286 bp sequence at -18 kb from Dmrt2 (shown by gel shift and chromatin immunoprecipitation), directly activating Dmrt2 expression. Dmrt2 in turn activates Myf5 via binding to its early epaxial enhancer, establishing a Pax3/Dmrt2/Myf5 regulatory cascade at the onset of epaxial myogenesis. In vitro gel shift assay; ChIP with in vivo extracts; transgenic reporter analysis; in vivo conditional overexpression PLoS genetics High 20368965
2010 Pax3 is regulated by monoubiquitination at specific residues that leads to proteasomal degradation during postnatal myogenesis. Taf1 (a component of the core transcriptional machinery) binds directly to Pax3 and mediates its monoubiquitination. Overexpression of Taf1 increases monoubiquitinated Pax3 and its degradation; knockdown of Taf1 decreases Pax3 monoubiquitination and increases Pax3 protein levels, enhancing Pax3-mediated inhibition of myogenic differentiation. Co-immunoprecipitation; monoubiquitination assay; overexpression and siRNA knockdown; myogenic differentiation assays Molecular cell High 21145483
2010 Pax3 acetylation on C-terminal lysine residues K437 and K475 regulates the transcription of Hes1 and Neurog2. Removal of these lysines increased Hes1 but decreased Neurog2 promoter activity. SIRT1 deacetylase associates with Hes1 and Neurog2 promoters during neural tube development and decreases Pax3 acetylation; SIRT1 siRNA knockdown increases Pax3 acetylation and Neurog2 expression. Site-directed mutagenesis of lysine residues; reporter assays; ChIP; SIRT1 siRNA knockdown Molecular biology of the cell Medium 21169561
2010 PAX3 and SOX10 synergistically activate MET receptor expression in melanoma. PAX3 directly binds elements in the MET promoter independently of MITF. SOX10 does not directly activate MET alone but synergizes with PAX3 or MITF for MET activation. Two pathways for PAX3-mediated MET induction exist: direct gene activation and indirect regulation through MITF. Promoter reporter assays; ChIP; siRNA knockdown; cell line comparisons Pigment cell & melanoma research Medium 20067553
2012 Pax3/7BP (a novel protein identified by yeast two-hybrid) physically interacts with both Pax7 and Pax3, and acts as an adaptor bridging Pax7 with the Wdr5-containing H3K4 methyltransferase complex. Knockdown of Pax3/7BP abolishes Pax3/7-associated H3K4 methyltransferase activity and inhibits proliferation of Pax7+ muscle precursor cells in vitro and in vivo. Yeast two-hybrid; co-immunoprecipitation; ChIP; histone methyltransferase activity assay; shRNA knockdown in culture and in vivo Cell stem cell High 22862948
2012 Pax-3 expression blocks induction of Oct-6 and Krox-20 (K20) by cAMP and completely inhibits K20-induced myelin gene expression in Schwann cells in a c-Jun-independent manner. Pax-3 expression alone is sufficient to inhibit TGFβ1-induced apoptosis and to induce Schwann cell proliferation in the absence of growth factors. Pax-3 overexpression in Schwann cells; apoptosis assays; proliferation assays; gene expression analysis Glia Medium 22532290
2012 Inhibition of PI3K signaling reduces Pax3 expression in melanoma cells. Pax3 directly binds and activates the Brn-2 promoter. PI3K inhibition reduces both Pax3 and Brn-2 expression, linking PI3K→Pax3→Brn-2 in a melanoma invasiveness pathway. PI3K inhibitor treatment; reporter assay; ChIP; gene expression analysis Molecular and cellular biology Medium 22988297
2012 Meis2 physically interacts with Pax3 and Pax7 in the tectal anlage. Meis2 acts downstream of Pax3/7 and requires balanced expression levels of both proteins. Pax3 and Pax7 mutually regulate each other's expression in the mesencephalic vesicle. In ovo electroporation; co-immunoprecipitation; gene expression analysis in chick embryos BMC developmental biology Medium 22390724
2013 Pax3 and Zic1 together are sufficient to trigger full neural crest commitment in Xenopus: coactivation of these two factors from various early embryonic lineages initiates neural crest specification and drives migration and differentiation of multiple neural crest derivatives. Overexpression of Pax3 and Zic1 in Xenopus animal caps and ectopic sites; in vitro differentiation assays; transplantation in vivo Proceedings of the National Academy of Sciences of the United States of America High 23509273
2013 PAX3-FOXO1 upregulates RASSF4 expression, which promotes cell cycle progression and senescence evasion through inhibition of the Hippo pathway tumor suppressor MST1, thereby suppressing Hippo signaling as a mechanism of tumorigenesis. RNAi knockdown; overexpression; cell cycle and senescence assays; epistasis analysis in aRMS cell lines and tumors The Journal of clinical investigation Medium 24334454
2013 PAX3-FOXO1 controls p57Kip2 transcription by directly destabilizing the EGR1 transcriptional activator. Myoblasts from PAX3-FOXO1 transgenic mice cannot upregulate p57Kip2, preventing myogenic differentiation. Neither PAX3 nor FOXO1 alone share this regulatory activity. Transgenic mouse myoblast isolation; gene expression analysis; direct protein interaction assay Proceedings of the National Academy of Sciences of the United States of America Medium 17986608
2014 PLK1 phosphorylates PAX3-FOXO1 at the novel site S503, leading to protein stabilization. PLK1 inhibition leads to elevated ubiquitination and rapid proteasomal degradation of PAX3-FOXO1. PLK1 physically interacts with PAX3-FOXO1. Kinome siRNA screen; small molecule screen; co-immunoprecipitation; phosphorylation assay; ubiquitination assay; xenograft mouse model Cancer research High 25398439
2017 PAX3-FOXO1 reprograms the cis-regulatory landscape by inducing de novo super enhancers and establishing autoregulatory loops with master transcription factors MYOG, MYOD, and MYCN. PAX3-FOXO1 recruits and requires BRD4 at super enhancers, creating a dependence on BET bromodomains. ChIP-seq; ATAC-seq; BRD4 co-occupancy analysis; BET inhibitor treatment; cell line and primary tumor analysis Cancer discovery High 28446439
2019 Aurora kinase A phosphorylates PAX3-FOXO1 and physically binds to the fusion protein, stabilizing it. Aurora kinase A inhibition reduces PAX3-FOXO1 protein levels through enhanced proteasomal degradation. Drug screen; co-immunoprecipitation; phosphorylation assay; protein stability assay; xenograft model Cancer research Medium 31888889
2019 Ldb1 is recruited to Pax3-bound chromatin elements independently of CTCF-Cohesin and mediates chromatin looping at a subset of Pax3 binding sites. Ldb1 is necessary for efficient H3K4me1 deposition at these sites. Deletion of Ldb1 in Pax3-expressing cells in vivo severely impairs specification of migratory myogenic progenitors. Mass spectrometry; ChIP-seq; 4C-seq; conditional Ldb1 deletion in Pax3-expressing cells; H3K4me1 ChIP Nature communications High 31127120
2019 Alternative polyadenylation of Pax3 mRNA, regulated by the small nucleolar RNA U1, produces isoforms with different 3' UTR lengths that are differentially susceptible to miR-206 regulation, resulting in varying Pax3 protein levels in different muscles and controlling the rate of muscle stem cell activation. 3' UTR reporter assays; miR-206 manipulation; U1 manipulation; in vivo muscle analysis; alternative polyadenylation mapping Science (New York, N.Y.) High 31699935
2022 PAX3-FOXO1 rapidly and continuously maintains chromatin accessibility and enhancer architecture at direct target enhancers. Degradation of PAX3-FOXO1 impairs RNA polymerase pause release and transcription elongation at most regulated gene targets, and affects single enhancer elements within super-enhancers. Chemical-genetic rapid protein degradation (auxin-inducible degron); CUT&RUN; ATAC-seq; nascent transcription analysis; eRNA analysis; deep proteomics; time-course analysis Molecular cell High 36395771
2001 Mox2 physically interacts with Pax3 (and Mox1 with Pax1) through the homeodomain of Mox proteins, demonstrated by yeast two-hybrid and in vitro biochemical assays. Yeast two-hybrid; in vitro binding assay FEBS letters Low 11423130
2012 GSK-3β directly phosphorylates PAX3 in vitro and physically interacts with PAX3 in melanoma cells. GSK-3 inhibition reduces PAX3 levels; maintaining PAX3 expression protects melanoma cells from the anti-tumor effects of GSK-3 inhibition. In vitro phosphorylation assay; co-immunoprecipitation; siRNA knockdown; small molecule inhibitor treatment Molecular cancer research : MCR Medium 22679108
2014 PAX3 and ETS1 directly interact and synergistically activate MET expression. The MET proximal promoter contains a PAX3 response element; robust activation of the first ETS1 motif requires PAX3 whereas the second site is PAX-independent. Inhibition of both PAX3 and ETS1 substantially reduces MET levels in melanoma cells. Co-immunoprecipitation; promoter reporter assays; ChIP; siRNA knockdown; in vivo xenograft Oncogene Medium 25531327

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 A Pax3/Pax7-dependent population of skeletal muscle progenitor cells. Nature 845 15843801
1991 Pax-3, a novel murine DNA binding protein expressed during early neurogenesis. The EMBO journal 828 2022185
2005 Pax3 and Pax7 have distinct and overlapping functions in adult muscle progenitor cells. The Journal of cell biology 527 16380438
1994 Regulation of Pax-3 expression in the dermomyotome and its role in muscle development. Development (Cambridge, England) 460 7600971
1992 An exonic mutation in the HuP2 paired domain gene causes Waardenburg's syndrome. Nature 430 1347149
1997 Ectopic Pax-3 activates MyoD and Myf-5 expression in embryonic mesoderm and neural tissue. Cell 357 9094722
1994 Pax-3 expression in segmental mesoderm marks early stages in myogenic cell specification. Development (Cambridge, England) 346 7600957
1996 Pax3 modulates expression of the c-Met receptor during limb muscle development. Proceedings of the National Academy of Sciences of the United States of America 302 8633043
2005 Msx1 and Pax3 cooperate to mediate FGF8 and WNT signals during Xenopus neural crest induction. Developmental cell 267 15691759
2017 PAX3-FOXO1 Establishes Myogenic Super Enhancers and Confers BET Bromodomain Vulnerability. Cancer discovery 262 28446439
2009 Muscle stem cell behavior is modified by microRNA-27 regulation of Pax3 expression. Proceedings of the National Academy of Sciences of the United States of America 255 19666532
2005 Six1 and Six4 homeoproteins are required for Pax3 and Mrf expression during myogenesis in the mouse embryo. Development (Cambridge, England) 249 15788460
2004 Divergent functions of murine Pax3 and Pax7 in limb muscle development. Genes & development 241 15132998
2004 Pax3:Fkhr interferes with embryonic Pax3 and Pax7 function: implications for alveolar rhabdomyosarcoma cell of origin. Genes & development 199 15520281
2015 PAX3 and PAX7 as upstream regulators of myogenesis. Seminars in cell & developmental biology 187 26424495
1999 The Pax3-FKHR oncoprotein is unresponsive to the Pax3-associated repressor hDaxx. The EMBO journal 184 10393185
1999 Pax3 functions in cell survival and in pax7 regulation. Development (Cambridge, England) 150 10079229
1994 Pax-3 contains domains for transcription activation and transcription inhibition. Proceedings of the National Academy of Sciences of the United States of America 141 7809114
2008 PAX3-FOXO1 fusion gene in rhabdomyosarcoma. Cancer letters 140 18457914
2001 Transcription factors in melanocyte development: distinct roles for Pax-3 and Mitf. Mechanisms of development 130 11231058
2001 Pax3 is essential for skeletal myogenesis and the expression of Six1 and Eya2. The Journal of biological chemistry 122 11262400
2006 Signals and myogenic regulatory factors restrict pax3 and pax7 expression to dermomyotome-like tissue in zebrafish. Developmental biology 120 17094960
2012 Mutations in MITF and PAX3 cause "splashed white" and other white spotting phenotypes in horses. PLoS genetics 116 22511888
2008 Pigmentation PAX-ways: the role of Pax3 in melanogenesis, melanocyte stem cell maintenance, and disease. Pigment cell & melanoma research 113 18983540
1993 Analysis of the Pax-3 gene in the mouse mutant splotch. Genomics 112 8406486
1994 Molecular basis of splotch and Waardenburg Pax-3 mutations. Proceedings of the National Academy of Sciences of the United States of America 111 7909605
2013 Alveolar rhabdomyosarcoma-associated PAX3-FOXO1 promotes tumorigenesis via Hippo pathway suppression. The Journal of clinical investigation 110 24334454
1998 Pax-3 is necessary but not sufficient for lbx1 expression in myogenic precursor cells of the limb. Mechanisms of development 106 9622616
1996 The hybrid PAX3-FKHR fusion protein of alveolar rhabdomyosarcoma transforms fibroblasts in culture. Proceedings of the National Academy of Sciences of the United States of America 103 8790412
2001 PAX3 is expressed in human melanomas and contributes to tumor cell survival. Cancer research 102 11221862
1999 Competence, specification and induction of Pax-3 in the trigeminal placode. Development (Cambridge, England) 100 9834194
2005 Transcriptional activity of Pax3 is co-activated by TAZ. Biochemical and biophysical research communications 98 16300735
2013 Pax3 and Zic1 drive induction and differentiation of multipotent, migratory, and functional neural crest in Xenopus embryos. Proceedings of the National Academy of Sciences of the United States of America 94 23509273
2012 Pax3/7BP is a Pax7- and Pax3-binding protein that regulates the proliferation of muscle precursor cells by an epigenetic mechanism. Cell stem cell 88 22862948
2007 Effects of PAX3-FKHR on malignant phenotypes in alveolar rhabdomyosarcoma. Biochemical and biophysical research communications 86 18022385
2006 Pax3 and Pax7 expression and regulation in the avian embryo. Anatomy and embryology 85 16506066
2010 A Pax3/Dmrt2/Myf5 regulatory cascade functions at the onset of myogenesis. PLoS genetics 81 20368965
2018 The expression and function of PAX3 in development and disease. Gene 80 29730428
2006 Comparative expression analysis of Pax3 and Pax7 during mouse myogenesis. The International journal of developmental biology 80 16323077
2008 Persistent expression of Pax3 in the neural crest causes cleft palate and defective osteogenesis in mice. The Journal of clinical investigation 70 18483623
1999 PAX3 gene structure, alternative splicing and evolution. Gene 68 10521655
1992 A frameshift mutation in the HuP2 paired domain of the probable human homolog of murine Pax-3 is responsible for Waardenburg syndrome type 1 in an Indonesian family. Human molecular genetics 68 1303193
1999 Predominant expression of alternative PAX3 and PAX7 forms in myogenic and neural tumor cell lines. Cancer research 67 10554014
2019 Alternative polyadenylation of Pax3 controls muscle stem cell fate and muscle function. Science (New York, N.Y.) 65 31699935
2013 β-catenin regulates Pax3 and Cdx2 for caudal neural tube closure and elongation. Development (Cambridge, England) 65 24284205
2001 PAX3-FKHR induces morphological change and enhances cellular proliferation and invasion in rhabdomyosarcoma. The American journal of pathology 65 11549601
2018 Therapeutic Approaches Targeting PAX3-FOXO1 and Its Regulatory and Transcriptional Pathways in Rhabdomyosarcoma. Molecules (Basel, Switzerland) 59 30373318
2010 PAX3 expression in normal skin melanocytes and melanocytic lesions (naevi and melanomas). PloS one 58 20421967
2008 Regulation of skeletal muscle stem cell behavior by Pax3 and Pax7. Cold Spring Harbor symposia on quantitative biology 57 19022756
2010 Low-intensity laser irradiation stimulates wound healing in diabetic wounded fibroblast cells (WS1). Diabetes technology & therapeutics 56 21128844
1994 Mutations in PAX3 associated with Waardenburg syndrome type I. Human mutation 56 8019556
2007 Segmental expression of Pax3/7 and engrailed homologs in tardigrade development. Development genes and evolution 54 17516081
1999 Expression pattern of PAX3 and PAX6 genes during human embryogenesis. The International journal of developmental biology 52 10610023
2012 Regulation of Schwann cell differentiation and proliferation by the Pax-3 transcription factor. Glia 51 22532290
2013 Identification of Pax3 and Zic1 targets in the developing neural crest. Developmental biology 48 24360908
1998 The role of Pax3 and Pax7 in development and cancer. Critical reviews in oncogenesis 48 9973247
1994 Pax-3-DNA interaction: flexibility in the DNA binding and induction of DNA conformational changes by paired domains. Nucleic acids research 48 8065927
2015 Pax3 and Pax7 play essential safeguard functions against environmental stress-induced birth defects. Developmental cell 47 25800090
1991 Waardenburg syndrome (WS): the analysis of a single family with a WS1 mutation showing linkage to RFLP markers on human chromosome 2q. American journal of human genetics 47 1670751
2019 Aurora A Kinase Inhibition Destabilizes PAX3-FOXO1 and MYCN and Synergizes with Navitoclax to Induce Rhabdomyosarcoma Cell Death. Cancer research 46 31888889
2018 PAX3-FOXO1 drives miR-486-5p and represses miR-221 contributing to pathogenesis of alveolar rhabdomyosarcoma. Oncogene 46 29367756
2012 Genetic and physical interaction of Meis2, Pax3 and Pax7 during dorsal midbrain development. BMC developmental biology 46 22390724
2018 PAX3-FOXO1 transgenic zebrafish models identify HES3 as a mediator of rhabdomyosarcoma tumorigenesis. eLife 45 29869612
2017 PAX3-FOXO1: Zooming in on an "undruggable" target. Seminars in cancer biology 45 29146205
2014 PLK1 phosphorylates PAX3-FOXO1, the inhibition of which triggers regression of alveolar Rhabdomyosarcoma. Cancer research 44 25398439
2008 PAX3 expression in primary melanomas and nevi. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 44 18327212
2013 Expression of genes in normal fibroblast cells (WS1) in response to irradiation at 660nm. Journal of photochemistry and photobiology. B, Biology 43 24333762
2011 PAX3-FOXO1 induces cannabinoid receptor 1 to enhance cell invasion and metastasis. Cancer research 43 22037868
2010 PAX3 and SOX10 activate MET receptor expression in melanoma. Pigment cell & melanoma research 43 20067553
2007 PAX3-FOXO1 controls expression of the p57Kip2 cell-cycle regulator through degradation of EGR1. Proceedings of the National Academy of Sciences of the United States of America 43 17986608
1999 Expression of genes for microphthalmia isoforms, Pax3 and MSG1, in human melanomas. Cellular and molecular biology (Noisy-le-Grand, France) 43 10644012
2019 Pax3 cooperates with Ldb1 to direct local chromosome architecture during myogenic lineage specification. Nature communications 42 31127120
2012 A phosphatidylinositol 3-kinase-Pax3 axis regulates Brn-2 expression in melanoma. Molecular and cellular biology 42 22988297
2010 Role of Pax3 acetylation in the regulation of Hes1 and Neurog2. Molecular biology of the cell 41 21169561
2002 The expression of the developmentally regulated proto-oncogene Pax-3 is modulated by N-Myc. The Journal of biological chemistry 39 12095979
2008 PAX3/7 expression coincides with MyoD during chronic skeletal muscle overload. Muscle & nerve 38 18508329
2022 Targeting KDM4 for treating PAX3-FOXO1-driven alveolar rhabdomyosarcoma. Science translational medicine 36 35857643
2011 Differential PAX3 functions in normal skin melanocytes and melanoma cells. Biochemical and biophysical research communications 36 21802410
2010 Taf1 regulates Pax3 protein by monoubiquitination in skeletal muscle progenitors. Molecular cell 35 21145483
2002 Pax3 induces cell aggregation and regulates phenotypic mesenchymal-epithelial interconversion. Journal of cell science 35 11861759
2018 Expression of PAX3 Distinguishes Biphenotypic Sinonasal Sarcoma From Histologic Mimics. The American journal of surgical pathology 34 29863547
2018 A PAX3/BRN2 rheostat controls the dynamics of BRAF mediated MITF regulation in MITFhigh /AXLlow melanoma. Pigment cell & melanoma research 34 30277012
2014 PAX3 and ETS1 synergistically activate MET expression in melanoma cells. Oncogene 34 25531327
2001 Homeodomain proteins Mox1 and Mox2 associate with Pax1 and Pax3 transcription factors. FEBS letters 34 11423130
2022 PAX3-FOXO1 coordinates enhancer architecture, eRNA transcription, and RNA polymerase pause release at select gene targets. Molecular cell 33 36395771
2019 Cellular mechanisms underlying Pax3-related neural tube defects and their prevention by folic acid. Disease models & mechanisms 33 31636139
2016 PAX3-FOXO1A Expression in Rhabdomyosarcoma Is Driven by the Targetable Nuclear Receptor NR4A1. Cancer research 31 27864345
1998 Normal and rearranged PAX3 expression in human rhabdomyosarcoma. Cancer genetics and cytogenetics 31 9546061
2018 miR-27b regulates myogenic proliferation and differentiation by targeting Pax3 in goat. Scientific reports 30 29500394
2009 PAX3 across the spectrum: from melanoblast to melanoma. Critical reviews in biochemistry and molecular biology 30 19401874
2023 PAX3-FOXO1 dictates myogenic reprogramming and rhabdomyosarcoma identity in endothelial progenitors. Nature communications 29 37968277
2013 MITF and PAX3 Play Distinct Roles in Melanoma Cell Migration; Outline of a "Genetic Switch" Theory Involving MITF and PAX3 in Proliferative and Invasive Phenotypes of Melanoma. Frontiers in oncology 29 24062982
2012 GSK-3 promotes cell survival, growth, and PAX3 levels in human melanoma cells. Molecular cancer research : MCR 29 22679108
2007 PAX3 and PAX3-FKHR promote rhabdomyosarcoma cell survival through downregulation of PTEN. Cancer letters 29 17350164
1993 Fluorescence in situ hybridization mapping of 25 markers on distal human chromosome 2q surrounding the human Waardenburg syndrome, type I (WS1) locus (PAX3 gene). Genomics 29 8486353
2003 Aberrant PAX3 and PAX7 expression. A link to the metastatic potential of embryonal rhabdomyosarcoma and cutaneous malignant melanoma? Histology and histopathology 28 12647804
1998 Reduced expression of pax-3 is associated with overexpression of cdc46 in the mouse embryo. Development genes and evolution 28 9601985
2020 An OTX2-PAX3 signaling axis regulates Group 3 medulloblastoma cell fate. Nature communications 27 32686664
2017 Apoptosis, Expression of PAX3 and P53, and Caspase Signal in Fetuses with Neural Tube Defects. Birth defects research 27 28786179
2014 Pax3 expression enhances PDGF-B-induced brainstem gliomagenesis and characterizes a subset of brainstem glioma. Acta neuropathologica communications 27 25330836

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