Affinage

TFAP2A

Transcription factor AP-2-alpha · UniProt P05549

Length
437 aa
Mass
48.1 kDa
Annotated
2026-06-10
100 papers in source corpus 39 papers cited in narrative 38 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TFAP2A (AP-2alpha) is a sequence-specific transcription factor that orchestrates neural crest development, craniofacial and organ morphogenesis, and lineage specification, with both activator and repressor functions (PMID:8622765, PMID:14985255, PMID:28249010). It is expressed in neural crest cells and their derivatives during embryogenesis (PMID:1989904), and its loss causes failure of cranial neural tube closure, craniofacial dysmorphogenesis, and increased neural crest apoptosis in mouse and zebrafish (PMID:8622765, PMID:14985255). Mechanistically, TFAP2A acts as a pioneer factor that remodels chromatin in a partner-specific manner: TFAP2A/C heterodimers drive neural plate border induction while TFAP2A/B heterodimers reorganize the epigenome for neural crest specification (PMID:31848212), and in melanocytes it (with TFAP2C) opens enhancers to facilitate MITF binding and co-operatively activate pigmentation genes such as TRPM1 (PMID:28249010, PMID:35580127). As an activator it binds and trans-activates target promoters including DBH, FXN (frataxin), and ERBB2, recruiting the CITED2 adaptor and p300/CBP co-activators (PMID:7616204, PMID:11694877, PMID:20808827, PMID:21375726); as a repressor it recruits the H3K9 methyltransferases Suv39h1 and G9a to deposit H3K9me2/me3 and silence targets such as C/EBPalpha, and directly represses EGFR, ZEB2, and Mn-SOD (PMID:24732798, PMID:16449191, PMID:28412966, PMID:11278550). Its DNA-binding activity is redox-regulated through oxidation of conserved cysteines (PMID:9712692), and SUMOylation at lysine 10 via UBC9 reduces its transactivation potential (PMID:12072434). In cancer, TFAP2A controls cell cycle S-phase progression through transcriptional activation of TGM2 and downstream AKT signaling (PMID:33753551), is epigenetically silenced in melanoma and glioma by CREB/E2F-1 and EZH2/DNMT1-mediated mechanisms (PMID:20805990, PMID:37330579), and partners with NuRD and YAP1/TEAD complexes to regulate target gene chromatin states (PMID:34210752, PMID:38219531). Human TFAP2A mutations, predominantly in the DNA-binding domain, cause Branchio-Oculo-Facial Syndrome, reducing transactivation and conferring dominant-negative activity (PMID:23578821).

Mechanistic history

Synthesis pass · year-by-year structured walk · 23 steps
  1. 1991 Medium

    Established where TFAP2A is deployed in the embryo, anchoring the hypothesis that it regulates neural crest and craniofacial programs.

    Evidence RNA in situ hybridization and RNase protection across mouse embryonic stages E8.5–E12.5

    PMID:1989904

    Open questions at the time
    • Expression alone does not establish function
    • No direct target genes identified
  2. 1996 High

    Demonstrated that TFAP2A is essential for neural tube closure and craniofacial development, converting an expression correlation into a causal developmental requirement.

    Evidence Targeted gene disruption in mouse with histology and in situ hybridization

    PMID:8622765

    Open questions at the time
    • Molecular targets driving the phenotype not defined
    • Cell-autonomy not resolved
  3. 1995 Medium

    Identified the first direct activation target and DNA-binding mechanism, showing TFAP2A trans-activates promoters through defined AP-2 sites.

    Evidence DNase footprinting, site-directed mutagenesis, and reporter assays on the DBH promoter; reporter/affinity work on c-erbB-2

    PMID:7616204 PMID:8895516

    Open questions at the time
    • Co-activator requirements not yet defined
    • In vivo relevance of these targets untested
  4. 1998 Medium

    Revealed that TFAP2A activity is post-translationally controlled, with DNA binding reversibly inhibited by cysteine oxidation, linking its function to cellular redox state.

    Evidence In vitro EMSA and non-reducing immunoblot with recombinant protein and oxidizing/reducing agents

    PMID:9712692

    Open questions at the time
    • In vitro reconstitution only
    • Physiological relevance of redox regulation in vivo unestablished
  5. 1998 Medium

    Distinguished cell-autonomous from non-cell-autonomous requirements, showing TFAP2A influences eye and limb patterning at the tissue level beyond its own lineage.

    Evidence Chimeric mouse analysis combining wild-type and AP-2-null cells

    PMID:9811866

    Open questions at the time
    • Signaling intermediaries mediating non-autonomous effects unknown
  6. 2001 High

    Identified CITED2 as a required co-activator, providing the first molecular partner explaining how TFAP2A activates transcription during development.

    Evidence Co-IP, reporter rescue in Cited2-/- fibroblasts, and knockout mouse phenotype overlap

    PMID:11694877

    Open questions at the time
    • Direct contact with general co-activators not mapped here
    • Target-specific recruitment unresolved
  7. 2002 High

    Defined SUMOylation at lysine 10 via UBC9 as a negative regulator of TFAP2A transactivation, establishing a covalent switch on its activity.

    Evidence Yeast two-hybrid, in vivo SUMOylation assay, K10 mutagenesis, reporter assays

    PMID:12072434

    Open questions at the time
    • SUMO E3 ligase not identified
    • Genomic targets affected by SUMOylation undefined
  8. 2002 Medium

    Established a conserved developmental fate-decision role, with AP-2alpha required for epidermal versus neural ectoderm choice.

    Evidence Gain- and loss-of-function in Xenopus with epidermal/neural gene readouts

    PMID:11969261

    Open questions at the time
    • Direct targets in epidermal determination not defined
  9. 2004 High

    Pinpointed the neural crest survival and craniofacial patterning role to the DNA-binding/dimerization domain and a downstream target network (sox9a, dlx2, hoxa2/b2), separating differentiation from specification and migration.

    Evidence Zebrafish positional cloning, marker in situ hybridization, apoptosis assays, and cell fate tracing in mont blanc/lockjaw mutants

    PMID:14699580 PMID:14985255

    Open questions at the time
    • Which targets are direct vs indirect not fully resolved
    • Mechanism of cell-type-specific apoptosis unknown
  10. 2006 High

    Defined TFAP2A as a direct transcriptional repressor in differentiated tissue, restraining EGFR and downstream PI3K/Akt signaling in epidermis.

    Evidence Conditional epidermal knockout, ChIP, and promoter reporter assays

    PMID:16449191

    Open questions at the time
    • Co-repressor machinery at EGFR not identified in this study
  11. 2010 Medium

    Expanded the direct target repertoire across activation (FXN) and repression (Mn-SOD, CDKN1A, TBX20), establishing TFAP2A as a bifunctional regulator engaging promoters context-dependently.

    Evidence ChIP, EMSA, promoter mutagenesis, reporter assays, and overexpression across cell and patient models

    PMID:11278550 PMID:18275040 PMID:20808827 PMID:21084835

    Open questions at the time
    • Determinants of activator vs repressor mode at a given promoter unclear
    • Co-factors mediating each mode not defined here
  12. 2010 Medium

    Showed TFAP2A is epigenetically silenced in melanoma via CREB/E2F-1, linking its loss to metastatic gene programs and p21/MCAM regulation.

    Evidence shRNA silencing of CREB, PKA inhibition, promoter ChIP, and rescue in melanoma cells

    PMID:20805990

    Open questions at the time
    • Whether CREB-driven silencing initiates or maintains melanoma progression untested
  13. 2012 Medium

    Established TFAP2A as a direct upstream activator of sox10 and traced the origin of this regulatory link to the evolutionary emergence of the neural crest.

    Evidence Zebrafish rescue with ortholog series, in situ hybridization, comparative enhancer analysis

    PMID:22241841

    Open questions at the time
    • Direct enhancer contacts in vertebrates not mapped at base-pair resolution
  14. 2014 High

    Reconstituted the repressive chromatin mechanism, showing TFAP2A recruits G9a and Suv39h1 to deposit H3K9me2/me3 and silence target genes such as C/EBPalpha.

    Evidence Co-IP, ChIP for H3K9me2/me3, and knockdown/overexpression in 3T3-L1 preadipocytes

    PMID:24732798

    Open questions at the time
    • Whether this complex operates at other repressed targets not tested here
  15. 2015 Medium

    Placed TFAP2A in defined transcriptional cascades for retinal amacrine cell fate and inner ear neurogenesis, showing it integrates signaling pathways during organ development.

    Evidence RNA-seq, epistasis, gain/loss-of-function in mouse retina and zebrafish inner ear with genetic mosaics and inhibitors

    PMID:25781991 PMID:25966682

    Open questions at the time
    • Direct vs indirect targets within these cascades not fully resolved
  16. 2017 High

    Defined TFAP2A (with TFAP2B) as the inducer of the melanocyte lineage and demonstrated genomic co-occupancy with MITF at pigmentation enhancers.

    Evidence Conditional double knockout (Wnt1-Cre), ChIP-seq, reporter site-deletion, and zebrafish genetic interaction

    PMID:28249010

    Open questions at the time
    • Mechanism of MITF facilitation not yet defined at chromatin level in this study
  17. 2017 Medium

    Added ZEB2 to the directly repressed targets, positioning TFAP2A within the core EMT gene regulatory network.

    Evidence EMSA and ChIP with knockdown/overexpression in the NMuMG EMT model

    PMID:28412966

    Open questions at the time
    • Single EMT model; broader EMT relevance untested
  18. 2019 High

    Established TFAP2A as a stage-specific pioneer factor, with distinct heterodimer partners directing chromatin opening at successive neural crest developmental programs.

    Evidence ChIP-seq and ATAC-seq with partner-specific analysis in Xenopus

    PMID:31848212

    Open questions at the time
    • Structural basis of partner-dependent pioneering not resolved
    • How the A/C-to-A/B switch is timed unknown
  19. 2019 Medium

    Embedded TFAP2A in tissue-specific genetic circuits, including a distal nephron autoregulatory loop with kctd15a/b and an Irf6-Tfap2a-Grhl3 neurulation/orofacial pathway.

    Evidence Forward genetic screen, knockdown/overexpression, epistasis in zebrafish pronephros and mouse models

    PMID:30689861 PMID:31160420

    Open questions at the time
    • Direct targets within each circuit incompletely defined
  20. 2020 High

    Revealed context-dependent oncogenic roles, with TFAP2A activating EZH2/E2F programs via NuRD interaction and driving S-phase progression through TGM2/AKT.

    Evidence BioID proximity labeling, ChIP, CRISPR/shRNA knockout, ChIP-seq, FACS cell cycle and drug sensitivity assays in melanoma and colon cancer

    PMID:33753551 PMID:34210752

    Open questions at the time
    • How TFAP2A switches between NuRD-repressive and activating outputs unclear
    • Direct vs indirect EZH2/E2F regulation not fully separated
  21. 2020 Medium

    Extended TFAP2A function to immune modulation and protein-level regulation, repressing CD274/PD-L1 transcription, promoting its endocytosis, and activating Elk-1 in lactate-stimulated tumor-associated macrophages.

    Evidence Reporter assays, ChIP/EMSA, flow cytometry, endocytosis assays, and macrophage-specific knockout mice

    PMID:32296015 PMID:37330579

    Open questions at the time
    • Mechanism linking nuclear translocation signal to PD-L1 protein trafficking unclear
  22. 2013 High

    Connected TFAP2A directly to human disease, showing Branchio-Oculo-Facial Syndrome mutations cluster in the DNA-binding domain and impair transactivation while exerting dominant-negative effects.

    Evidence Systematic functional analysis of BOFS mutants by EMSA, reporter assays, and subcellular localization

    PMID:23578821

    Open questions at the time
    • Genotype-phenotype correlation for variable BOFS features not resolved
  23. 2024 Medium

    Identified a YAP1/TEAD-TFAP2A complex assembled by SRC-mediated YAP1 phosphorylation that drives trastuzumab-resistance genes, defining a druggable TFAP2A-containing complex.

    Evidence Co-IP, ChIP-seq, reporter assays, SRC inhibition, and drug sensitivity in HER2+ breast cancer models

    PMID:38219531

    Open questions at the time
    • Structural details of the YTT complex not resolved
    • Generalizability beyond HER2+ breast cancer untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved what molecular determinants dictate TFAP2A's switch between activator and repressor modes at a given locus, and how dimer-partner choice, SUMOylation, redox state, and co-factor recruitment are integrated to control its pioneer and lineage-specifying functions.
  • No unified model linking post-translational state to activator/repressor choice
  • Structural basis of partner-specific pioneering unknown
  • Hierarchy among co-activator (CITED2/p300) and co-repressor (G9a/Suv39h1/NuRD) recruitment unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 9 GO:0003677 DNA binding 7
Localization
GO:0000228 nuclear chromosome 2 GO:0005634 nucleus 2
Pathway
R-HSA-74160 Gene expression (Transcription) 5 R-HSA-1266738 Developmental Biology 4 R-HSA-1643685 Disease 3 R-HSA-4839726 Chromatin organization 3 R-HSA-1640170 Cell Cycle 2
Partners
CITED2G9A (EHMT2)MITFSUV39H1TFAP2BTFAP2CUBC9YAP1
Complex memberships
NuRD complex (interactor)YAP1/TEAD-TFAP2A (YTT) complex

Evidence

Reading pass · 38 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1991 TFAP2A mRNA is expressed in neural crest cells and their major derivatives (cranial and spinal sensory ganglia, facial mesenchyme) during mouse embryogenesis between E8.5 and E12.5, as determined by RNA in situ hybridization, consistent with a transcriptional regulatory role in peripheral nervous system and craniofacial morphogenesis. RNA in situ hybridization, RNase protection assay Genes & development Medium 1989904
1996 Targeted disruption of the mouse AP-2 (Tcfap2a) gene causes perinatal lethality with cranio-abdominoschisis, severe craniofacial dysmorphogenesis, and failure of cranial neural tube closure coinciding with increased apoptosis in the midbrain and first branchial arch; loss of AP-2 does not eliminate expression of twist or Pax-3. Targeted gene disruption (knockout mouse), histology, in situ hybridization Nature High 8622765
1996 AP-2alpha and AP-2gamma (but not AP-2beta) bind to and activate the c-erbB-2 (HER2) promoter as homo- or heterodimers, with AP-2alpha and AP-2gamma being 3–4 times more transcriptionally active than AP-2beta at this promoter. DNA binding assays, reporter gene (transient transfection), protein purification/sequencing Oncogene Medium 8895516
1998 AP-2alpha DNA-binding activity is reversibly inhibited by oxidation of conserved cysteine residues (by diamide or hydrogen peroxide) and restored by reducing agents including thioredoxin, as shown by in vitro DNA-binding and non-reducing immunoblot assays with recombinant human AP-2. In vitro DNA-binding assay (EMSA), non-reducing SDS-PAGE/immunoblot, recombinant protein Biochemical and biophysical research communications Medium 9712692
1998 AP-2 exerts a non-cell-autonomous influence on eye formation and limb patterning (causing major limb duplications) in addition to its cell-autonomous requirements in the neural tube and body wall, as revealed by chimeric mice composed of wild-type and AP-2-null cells. Chimeric mouse analysis (wild-type/AP-2-null) Proceedings of the National Academy of Sciences of the United States of America Medium 9811866
1995 AP-2 directly trans-activates the dopamine beta-hydroxylase (DBH) gene promoter by binding to an AP-2 site at -136 to -115; mutation of this site reduces basal reporter expression 7-fold, and co-transfection of AP-2 expression vector stimulates reporter expression 6-fold. DNase footprinting, reporter gene assay (co-transfection), site-directed mutagenesis Journal of neurochemistry Medium 7616204
1999 AP-2 transcription factors (all three members) repress Mn-SOD promoter activity in a DNA-binding-dependent manner; a dominant-negative AP-2 (AP-2B) that cannot bind DNA relieves this repression; AP-2alpha and AP-2gamma are more active repressors than AP-2beta. Reporter gene co-transfection assay, dominant-negative AP-2 expression The Journal of biological chemistry Medium 11278550
2001 CITED2 directly interacts with and co-activates all TFAP2 isoforms; TFAP2 transactivation is defective in Cited2-/- embryonic fibroblasts and rescued by ectopic CITED2 expression, establishing CITED2 as a TFAP2 co-activator required for normal neural crest, neural tube, and cardiac development. Co-immunoprecipitation, reporter gene assay in Cited2-/- fibroblasts, rescue by ectopic expression, knockout mouse phenotype Nature genetics High 11694877
2002 TFAP2A interacts with the SUMO-conjugating enzyme UBC9 (identified by two-hybrid screen) via its C-terminal DNA-binding/dimerization domain; endogenous AP-2 is SUMOylated in mammalian cells at conserved lysine 10, and SUMOylation decreases TFAP2A transcriptional activation potential. Yeast two-hybrid screen, in vivo SUMOylation assay, site-directed mutagenesis (K10), reporter gene (transient transfection) The Journal of biological chemistry High 12072434
2002 XAP-2 (Xenopus AP-2alpha) is a critical regulator of epidermal determination; ectopic XAP-2 expression restores epidermal gene transcription in neuralized ectoderm, while loss-of-function via antisense oligonucleotides or antimorphic derivatives causes loss of epidermal and gain of neural gene expression, and results in gastrulation failure. Ectopic overexpression in Xenopus embryo, antisense oligonucleotide knockdown, dominant-negative (antimorphic) expression Developmental biology Medium 11969261
2004 In zebrafish, tfap2a (mont blanc/mob) is required for the normal developmental program and survival of neural crest cells in pharyngeal arches 2–7 and trunk; the mutation disrupts the DNA-binding/dimerization domain, abolishes expression of sox9a, wnt5a, dlx2, hoxa2/b2 in craniofacial primordia, and causes apoptosis of a subset of neural crest cells without affecting initial specification or migration. Positional candidate cloning, splice-site mutation characterization, in situ hybridization (neural crest markers), TUNEL/Acridine Orange apoptosis assay, live cell fate tracing Development (Cambridge, England) High 14985255
2004 In zebrafish tfap2a (lockjaw) mutants, defects in hyoid arch cartilage correlate with loss of Hox group 2 gene expression (suggesting homeotic transformation to mandibular fate), and early melanophores fail to develop partly through loss of kit function affecting migration, revealing independent roles for tfap2a in pigment cell specification and Hox-mediated skeletal patterning. Zebrafish mutant analysis, in situ hybridization (Hox genes, pigment markers), genetic interaction with kit Developmental dynamics Medium 14699580
2006 Conditional knockout of AP-2alpha in mouse epidermis causes elevated EGFR expression in differentiating layers, hyperproliferation upon EGF stimulation, and excessive PI3K/Akt activity; chromatin immunoprecipitation and promoter assays identify EGFR as a direct transcriptional target of AP-2alpha repression. Conditional knockout mouse (cre-lox), chromatin immunoprecipitation (ChIP), promoter reporter assay The Journal of cell biology High 16449191
2006 In zebrafish, tfap2a and tfap2c act redundantly in neural crest induction; simultaneous inhibition of both genes utterly prevents neural crest induction, and cell transplant experiments indicate this role is cell-autonomous. Antisense morpholino knockdown, cell transplantation assay, in situ hybridization Developmental biology Medium 17258188
2008 TFAP2 transcription factors are identified as repressors of the TBX20 gene: functional TFAP2 binding sites were found within the human TBX20 core promoter, and TFAP2 repressed TBX20 expression in vitro (reporter assay) and in vivo (ChIP and cardiac biopsy analysis showing decreased TFAP2C in TOF patients). Reporter gene assay, ChIP, cardiac biopsy expression analysis Journal of cellular biochemistry Medium 18275040
2010 AP-2alpha (TFAP2A) directly binds to two regions of the CDKN1A (p21cip) promoter—a proximal AP-2 site and an upstream region near the p53 binding site—as shown by ChIP; mutation of the proximal AP-2 site reduces p53-independent p21 expression, and this interaction pattern changes temporally post-induction. ChIP, site-directed mutagenesis of promoter, reporter gene assay Cell cycle (Georgetown, Tex.) Medium 21084835
2010 In AP-2alpha knockout mice, loss of AP-2alpha in multiple craniofacial tissues disrupts optic cup patterning and optic stalk morphogenesis; ectopic neural retina replaces RPE, coloboma and optic stalk extension failure occur, associated with increased Sonic Hedgehog signaling and expanded PAX2-positive optic stalk-like tissue in the optic cup. AP-2alpha knockout mouse, in situ hybridization, immunofluorescence, Shh pathway analysis Human molecular genetics Medium 20150232
2010 TFAP2 and SRF bind directly to FXN (frataxin) promoter sequences as shown by ChIP and EMSA; mutagenesis of these binding sites reduces FXN promoter activity; overexpression of TFAP2 increases frataxin mRNA and protein levels in HEK293 and SH-SY5Y cells and in Friedreich ataxia patient lymphoblasts. ChIP, EMSA, luciferase reporter mutagenesis, overexpression in cell lines and patient cells PloS one Medium 20808827
2010 CREB suppresses AP-2alpha (TFAP2A) expression in metastatic melanoma via a dual mechanism: direct binding of CREB to the AP-2alpha promoter and CREB-induced upregulation of E2F-1, both of which repress AP-2alpha; silencing CREB restores AP-2alpha expression and upregulates p21Waf1 and downregulates MCAM/MUC18. shRNA silencing of CREB, PKA inhibitor treatment, promoter ChIP, rescue expression PloS one Medium 20805990
2012 Tfap2a directly activates sox10 expression in neural crest cells; zebrafish rescue experiments (depleting endogenous tfap2a and replacing with various Tfap2 orthologs) show this regulatory interaction arose with the emergence of the neural crest, as AP2 and SoxE are not co-expressed in amphioxus and neural crest enhancers are absent proximal to amphioxus soxE. Zebrafish rescue with ortholog series, in situ hybridization, enhancer analysis Development (Cambridge, England) Medium 22241841
2013 TFAP2A mutations causing Branchio-Oculo-Facial Syndrome (BOFS) localize predominantly to the DNA-binding domain; functional analysis shows that individual mutations reduce DNA binding to different extents, yet all show significantly reduced transcriptional activity; several mutants show altered nuclear:cytoplasmic distribution and can exert dominant-negative activity on wild-type AP-2alpha. Reporter gene assay (transcriptional activity), EMSA (DNA binding), subcellular localization (immunofluorescence), dominant-negative assay Human molecular genetics High 23578821
2014 AP-2alpha recruits the histone H3K9 methyltransferases Suv39h1 and G9a to the C/EBPalpha promoter; G9a deposits H3K9me2 (substrate for Suv39h1) and Suv39h1 deposits H3K9me3, together mediating AP-2alpha-dependent transcriptional repression of C/EBPalpha to inhibit adipogenesis. Co-immunoprecipitation (AP-2alpha with Suv39h1 and G9a), ChIP (H3K9me2/me3 at C/EBPalpha promoter), knockdown/overexpression in 3T3-L1 preadipocytes Molecular and cellular biology High 24732798
2015 Tfap2a and Tfap2b act downstream of Ptf1a to promote amacrine cell differentiation in the mouse retina; RNA-seq shows Tfap2a/b expression is dramatically reduced in Ptf1a-null retinas; overexpression promotes glycinergic/GABAergic amacrine cells at the expense of photoreceptors, and simultaneous knockdown has the opposite effect, placing Tfap2a/b in the Foxn4/RORβ1–Ptf1a–Tfap2a/b cascade. RNA-seq, immunolabeling, overexpression, simultaneous knockdown (siRNA/shRNA), retinal explant analysis Molecular brain Medium 25966682
2015 In zebrafish inner ear, Tfap2a coordinates BMP7a, Fgf, and Notch signaling to regulate statoacoustic ganglion (SAG) neurogenesis; Tfap2a acts non-cell-autonomously to activate Bmp7a expression, which in turn inhibits both Fgf and Notch; blocking Bmp signaling reverses the effects of Tfap2a overexpression. Loss-of-function/gain-of-function in zebrafish, genetic mosaic analysis, pharmacological inhibitors, in situ hybridization PLoS genetics Medium 25781991
2017 TFAP2A paralogs (TFAP2A and TFAP2B) in mouse neural crest are required for induction of the melanocyte lineage; Wnt1-Cre deletion of both Tfap2a and Tfap2b almost completely eliminates melanocytes but retains sensory ganglia; ChIP-seq shows TFAP2A co-occupies regulatory elements with MITF at pigmentation genes (e.g., TRPM1 promoter), and deletion of TFAP2A binding sites abolishes TRPM1 promoter activity. Conditional double knockout (Wnt1-Cre), ChIP-seq, luciferase reporter with site deletion, zebrafish genetic interaction PLoS genetics High 28249010
2017 TFAP2A functions as a repressor of ZEB2 by directly binding the ZEB2 promoter, as demonstrated by EMSA and ChIP in NMuMG cells undergoing EMT; TFAP2A is a component of the core EMT gene regulatory network. EMSA, ChIP, overexpression and endogenous knockdown analysis in NMuMG EMT model Biology direct Medium 28412966
2018 TFAP2 family members mediate Wnt3a-induced lipid droplet biogenesis; TFAP2 knockdown prevents Wnt-induced lipid droplet formation, identifying TFAP2 transcription factors as regulators of lipid droplet biogenesis downstream of Wnt signaling and independent of canonical TCF/LEF factors. RNAi knockdown, lipid droplet quantification (imaging), reporter assays eLife Medium 30256193
2019 TFAP2A acts as a pioneer factor that activates distinct sets of genomic regions at different stages of neural crest development; TFAP2A/C heterodimers activate neural plate border induction programs during gastrula stages, while TFAP2A/B heterodimers reorganize the epigenomic landscape during neurulation to promote neural crest specification, representing a stage-specific molecular switch. ChIP-seq (genomic occupancy), ATAC-seq (chromatin accessibility), in vivo Xenopus model, dimerization partner analysis Genome research High 31848212
2019 In the zebrafish pronephros, tfap2a acts downstream of irx3b (a distal lineage transcription factor) to activate a gene regulatory circuit comprising tfap2b, irx1a, and solute transporter genes (slc12a1, kcnj1a.1, stc1) that dictate distal nephron segment identity; kctd15a/b repress Tfap2a activity, and tfap2a reciprocally promotes kctd15a/b transcription, forming an autoregulatory feedback circuit. Forward genetic screen (zebrafish), morpholino knockdown, overexpression, in situ hybridization, epistasis analysis Development (Cambridge, England) Medium 31160420 33028614
2019 AP-2alpha directly binds the Nanog gene regulatory region (shown by EMSA and luciferase reporter assay) and reduces Nanog, Sox2, and CD133 expression; AP-2alpha also indirectly downregulates Nanog by inhibiting the IL6/JAK2/STAT3 signaling pathway, thereby reducing MGMT and PD-L1 expression and suppressing glioma stem cell self-renewal. Luciferase reporter assay, EMSA, Western blot, sphere-formation assay, xenograft model Theranostics Medium 31534499
2019 Over-expression of the Tfap2a-Irf6-Grhl3 genetic pathway is conserved in neurulation: over-expression of Irf6 causes exencephaly by suppressing Tfap2a and Grhl3 expression, while loss of Irf6 reduces Tfap2a and Grhl3 in tail tissues; Tfap2a and Grhl3 are thus epistatic to Irf6 in this pathway controlling both neural tube closure and orofacial development. Mouse overexpression and loss-of-function models, in situ hybridization, sequencing of human neural tube defect samples Human molecular genetics Medium 30689861
2020 In melanoma, AP-2alpha (TFAP2A) drives metastasis by transcriptionally activating EZH2 and other E2F pathway genes; BioID screen reveals AP-2alpha interacts with members of the NuRD complex; loss of AP-2alpha removes activating chromatin marks from EZH2 and E2F target gene promoters through NuRD-mediated repression; tazemetostat (EZH2 inhibitor) efficacy is AP-2alpha-dependent. BioID proximity labeling screen, ChIP (histone marks), CRISPR/shRNA knockout, drug sensitivity assay, single-cell RNA-seq Cancer research Medium 34210752
2020 AP-2alpha (TFAP2A) binds directly to the CD274 (PD-L1) promoter and inhibits its transcriptional activity; AP-2alpha also enhances endocytosis and degradation of PD-L1 protein; AP-2alpha gene is epigenetically silenced in glioma by an EZH2/H3K27Me3/DNMT1 complex-mediated methylation mechanism. Reporter gene assay, ChIP (AP-2alpha on CD274 promoter), flow cytometry (PD-L1 surface levels), endocytosis assay, bisulfite sequencing/ChIP for H3K27me3/DNMT1 Cell death & disease Medium 37330579
2021 AP-2alpha (TFAP2A) drives cell cycle S-phase progression in colon cancer through transcriptional activation of TGM2, which in turn activates AKT phosphorylation; CRISPR/shRNA knockout of TFAP2A delays S-phase to G2-M progression and decreases pAKT, mediated through TGM2; loss of AP-2alpha also induces resistance to PI3K inhibitor buparlisib. CRISPR-Cas9 and shRNA knockout, ChIP-seq, RNA-seq, FACS cell cycle analysis, Premo FUCCI cell cycle reporter, AKT phosphorylation assay, xenograft Molecular cancer research High 33753551
2022 TFAP2 paralogs (TFAP2A and TFAP2C) are required for MITF binding and chromatin accessibility at pigmentation and proliferation gene enhancers in melanoma cells; TFAP2-KO (CRISPR) cells show reduced H3K27Ac and MITF binding at co-occupied enhancers, decreased proliferation, and increased cell adhesion; TFAP2 and MITF co-operatively activate a subset of enhancers with TFAP2 acting upstream to facilitate MITF access. CRISPR knockout, ATAC-seq, ChIP-seq (TFAP2A, MITF, H3K27Ac, H3K27Me3), RNA-seq PLoS genetics High 35580127
2011 Alternative TFAP2A isoforms differ in transcriptional activity: isoforms 1a, 1b, and 1c share a transactivation mechanism recruiting CITED2/4 adaptor proteins and the p300/CBP co-activators, but isoform 1b and 1c are stronger activators of the ERBB2 promoter; only isoform 1a can repress transcription, and this repressor activity requires an intact sumoylation motif in its unique N-terminus. Reporter gene assay, isoform-specific antibody characterization, isoform expression in breast cell lines and tumors Breast cancer research Medium 21375726
2024 SRC-mediated tyrosine phosphorylation of YAP1 facilitates YAP1 interaction with TFAP2A, forming a YAP1/TEAD-TFAP2A (YTT) complex that co-occupies regulatory regions of trastuzumab resistance genes (EGFR, HER2, H19, CTGF) and drives their transcription; disruption of the YTT complex or SRC inhibition sensitizes HER2+ breast cancer cells to trastuzumab. Co-IP (YAP1-TFAP2A interaction), ChIP-seq (YTT complex occupancy), reporter gene assay, SRC inhibition, drug sensitivity assay in vitro and in vivo Drug resistance updates Medium 38219531
2020 Lactate from CRC cells induces nuclear translocation of Ap-2alpha in tumor-associated macrophages (TAMs), where it functions as a transcriptional activator of Elk-1 by binding the conserved element GCCTGC at -1396/-1391 in the mouse Elk-1 promoter; Elk-1 then binds the Sirpα promoter to upregulate Sirpα and suppress TAM phagocytosis. Reporter gene assay, EMSA/ChIP (Ap-2alpha binding to Elk-1 promoter), macrophage-specific knockout mouse, nuclear translocation assay Signal transduction and targeted therapy Medium 32296015

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 Clathrin-mediated endocytosis in AP-2-depleted cells. The Journal of cell biology 564 12952941
1991 Transcription factor AP-2 is expressed in neural crest cell lineages during mouse embryogenesis. Genes & development 564 1989904
1996 Transcription factor AP-2 essential for cranial closure and craniofacial development. Nature 523 8622765
2005 The AP-2 family of transcription factors. Genome biology 361 16420676
1998 AP-2/Eps15 interaction is required for receptor-mediated endocytosis. The Journal of cell biology 310 9490719
2001 Cardiac malformations, adrenal agenesis, neural crest defects and exencephaly in mice lacking Cited2, a new Tfap2 co-activator. Nature genetics 282 11694877
1999 Phosphoinositide-AP-2 interactions required for targeting to plasma membrane clathrin-coated pits. The Journal of cell biology 233 10459011
2001 Disabled-2 colocalizes with the LDLR in clathrin-coated pits and interacts with AP-2. Traffic (Copenhagen, Denmark) 223 11247302
1996 A family of AP-2 proteins regulates c-erbB-2 expression in mammary carcinoma. Oncogene 199 8895516
2009 Critical function of AP-2 gamma/TCFAP2C in mouse embryonic germ cell maintenance. Biology of reproduction 161 19776388
2003 Differential requirements for AP-2 in clathrin-mediated endocytosis. The Journal of cell biology 161 12952931
1998 AP-2-null cells disrupt morphogenesis of the eye, face, and limbs in chimeric mice. Proceedings of the National Academy of Sciences of the United States of America 149 9811866
2006 Stonin 2 is an AP-2-dependent endocytic sorting adaptor for synaptotagmin internalization and recycling. Developmental cell 137 16459302
2004 Neural crest survival and differentiation in zebrafish depends on mont blanc/tfap2a gene function. Development (Cambridge, England) 133 14985255
2010 Roles of AP-2 in clathrin-mediated endocytosis. PloS one 124 20485680
2006 Redundant activities of Tfap2a and Tfap2c are required for neural crest induction and development of other non-neural ectoderm derivatives in zebrafish embryos. Developmental biology 121 17258188
2005 Clathrin adaptor AP-2 is essential for early embryonal development. Molecular and cellular biology 120 16227583
2019 The miR-26a/AP-2α/Nanog signaling axis mediates stem cell self-renewal and temozolomide resistance in glioma. Theranostics 96 31534499
2007 Tfap2 transcription factors in zebrafish neural crest development and ectodermal evolution. Journal of experimental zoology. Part B, Molecular and developmental evolution 93 17724731
1999 AP180 and AP-2 interact directly in a complex that cooperatively assembles clathrin. The Journal of biological chemistry 93 10428863
2001 Gene regulation in melanoma progression by the AP-2 transcription factor. Pigment cell research 91 11310795
2002 Transcription factor AP-2 is an essential and direct regulator of epidermal development in Xenopus. Developmental biology 88 11969261
2017 Tubular clathrin/AP-2 lattices pinch collagen fibers to support 3D cell migration. Science (New York, N.Y.) 86 28619886
2005 The small G-protein Arf6GTP recruits the AP-2 adaptor complex to membranes. The Journal of biological chemistry 86 15802264
2019 Heterodimerization of TFAP2 pioneer factors drives epigenomic remodeling during neural crest specification. Genome research 85 31848212
2006 Functional analysis of AP-2 alpha and mu2 subunits. Molecular biology of the cell 79 17035630
2013 miR-214 coordinates melanoma progression by upregulating ALCAM through TFAP2 and miR-148b downmodulation. Cancer research 78 23667173
1999 Role of AP-2 in tumor growth and metastasis of human melanoma. Cancer metastasis reviews 77 10721491
2006 AP-2alpha: a regulator of EGF receptor signaling and proliferation in skin epidermis. The Journal of cell biology 74 16449191
2002 Transcription factor AP-2 interacts with the SUMO-conjugating enzyme UBC9 and is sumolated in vivo. The Journal of biological chemistry 72 12072434
2017 TFAP2 paralogs regulate melanocyte differentiation in parallel with MITF. PLoS genetics 68 28249010
2009 Reduced TFAP2A function causes variable optic fissure closure and retinal defects and sensitizes eye development to mutations in other morphogenetic regulators. Human genetics 66 19685247
2013 TFAP2A regulates nasopharyngeal carcinoma growth and survival by targeting HIF-1α signaling pathway. Cancer prevention research (Philadelphia, Pa.) 65 24335623
2008 AP-2alpha and AP-2gamma regulate tumor progression via specific genetic programs. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 65 18443366
2019 The biological characteristics of transcription factors AP-2α and AP-2γ and their importance in various types of cancers. Bioscience reports 60 30824562
2000 Expression of transcription factor AP-2alpha predicts survival in epithelial ovarian cancer. British journal of cancer 59 10864206
2015 Tfap2a and 2b act downstream of Ptf1a to promote amacrine cell differentiation during retinogenesis. Molecular brain 58 25966682
2001 A family of AP-2 proteins down-regulate manganese superoxide dismutase expression. The Journal of biological chemistry 58 11278550
2021 TFAP2A potentiates lung adenocarcinoma metastasis by a novel miR-16 family/TFAP2A/PSG9/TGF-β signaling pathway. Cell death & disease 57 33824285
2021 Curcumin suppresses LGR5(+) colorectal cancer stem cells by inducing autophagy and via repressing TFAP2A-mediated ECM pathway. Journal of natural medicines 56 33713277
2000 AP-2 transcription factors in the regulation of ERBB2 gene transcription by oestrogen. Oncogene 54 10645007
2010 CREB inhibits AP-2alpha expression to regulate the malignant phenotype of melanoma. PloS one 53 20805990
1999 Transcription factors Sp1 and AP-2 mediate induction of acid sphingomyelinase during monocytic differentiation. Journal of lipid research 53 10224156
2010 AP-2alpha knockout mice exhibit optic cup patterning defects and failure of optic stalk morphogenesis. Human molecular genetics 52 20150232
2008 Characterization of TBX20 in human hearts and its regulation by TFAP2. Journal of cellular biochemistry 52 18275040
2004 Skeletal and pigment cell defects in the lockjaw mutant reveal multiple roles for zebrafish tfap2a in neural crest development. Developmental dynamics : an official publication of the American Association of Anatomists 52 14699580
2003 Expression of Tfap2d, the gene encoding the transcription factor Ap-2 delta, during mouse embryogenesis. Gene expression patterns : GEP 51 12711551
2004 Expression of HER2 and its association with AP-2 in breast cancer. European journal of cancer (Oxford, England : 1990) 50 15196531
2020 AP-2 reduces amyloidogenesis by promoting BACE1 trafficking and degradation in neurons. EMBO reports 46 32323475
2020 TFAP2A is a novel regulator that modulates ferroptosis in gallbladder carcinoma cells via the Nrf2 signalling axis. European review for medical and pharmacological sciences 46 32432738
1998 Redox modulation of AP-2 DNA binding activity in vitro. Biochemical and biophysical research communications 46 9712692
2020 The Ap-2α/Elk-1 axis regulates Sirpα-dependent tumor phagocytosis by tumor-associated macrophages in colorectal cancer. Signal transduction and targeted therapy 45 32296015
2012 Novel Tfap2-mediated control of soxE expression facilitated the evolutionary emergence of the neural crest. Development (Cambridge, England) 45 22241841
2006 Analysis of transcription factor AP-2 expression and function during mouse preimplantation development. Biology of reproduction 45 16672719
2000 AP-2 family members regulate basal and cAMP-induced expression of human chorionic gonadotropin. Nucleic acids research 44 10648798
2014 Suv39h1 mediates AP-2α-dependent inhibition of C/EBPα expression during adipogenesis. Molecular and cellular biology 41 24732798
2018 TFAP2 transcription factors are regulators of lipid droplet biogenesis. eLife 39 30256193
2011 ARFGAP1 promotes AP-2-dependent endocytosis. Nature cell biology 39 21499258
2005 Transcription factor AP-2 and monoaminergic functions in the central nervous system. Journal of neural transmission (Vienna, Austria : 1996) 39 15959839
1995 Transcription factor AP-2 regulates expression of the dopamine beta-hydroxylase gene. Journal of neurochemistry 39 7616204
2004 Identification and embryonic expression of a new AP-2 transcription factor, AP-2 epsilon. Developmental dynamics : an official publication of the American Association of Anatomists 37 15305293
2019 Tfap2a is a novel gatekeeper of nephron differentiation during kidney development. Development (Cambridge, England) 36 31160420
2002 Ectopic expression of AP-2alpha transcription factor in the lens disrupts fiber cell differentiation. Developmental biology 36 11969252
2001 Differential expression of AP-2gamma and AP-2alpha during human trophoblast differentiation. Life sciences 36 11669459
2020 TFAP2A Induced ITPKA Serves as an Oncogene and Interacts with DBN1 in Lung Adenocarcinoma. International journal of biological sciences 35 32015686
2015 Tfap2a promotes specification and maturation of neurons in the inner ear through modulation of Bmp, Fgf and notch signaling. PLoS genetics 35 25781991
2015 AP-2-complex-mediated endocytosis of Drosophila Crumbs regulates polarity by antagonizing Stardust. Journal of cell science 33 26527400
2022 TFAP2 paralogs facilitate chromatin access for MITF at pigmentation and cell proliferation genes. PLoS genetics 32 35580127
2021 AP-2α-Mediated Activation of E2F and EZH2 Drives Melanoma Metastasis. Cancer research 32 34210752
2017 Distinct Activities of Tfap2A and Tfap2B in the Specification of GABAergic Interneurons in the Developing Cerebellum. Frontiers in molecular neuroscience 32 28912684
2013 Analysis of TFAP2A mutations in Branchio-Oculo-Facial Syndrome indicates functional complexity within the AP-2α DNA-binding domain. Human molecular genetics 32 23578821
2019 The TFAP2A-IRF6-GRHL3 genetic pathway is conserved in neurulation. Human molecular genetics 31 30689861
2019 Long Non-Coding RNA TFAP2A-AS1 Inhibits Cell Proliferation and Invasion in Breast Cancer via miR-933/SMAD2. Medical science monitor : international medical journal of experimental and clinical research 31 30768589
2017 TFAP2A is a component of the ZEB1/2 network that regulates TGFB1-induced epithelial to mesenchymal transition. Biology direct 31 28412966
2016 AP-2α inhibits hepatocellular carcinoma cell growth and migration. International journal of oncology 29 26780928
2014 Aberrant CpG methylation of the TFAP2A gene constitutes a mechanism for loss of TFAP2A expression in human metastatic melanoma. Epigenetics 29 25625848
2010 Identification of functional TFAP2A and SP1 binding sites in new TFAP2A-modulated genes. BMC genomics 29 20525283
2010 Expression of human frataxin is regulated by transcription factors SRF and TFAP2. PloS one 29 20808827
2023 Epigenetically modified AP-2α by DNA methyltransferase facilitates glioma immune evasion by upregulating PD-L1 expression. Cell death & disease 28 37330579
2022 Overexpression of Tfap2a in Mouse Oocytes Impaired Spindle and Chromosome Organization. International journal of molecular sciences 28 36430853
2017 Long non-coding RNA CCAL promotes hepatocellular carcinoma progression by regulating AP-2α and Wnt/β-catenin pathway. International journal of biological macromolecules 28 29275200
2008 Transcription factor AP2alpha (TFAP2a) regulates differentiation and proliferation of neuroblastoma cells. Cancer letters 26 18620802
2006 Inefficient proteasomal-degradation pathway stabilizes AP-2alpha and activates HER-2/neu gene in breast cancer. International journal of cancer 26 16108032
1998 Cloning and characterization of the Drosophila homologue of the AP-2 transcription factor. Oncogene 26 9788434
1996 Craniofacial defects in AP-2 null mutant mice. BioEssays : news and reviews in molecular, cellular and developmental biology 26 8885715
2021 TFAP2A-induced SLC2A1-AS1 promotes cancer cell proliferation. Biological chemistry 25 33580997
2019 AP-2-Dependent Endocytic Recycling of the Chitin Synthase Chs3 Regulates Polarized Growth in Candida albicans. mBio 24 30890602
2012 AP-2α-dependent regulation of Bcl-2/Bax expression affects apoptosis in the trophoblast. Journal of molecular histology 22 22886241
1999 Distribution of AP-2 subtypes in the adult mouse brain. Neuroscience research 22 10401980
2024 Tyrosine phosphorylation-mediated YAP1-TFAP2A interactions coordinate transcription and trastuzumab resistance in HER2+ breast cancer. Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy 21 38219531
2020 Nef homodimers down-regulate SERINC5 by AP-2-mediated endocytosis to promote HIV-1 infectivity. The Journal of biological chemistry 21 32873704
2020 Kctd15 regulates nephron segment development by repressing Tfap2a activity. Development (Cambridge, England) 20 33028614
2017 AP-2α reverses vincristine-induced multidrug resistance of SGC7901 gastric cancer cells by inhibiting the Notch pathway. Apoptosis : an international journal on programmed cell death 20 28439677
2016 Tfap2 and Sox1/2/3 cooperatively specify ectodermal fates in ascidian embryos. Development (Cambridge, England) 20 27888190
2011 Alternative TFAP2A isoforms have distinct activities in breast cancer. Breast cancer research : BCR 20 21375726
2010 Dual association by TFAP2A during activation of the p21cip/CDKN1A promoter. Cell cycle (Georgetown, Tex.) 20 21084835
2007 The AP-2alpha transcription factor regulates tumor cell migration and apoptosis. Advances in experimental medicine and biology 20 17695722
2023 TFAP2A activates HMGA1 to promote glycolysis and lung adenocarcinoma progression. Pathology, research and practice 19 37586214
2020 Role of AP-2α/TGF-β1/Smad3 axis in rats with intervertebral disc degeneration. Life sciences 19 33038379
2021 AP-2α Regulates S-Phase and Is a Marker for Sensitivity to PI3K Inhibitor Buparlisib in Colon Cancer. Molecular cancer research : MCR 18 33753551

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