Transcription factor AP-2 gamma (AP-2gamma, TFAP2C; also known as ERF-1) is a nuclear, sequence-specific DNA-binding transcription factor of the AP-2 family. It binds GC-rich GCC(N3)GGC-type elements as a homodimer or as a heterodimer with other AP-2 proteins (notably AP-2alpha), using a basic region and a C-terminal helix-span-helix dimerization domain, and an N-terminal proline-rich domain mediates transactivation. It mainly activates RNA polymerase II target genes, with the coactivators CITED2 and p300/CBP, and represses selected targets such as SOD2 and CDKN1A. KCTD1, SUMOylation on Lys-10 and cytoplasmic retention by WWOX restrain its activity. AP-2gamma is a lineage regulator of early mammalian development. In the embryo it activates trophectoderm genes and is required for trophoblast and placental development, and in human trophoblast stem cells it primes extravillous trophoblast enhancers. In the germ line it acts with SOX17, PRDM1 and GATA3/2 to specify primordial germ cells, inducing SOX17 and OCT4 and suppressing somatic fates, and it maintains early germ cells. In the vertebrate embryonic ectoderm it is expressed in non-neural ectoderm and transiently at the neural plate border, where, as a partner of AP-2alpha, it contributes to border induction and is required together with AP-2alpha for neural crest induction; it is later replaced by AP-2beta in crest progenitors and persists in the epidermis. It also acts redundantly with AP-2alpha in epidermal differentiation, and in mammary epithelium and cortical progenitors. In breast cancer it regulates luminal genes including ESR1, FOXA1 and RET, and it is highly expressed in seminoma and other germ cell tumours.
Definition: The formation of the neural plate border, the region of ectoderm at the boundary between the neural plate and the non-neural ectoderm that is competent to give rise to neural crest, preplacodal ectoderm, dorsal neural tube and epidermis.
Justification: GO has no term for the neural plate border. GO:0014029 neural crest formation is defined as forming this ectodermal region but is placed under epithelial to mesenchymal transition, so border specifiers end up annotated to an EMT term. The border is conserved in chordates without neural crest (amphioxus, tunicates), so it cannot be a part of neural crest formation. See projects/NEURAL_CREST_FORMATION_OBSOLETION.md.
Parent term: ectoderm development
Supporting Evidence:
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000122 negative regulation of transcription by RNA polymerase II | IEA GO_REF:0000108 | ACCEPT | Summary: Logical inference from the repressor activity term (GO:0001227). AP-2gamma represses selected Pol II promoters, such as Mn-SOD, in a DNA-binding-dependent way. Reason: AP-2gamma is a promoter-specific repressor as well as an activator: it represses Mn-SOD and a share of its ChIP-seq primary targets in breast cancer cells. The process term is correct for this context-dependent activity. Supporting Evidence: PMID:11278550 Repression of Mn-SOD by AP-2 was dependent on DNA binding PMID:11278550 AP-2alpha and AP-2gamma were more active in this regard than AP-2beta PMID:20629094 a conservative estimate that 8% of genes altered by TFAP2C expression are primary target genes and includes genes that are both induced and repressed by TFAP2C |
| GO:0000785 chromatin | ISA GO_REF:0000113 | ACCEPT | Summary: TFClass-based assignment of chromatin location for a sequence-specific DNA-binding TF. Reason: TFAP2C occupies promoters and enhancers in chromatin (MCF-7 ChIP-seq; CUT&RUN at chick border enhancers; pre-occupancy of EVT enhancers in human trophoblast). Supporting Evidence: PMID:20629094 a conservative estimate that 8% of genes altered by TFAP2C expression are primary target genes and includes genes that are both induced and repressed by TFAP2C PMID:38346993 TFAP2C pre-occupies the regulatory elements of the inactive extravillous trophoblast-active genes during the early stage of differentiation |
| GO:0000977 RNA polymerase II transcription regulatory region sequence-specific DNA binding | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT inference of Pol II regulatory-region sequence-specific DNA binding for the AP-2 family node (PTN000087637), with TFAP2C itself among the experimentally grounded descendants. Reason: Core activity. AP-2gamma binds GCC(N3)GGC-type sites at Pol II promoters and enhancers (ERF-1 binding the ESR1 promoter; ChIP-seq motif SCCTSRGGS). Supporting Evidence: PMID:9113991 ERF-1 activates ER gene transcription by binding to the imperfect palindrome CCCTGCGGGG within the promoter of the ER gene PMID:20629094 a conservative estimate that 8% of genes altered by TFAP2C expression are primary target genes and includes genes that are both induced and repressed by TFAP2C |
| GO:0000977 RNA polymerase II transcription regulatory region sequence-specific DNA binding | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl Compara transfer from mouse Tfap2c of Pol II regulatory-region sequence-specific DNA binding. Reason: Correct and consistent with the IBA and direct human evidence. Supporting Evidence: PMID:9113991 ERF-1 activates ER gene transcription by binding to the imperfect palindrome CCCTGCGGGG within the promoter of the ER gene |
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | IDA PMID:24413532 Differential regulation of estrogen receptor Ξ± expression in... | ACCEPT | Summary: TFAP2C was identified in the MTA1 complex pulled down by an ESR1 promoter oligonucleotide (ERpro315) and activated an ERpro315 reporter in MCF7 cells. Reason: Binding to a Pol II cis-regulatory region of ESR1 is consistent with the original identification of AP-2gamma as ERF-1, the ESR1 promoter-binding factor. Full text not cached; deferring to the curator. Supporting Evidence: PMID:24413532 the transcription factor AP-2Ξ³ (TFAP2C) and the IFN-Ξ³-inducible protein 16 (IFI16) were components of the complex PMID:24413532 in MCF7, TFAP2C activated the reporter encoding ERpro315 and the level of ERΞ± mRNA PMID:9113991 ERF-1 activates ER gene transcription by binding to the imperfect palindrome CCCTGCGGGG within the promoter of the ER gene |
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl Compara transfer from mouse Tfap2c of Pol II cis-regulatory region sequence-specific DNA binding. Reason: Correct; matches the human IDA. Supporting Evidence: PMID:9113991 ERF-1 activates ER gene transcription by binding to the imperfect palindrome CCCTGCGGGG within the promoter of the ER gene |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl Compara transfer of Pol II-specific DNA-binding TF activity from mouse Tfap2c. Reason: Correct parent of the activator and repressor terms that TFAP2C carries by IDA. Supporting Evidence: file:human/TFAP2C/TFAP2C-uniprot.txt Sequence-specific DNA-binding transcription factor that interacts with cellular enhancer elements to regulate transcription of selected genes |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | ISA GO_REF:0000113 | ACCEPT | Summary: TFClass-based assignment of Pol II-specific DNA-binding TF activity (AP-2 class). Reason: Correct; the activator/repressor children are also carried. Supporting Evidence: file:human/TFAP2C/TFAP2C-uniprot.txt Sequence-specific DNA-binding transcription factor that interacts with cellular enhancer elements to regulate transcription of selected genes |
| GO:0001227 DNA-binding transcription repressor activity, RNA polymerase II-specific | IDA PMID:11278550 A family of AP-2 proteins down-regulate manganese superoxide... | ACCEPT | Summary: AP-2gamma represses the Mn-SOD (SOD2) promoter in HepG2 co-transfection, more strongly than AP-2beta, and repression depends on DNA binding. Reason: Direct reporter evidence for DNA-binding-dependent repression. AP-2gamma represses a subset of targets (Mn-SOD; repressed primary targets in MCF-7 ChIP/knockdown). A context-dependent but genuine activity, consistent with TFAP2A. Supporting Evidence: PMID:11278550 Repression of Mn-SOD by AP-2 was dependent on DNA binding PMID:11278550 AP-2alpha and AP-2gamma were more active in this regard than AP-2beta PMID:20629094 a conservative estimate that 8% of genes altered by TFAP2C expression are primary target genes and includes genes that are both induced and repressed by TFAP2C |
| GO:0001228 DNA-binding transcription activator activity, RNA polymerase II-specific | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT inference of Pol II-specific transcription activator activity at the AP-2 family node, with human TFAP2A, TFAP2B and TFAP2C among the grounded descendants. Reason: Activation is the main AP-2gamma activity (ESR1, PITX2C, c-erbB-3, trophoblast and germline genes). The IBA is placed correctly. Supporting Evidence: PMID:9113991 ERF-1 activates ER gene transcription by binding to the imperfect palindrome CCCTGCGGGG within the promoter of the ER gene PMID:22735262 cooperation between CITED2 and transcription factor AP2-gamma (TFAP2C) in the transactivation of the PITX2C gene |
| GO:0001228 DNA-binding transcription activator activity, RNA polymerase II-specific | IDA PMID:11278550 A family of AP-2 proteins down-regulate manganese superoxide... | ACCEPT | Summary: In the same study that found Mn-SOD repression, AP-2 proteins including AP-2gamma transactivated the c-erbB-3 promoter. Reason: Direct reporter evidence of activator activity on a canonical AP-2 target. Core MF. Supporting Evidence: PMID:11278550 another AP-2-responsive gene, c-erbB-3, was transactivated by AP-2 PMID:9113991 ERF-1 activates ER gene transcription by binding to the imperfect palindrome CCCTGCGGGG within the promoter of the ER gene |
| GO:0001826 inner cell mass cell differentiation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl Compara transfer from mouse Tfap2c (IMP, PMID:38243114): in 8-cell mouse embryos Tfap2c activates early ICM genes as well as TE genes, and its loss reduces ICM cell number. Reason: Real in mouse, where TFAP2C acts as a 'bipotency activator' before the first lineage split. TFAP2C's lasting role is on the trophectoderm side; the ICM effect is a transient, early totipotent-stage function and human preimplantation evidence is lacking. Kept as non-core. Supporting Evidence: PMID:38243114 TFAP2C, a trophoblast regulator, bound and activated both early TE and inner cell mass (ICM) genes at the totipotent (two- to eight-cell) stages PMID:38243114 Tfap2c deficiency caused downregulation of early ICM genes, including Nanog, Nr5a2, and Tdgf1 |
| GO:0003677 DNA binding | IDA PMID:12072434 Transcription factor AP-2 interacts with the SUMO-conjugatin... | ACCEPT | Summary: DNA binding of AP-2 in the UBC9/SUMOylation study (AP-2 interacts with UBC9 through its C-terminal DNA-binding/dimerization half). Reason: True but general. More specific DNA-binding terms are carried. The curator read the full text; accepted. Supporting Evidence: PMID:12072434 sumolation of AP-2 decreases its transcription activation potential PMID:9113991 ERF-1 activates ER gene transcription by binding to the imperfect palindrome CCCTGCGGGG within the promoter of the ER gene |
| GO:0003677 DNA binding | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl Compara transfer of DNA binding from mouse Tfap2c. Reason: Correct, general. Supporting Evidence: PMID:9113991 ERF-1 activates ER gene transcription by binding to the imperfect palindrome CCCTGCGGGG within the promoter of the ER gene |
| GO:0003700 DNA-binding transcription factor activity | IEA GO_REF:0000120 | ACCEPT | Summary: Combined IEA (InterPro TF_AP-2 domains, ortholog) for DNA-binding TF activity. Reason: Correct, general. Supporting Evidence: file:human/TFAP2C/TFAP2C-uniprot.txt Sequence-specific DNA-binding transcription factor that interacts with cellular enhancer elements to regulate transcription of selected genes |
| GO:0003700 DNA-binding transcription factor activity | TAS PMID:9113991 Identification of ERF-1 as a member of the AP2 transcription... | ACCEPT | Summary: ERF-1, the ESR1 promoter-binding activator purified from MCF7 cells, was identified as AP-2gamma. Reason: The paper directly supports sequence-specific DNA-binding TF activity (gel shift with native and recombinant ERF-1; activation of ER gene transcription). Supporting Evidence: PMID:9113991 This cDNA encodes a protein of 48 kDa previously identified as the AP2gamma transcription factor PMID:9113991 ERF-1 activates ER gene transcription by binding to the imperfect palindrome CCCTGCGGGG within the promoter of the ER gene |
| GO:0005515 protein binding | IPI PMID:11694877 Cardiac malformations, adrenal agenesis, neural crest defect... | MODIFY | Summary: CITED2 interacts with and co-activates all AP-2 isoforms; TFAP2 transactivation is defective in Cited2-/- fibroblasts and rescued by CITED2. Reason: The interaction is functional coactivation, so the informative MF is transcription coactivator binding, as for TFAP2A and TFAP2B. Generic protein binding is uninformative. Proposed replacements: transcription coactivator binding Supporting Evidence: PMID:11694877 CITED2 interacts with and co-activates all isoforms of transcription factor AP-2 (TFAP2) |
| GO:0005515 protein binding | IPI PMID:12072434 Transcription factor AP-2 interacts with the SUMO-conjugatin... | REMOVE | Summary: UBC9 (UBE2I) two-hybrid and in vivo interaction; AP-2 is SUMOylated on K10, which lowers transactivation. Reason: The interaction shows that AP-2gamma is a SUMOylation substrate, a property of the substrate rather than a molecular function. Generic protein binding is uninformative; the removal does not dispute the interaction. Consistent with TFAP2A. Supporting Evidence: PMID:12072434 sumolation of AP-2 decreases its transcription activation potential |
| GO:0005515 protein binding | IPI PMID:12586840 Physical and functional interactions among AP-2 transcriptio... | MODIFY | Summary: CITED2 binds the TFAP2C dimerization domain and, with p300/CBP, coactivates AP-2. Reason: The partner (CITED2) is an AP-2 coactivator, so transcription coactivator binding is the informative replacement. Proposed replacements: transcription coactivator binding Supporting Evidence: PMID:12586840 CITED2 interacted with the dimerization domain of TFAP2C, which is highly conserved in TFAP2A/B PMID:11694877 CITED2 interacts with and co-activates all isoforms of transcription factor AP-2 (TFAP2) |
| GO:0005515 protein binding | IPI PMID:12586840 Physical and functional interactions among AP-2 transcriptio... | MODIFY | Summary: Second IPI row from Braganca et al. 2003 with the CITED2 isoform 1 partner (Q99967-1), which binds the TFAP2C dimerization domain. Reason: As for the other row from this paper: the partner is a coactivator, so this becomes transcription coactivator binding. Proposed replacements: transcription coactivator binding Supporting Evidence: PMID:12586840 CITED2 interacted with the dimerization domain of TFAP2C, which is highly conserved in TFAP2A/B |
| GO:0005515 protein binding | IPI PMID:19115315 The interaction of KCTD1 with transcription factor AP-2alpha... | MODIFY | Summary: KCTD1 binds the major AP-2 family members, including AP-2gamma, and inhibits their transcriptional activity through its BTB domain. Reason: KCTD1 acts as a transcriptional repressor of AP-2 factors (it carries GO:0003714 corepressor activity from this paper, as checked for the TFAP2A review). Transcription corepressor binding is the informative MF, consistent with TFAP2A. Proposed replacements: transcription corepressor binding Supporting Evidence: PMID:19115315 KCTD1 interacted with three major members of the AP-2 family and inhibited their transcriptional activities |
| GO:0005515 protein binding | IPI PMID:24413532 Differential regulation of estrogen receptor Ξ± expression in... | MODIFY | Summary: TFAP2C was identified by proteomics in the MTA1 (NuRD) complex bound to the ESR1 ERpro315 region; in MCF7 TFAP2C activated ERpro315, while MTA1-mediated regulation of ESR1 differed between cell lines. Reason: MTA1 is a transcription coregulator (NuRD/HDAC complex component). Because the outcome of the MTA1-TFAP2C complex on ESR1 is activation in MCF7 and context-dependent elsewhere, the sign-neutral transcription coregulator binding is the informative and defensible replacement for protein binding. Proposed replacements: transcription coregulator binding Supporting Evidence: PMID:24413532 the transcription factor AP-2Ξ³ (TFAP2C) and the IFN-Ξ³-inducible protein 16 (IFI16) were components of the complex PMID:24413532 in MCF7, TFAP2C activated the reporter encoding ERpro315 and the level of ERΞ± mRNA |
| GO:0005515 protein binding | IPI PMID:24835590 Sumoylation pathway is required to maintain the basal breast... | REMOVE | Summary: UBC9 pull-down/co-IP with TFAP2A and TFAP2C in a study of SUMOylation in basal breast cancer. Reason: Reflects AP-2gamma being a SUMOylation substrate (UBC9 is the SUMO E2). Generic protein binding is uninformative; the removal does not dispute the interaction. Supporting Evidence: PMID:24835590 GST pull-down and co-immunoprecipitation confirmed that Ubc9 bound to both TFAP2A and TFAP2C |
| GO:0005634 nucleus | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT inference of nuclear location for the AP-2 family. Reason: Correct; AP-2gamma is a nuclear TF. Supporting Evidence: file:human/TFAP2C/TFAP2C-uniprot.txt SUBCELLULAR LOCATION: Nucleus |
| GO:0005634 nucleus | IDA PMID:24413532 Differential regulation of estrogen receptor Ξ± expression in... | ACCEPT | Summary: Nuclear localisation of TFAP2C observed in breast cancer cells (UniProt cites this paper for the nuclear location). Reason: Consistent with its DNA-binding TF function. Supporting Evidence: file:human/TFAP2C/TFAP2C-uniprot.txt SUBCELLULAR LOCATION: Nucleus |
| GO:0005634 nucleus | IEA GO_REF:0000120 | ACCEPT | Summary: Combined IEA for nuclear location. Reason: Correct. Supporting Evidence: file:human/TFAP2C/TFAP2C-uniprot.txt SUBCELLULAR LOCATION: Nucleus |
| GO:0005654 nucleoplasm | IDA GO_REF:0000052 | ACCEPT | Summary: Human Protein Atlas immunofluorescence shows nucleoplasm. Reason: Consistent with nuclear TF function. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-3234094 | ACCEPT | Summary: Reactome reaction (Reactome:R-HSA-3234094) placing TFAP2C, its dimers or its promoter-bound complexes in the nucleoplasm. Reason: Nucleoplasm is the correct site of AP-2gamma dimerisation, cofactor binding, SUMOylation and promoter engagement. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-8864278 | ACCEPT | Summary: Reactome reaction (Reactome:R-HSA-8864278) placing TFAP2C, its dimers or its promoter-bound complexes in the nucleoplasm. Reason: Nucleoplasm is the correct site of AP-2gamma dimerisation, cofactor binding, SUMOylation and promoter engagement. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-8864307 | ACCEPT | Summary: Reactome reaction (Reactome:R-HSA-8864307) placing TFAP2C, its dimers or its promoter-bound complexes in the nucleoplasm. Reason: Nucleoplasm is the correct site of AP-2gamma dimerisation, cofactor binding, SUMOylation and promoter engagement. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-8864343 | ACCEPT | Summary: Reactome reaction (Reactome:R-HSA-8864343) placing TFAP2C, its dimers or its promoter-bound complexes in the nucleoplasm. Reason: Nucleoplasm is the correct site of AP-2gamma dimerisation, cofactor binding, SUMOylation and promoter engagement. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-8864381 | ACCEPT | Summary: Reactome reaction (Reactome:R-HSA-8864381) placing TFAP2C, its dimers or its promoter-bound complexes in the nucleoplasm. Reason: Nucleoplasm is the correct site of AP-2gamma dimerisation, cofactor binding, SUMOylation and promoter engagement. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-8864412 | ACCEPT | Summary: Reactome reaction (Reactome:R-HSA-8864412) placing TFAP2C, its dimers or its promoter-bound complexes in the nucleoplasm. Reason: Nucleoplasm is the correct site of AP-2gamma dimerisation, cofactor binding, SUMOylation and promoter engagement. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-8864426 | ACCEPT | Summary: Reactome reaction (Reactome:R-HSA-8864426) placing TFAP2C, its dimers or its promoter-bound complexes in the nucleoplasm. Reason: Nucleoplasm is the correct site of AP-2gamma dimerisation, cofactor binding, SUMOylation and promoter engagement. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-8864577 | ACCEPT | Summary: Reactome reaction (Reactome:R-HSA-8864577) placing TFAP2C, its dimers or its promoter-bound complexes in the nucleoplasm. Reason: Nucleoplasm is the correct site of AP-2gamma dimerisation, cofactor binding, SUMOylation and promoter engagement. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-8864718 | ACCEPT | Summary: Reactome reaction (Reactome:R-HSA-8864718) placing TFAP2C, its dimers or its promoter-bound complexes in the nucleoplasm. Reason: Nucleoplasm is the correct site of AP-2gamma dimerisation, cofactor binding, SUMOylation and promoter engagement. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-8865265 | ACCEPT | Summary: Reactome reaction (Reactome:R-HSA-8865265) placing TFAP2C, its dimers or its promoter-bound complexes in the nucleoplasm. Reason: Nucleoplasm is the correct site of AP-2gamma dimerisation, cofactor binding, SUMOylation and promoter engagement. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-8865280 | ACCEPT | Summary: Reactome reaction (Reactome:R-HSA-8865280) placing TFAP2C, its dimers or its promoter-bound complexes in the nucleoplasm. Reason: Nucleoplasm is the correct site of AP-2gamma dimerisation, cofactor binding, SUMOylation and promoter engagement. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-8874789 | ACCEPT | Summary: Reactome reaction (Reactome:R-HSA-8874789) placing TFAP2C, its dimers or its promoter-bound complexes in the nucleoplasm. Reason: Nucleoplasm is the correct site of AP-2gamma dimerisation, cofactor binding, SUMOylation and promoter engagement. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9827862 | ACCEPT | Summary: Reactome reaction (Reactome:R-HSA-9827862) placing TFAP2C, its dimers or its promoter-bound complexes in the nucleoplasm. Reason: Nucleoplasm is the correct site of AP-2gamma dimerisation, cofactor binding, SUMOylation and promoter engagement. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9827867 | ACCEPT | Summary: Reactome reaction (Reactome:R-HSA-9827867) placing TFAP2C, its dimers or its promoter-bound complexes in the nucleoplasm. Reason: Nucleoplasm is the correct site of AP-2gamma dimerisation, cofactor binding, SUMOylation and promoter engagement. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9827870 | ACCEPT | Summary: Reactome reaction (Reactome:R-HSA-9827870) placing TFAP2C, its dimers or its promoter-bound complexes in the nucleoplasm. Reason: Nucleoplasm is the correct site of AP-2gamma dimerisation, cofactor binding, SUMOylation and promoter engagement. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9827882 | ACCEPT | Summary: Reactome reaction (Reactome:R-HSA-9827882) placing TFAP2C, its dimers or its promoter-bound complexes in the nucleoplasm. Reason: Nucleoplasm is the correct site of AP-2gamma dimerisation, cofactor binding, SUMOylation and promoter engagement. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9828024 | ACCEPT | Summary: Reactome reaction (Reactome:R-HSA-9828024) placing TFAP2C, its dimers or its promoter-bound complexes in the nucleoplasm. Reason: Nucleoplasm is the correct site of AP-2gamma dimerisation, cofactor binding, SUMOylation and promoter engagement. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9828027 | ACCEPT | Summary: Reactome reaction (Reactome:R-HSA-9828027) placing TFAP2C, its dimers or its promoter-bound complexes in the nucleoplasm. Reason: Nucleoplasm is the correct site of AP-2gamma dimerisation, cofactor binding, SUMOylation and promoter engagement. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9828032 | ACCEPT | Summary: Reactome reaction (Reactome:R-HSA-9828032) placing TFAP2C, its dimers or its promoter-bound complexes in the nucleoplasm. Reason: Nucleoplasm is the correct site of AP-2gamma dimerisation, cofactor binding, SUMOylation and promoter engagement. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9836270 | ACCEPT | Summary: Reactome reaction (Reactome:R-HSA-9836270) placing TFAP2C, its dimers or its promoter-bound complexes in the nucleoplasm. Reason: Nucleoplasm is the correct site of AP-2gamma dimerisation, cofactor binding, SUMOylation and promoter engagement. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8864569 | KEEP AS NON CORE | Summary: Reactome: the tumour suppressor WWOX binds TFAP2C in the cytosol and prevents its nuclear translocation. Reason: Cytosolic TFAP2C reflects a regulated, inhibited state (WWOX sequestration), not the site of its function. Kept as a real but non-core location. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8864577 | KEEP AS NON CORE | Summary: Reactome nuclear translocation reaction, with cytosolic TFAP2C as the input. Reason: Newly synthesised or WWOX-retained TFAP2C is cytosolic before import; the functional location is the nucleus. Non-core. |
| GO:0006355 regulation of DNA-templated transcription | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro mapping to regulation of DNA-templated transcription. Reason: Correct, general. Supporting Evidence: file:human/TFAP2C/TFAP2C-uniprot.txt Sequence-specific DNA-binding transcription factor that interacts with cellular enhancer elements to regulate transcription of selected genes |
| GO:0006357 regulation of transcription by RNA polymerase II | TAS PMID:9113991 Identification of ERF-1 as a member of the AP2 transcription... | ACCEPT | Summary: ERF-1/AP-2gamma activates ER gene transcription from the ESR1 promoter. Reason: Correct; the more specific positive regulation term is also carried. Supporting Evidence: PMID:9113991 ERF-1 activates ER gene transcription by binding to the imperfect palindrome CCCTGCGGGG within the promoter of the ER gene |
| GO:0007267 cell-cell signaling | TAS PMID:9113991 Identification of ERF-1 as a member of the AP2 transcription... | REMOVE | Summary: ProtInc TAS from the paper identifying ERF-1 as AP-2gamma. Reason: AP-2gamma is a nuclear transcription factor; neither this paper nor other evidence shows it mediates transfer of information between cells. Any intercellular effects (e.g. via its target genes) are indirect. Not an experimental annotation; removed as unsupported. Supporting Evidence: PMID:9113991 This cDNA encodes a protein of 48 kDa previously identified as the AP2gamma transcription factor |
| GO:0008584 male gonad development | IEP PMID:17848411 Developmental changes in human fetal testicular cell numbers... | MARK AS OVER ANNOTATED | Summary: Expression study of second-trimester human fetal testis; TFAP2C transcript is a germ cell marker whose per-cell level declines. Reason: Expression of a germ cell marker in the developing testis does not show that TFAP2C acts in gonad development. Its genuine role is in the germ line itself (hPGCLC specification, mouse PGC maintenance), captured by the NEW germ cell development annotation. Supporting Evidence: PMID:17848411 germ (CKIT, TFAP2C) cell-specific products increased per testis through the second trimester PMID:19776388 In the mutant animals, PGCs were specified but were lost around E 8.0. |
| GO:0042127 regulation of cell population proliferation | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: PAINT inference of regulation of cell population proliferation for the AP-2 family. Reason: AP-2gamma affects proliferation in several contexts (mouse trophoblast via Cdkn1a repression; breast cancer cells), with context-dependent sign. Correct but downstream of its transcriptional role; non-core, as for TFAP2A. Supporting Evidence: PMID:26811378 TFAP2C in trophoblasts controls proliferation by repressing Cdkn1a and activating the MAPK pathway |
| GO:0045814 negative regulation of gene expression, epigenetic | IMP PMID:24413532 Differential regulation of estrogen receptor Ξ± expression in... | UNDECIDED | Summary: MTA1 complex study of ESR1 regulation in breast cancer cells. The abstract reports that TFAP2C activated the ESR1 ERpro315 reporter and ERalpha mRNA in MCF7, and attributes epigenetic repression in ER-negative cells to MTA1, IFI16 and class II HDACs. Reason: The cached abstract does not show TFAP2C loss-of-function leading to epigenetic silencing; if anything TFAP2C is the activating partner in MCF7. The full text, which the curator read, is not available, so the IMP cannot be adjudicated. Supporting Evidence: PMID:24413532 in MCF7, TFAP2C activated the reporter encoding ERpro315 and the level of ERΞ± mRNA PMID:24413532 the MTA1-TFAP2C or the MTA1-IFI16 complex may contribute to the epigenetic regulation of ESR1 expression in breast cancer |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT inference of positive regulation of Pol II transcription at the AP-2 family node. Reason: Core biological consequence of AP-2gamma activator activity. Supporting Evidence: PMID:9113991 ERF-1 activates ER gene transcription by binding to the imperfect palindrome CCCTGCGGGG within the promoter of the ER gene PMID:22735262 cooperation between CITED2 and transcription factor AP2-gamma (TFAP2C) in the transactivation of the PITX2C gene |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IDA PMID:22735262 CITED2 mutation links congenital heart defects to dysregulat... | ACCEPT | Summary: CITED2 and TFAP2C cooperate to transactivate the PITX2C promoter; CHD-associated CITED2 mutants reduce this cooperation. Reason: Direct reporter evidence for TFAP2C-driven Pol II transcriptional activation with its coactivator CITED2. Supporting Evidence: PMID:22735262 cooperation between CITED2 and transcription factor AP2-gamma (TFAP2C) in the transactivation of the PITX2C gene |
| GO:0140001 morula formation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl Compara transfer from mouse Tfap2c (IDA, PMID:38243114) of morula formation. Reason: In mouse 2- to 8-cell embryos Tfap2c binds and activates early TE and ICM genes and (per UniProt) cell-polarity genes. A real early role in mouse, but a transient precursor of its trophectoderm function and not shown in human; non-core. Supporting Evidence: PMID:38243114 TFAP2C, a trophoblast regulator, bound and activated both early TE and inner cell mass (ICM) genes at the totipotent (two- to eight-cell) stages |
| GO:0140001 morula formation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: UniProt ISS transfer of morula formation from mouse Tfap2c. Reason: As for the IEA row: correct transfer of a mouse preimplantation role, kept as non-core pending human evidence. Supporting Evidence: PMID:38243114 TFAP2C, a trophoblast regulator, bound and activated both early TE and inner cell mass (ICM) genes at the totipotent (two- to eight-cell) stages file:human/TFAP2C/TFAP2C-uniprot.txt At the 8-cell stage, during morula development, controls expression of cell-polarity genes |
| GO:1990837 sequence-specific double-stranded DNA binding | IDA PMID:28473536 Impact of cytosine methylation on DNA binding specificities ... | ACCEPT | Summary: Methyl-SELEX profiling of human TF DNA-binding specificities, including AP-2 family members. Reason: Sequence-specific dsDNA binding is the core AP-2gamma activity. Supporting Evidence: PMID:28473536 By analysis of 542 human TFs with methylation-sensitive SELEX |
| NTR neural plate border formation | ISS PMID:31848212 Heterodimerization of TFAP2 pioneer factors drives epigenomi... | NEW | Summary: AP-2gamma is a gastrula-stage neural plate border factor. In chick it is enriched at the border, heterodimerises with TFAP2A, co-occupies most TFAP2A border-induction peaks, and is required for border gene expression (MSX1, PAX7, ZIC1, GBX2) but not for crest specification genes; it is then lost from the crest. In zebrafish, tfap2a and tfap2c together are cell-autonomously required during gastrulation for crest induction. Reason: Human TFAP2C has no neural crest term. Layer: border, not crest specifier. TFAP2C acts only during border induction and is switched off in crest progenitors by TFAP2B; its knockdown leaves specification genes unaffected and it cannot replace TFAP2B in specification. The term is therefore the proposed term 'neural plate border formation' (NTR), which replaces GO:0014029 (proposed for obsoletion: its text describes the border region but it is placed under epithelial to mesenchymal transition), rather than GO:0014034/GO:0014036, matching the project convention for border genes and the TFAP2A border row. Participation: TFAP2C is a DNA-binding TF that co-occupies border enhancers with TFAP2A as a heterodimer, so it does part of the work. Comparator (QuickGO 2026-10-08): zebrafish tfap2c carries GO:0014032 (IGI) and GO:0014036 (IGI); zebrafish and mouse Tfap2a carry crest terms; no TFAP2B/C/D/E in human, mouse, rat, chicken or Xenopus carries any, and mouse Tfap2c nulls die before crest forms. So the absence is a coverage gap. GO:0014036 on zebrafish tfap2c comes from double knockdown with tfap2a and is not transferred, because chick data place TFAP2C itself before specification. ISS because the evidence is from chick and zebrafish orthologs; the role is shared redundantly with TFAP2A. Supporting Evidence: PMID:31848212 although TFAP2C was enriched at the neural plate border, it was lost in the neural crest lineage at later stages and its expression became restricted to the presumptive epidermis PMID:31848212 TFAP2C knockdown during induction resulted in a down-regulation of the neural plate border markers MSX1, PAX7, ZIC1, and GBX2 but had no significant effects on the expression of specification genes FOXD3, ETS1, SOX9, and SOX10 PMID:31848212 TFAP2A/C heterodimers mediate neural plate border induction, whereas TFAP2A/B heterodimers promote neural crest specification PMID:31848212 Pulldown of TFAP2A with streptavidin beads resulted in co-IP of both FLAG-tagged TFAP2B and TFAP2C, confirming that these factors form heterodimers in avian embryos PMID:31848212 overexpression of TFAP2C does not adequately rescue the expression of specification genes PMID:17258188 simultaneous inhibition of tfap2a and tfap2c utterly prevents neural crest induction, supporting a conserved role for Tfap2-type activity in neural crest induction PMID:17258188 Because tfap2c expression is rapidly down regulated in neural crest, Tfap2a/c function in neural crest induction must occur during gastrula stage. |
| GO:0007281 germ cell development | IMP PMID:31875561 Human Primordial Germ Cells Are Specified from Lineage-Prime... | NEW | Summary: TFAP2C is a core component of the human primordial germ cell specification circuit: TFAP2C-null hESCs fail to make hPGCLCs, TFAP2C acts upstream of PRDM1 to induce SOX17 and to block somatic fates, it binds and requires the OCT4 naive enhancer, and with GATA3/2 and SOX17 it is sufficient to induce hPGCLCs. In mouse, PGCs are specified without Tfap2c but are lost by E8.0. Reason: Human TFAP2C has no germline process term despite direct human loss- and gain-of-function evidence. Participation: TFAP2C is the DNA-binding TF that activates SOX17/OCT4 regulatory elements and represses somatic programmes in the nascent germ line. Comparator (QuickGO 2026-10-08): mouse Prdm1 carries GO:0007281 (IGI) and mouse Tfap2c carries GO:0030718 germ-line stem cell population maintenance (IMP, PMID:19776388); human PRDM1 and SOX17 carry no germ cell term, so this is a coverage gap. GO:0007281 (from formation of the PGC onwards) is chosen because GO has no primordial germ cell specification term. Supporting Evidence: PMID:31875561 TFAP2C functions in the TFAP2A+ progenitors upstream of PRDM1 to regulate the expression of SOX17 PMID:31875561 This serves to protect hPGCLCs from crossing the Weismann's barrier to adopt somatic cell fates PMID:30590035 deleting the TFAP2C-bound naive enhancer at the OCT4 locus (also called POU5F1) results in impaired OCT4 expression and a negative effect on hPGCLC identity PMID:33608411 GATA3 or GATA2, immediate BMP effectors, combined with SOX17 and TFAP2C, generated hPGCLCs PMID:19776388 In the mutant animals, PGCs were specified but were lost around E 8.0. |
| GO:0001829 trophectodermal cell differentiation | ISS PMID:38243114 Lineage regulators TFAP2C and NR5A2 function as bipotency ac... | NEW | Summary: AP-2gamma is a trophectoderm/trophoblast lineage TF. In mouse it binds late TE genes with CDX2 in blastocysts and later extra-embryonic ectoderm genes, and loss of Tfap2c causes extra-embryonic failure and lethality at E7.5. In human trophoblast stem cells it is the early-stage TF that pre-occupies extravillous trophoblast enhancers. Reason: Mouse Tfap2c carries GO:0001829 by IMP (PMID:20404091, PMID:38243114; QuickGO 2026-10-08), but human TFAP2C received only the ICM and morula IEAs. The trophectoderm role is the best-established in vivo function of the gene in mammals, and human TSC data show the same lineage-regulator behaviour. ISS from mouse. Supporting Evidence: PMID:38243114 Upon trophoblast commitment, TFAP2C left early ICM genes but acquired binding to late TE genes in blastocysts, where it co-bound with CDX2 PMID:26811378 Loss of TFAP2C in mouse leads to developmental defects in the extra-embryonic compartment with lethality at embryonic day (E)7.5 PMID:38346993 TFAP2C pre-occupies the regulatory elements of the inactive extravillous trophoblast-active genes during the early stage of differentiation file:human/TFAP2C/TFAP2C-deep-research-falcon.md TFAP2C is a temporally restricted early regulator that pre-occupies relatively inaccessible EVT-active loci |
Loading supporting contentβ¦
Download this section (compressed HTML)Q: Chick knockdown places TFAP2C upstream of MSX1/PAX7/ZIC1/GBX2, whereas in zebrafish tfap2a/tfap2c double loss leaves pax3/msxb/zic2b intact. Is the AP-2 position relative to the other border genes species-specific, and does it affect which AP-2 paralogs belong under the proposed 'neural plate border formation' term?
Q: Zebrafish tfap2c carries GO:0014036 by IGI from double knockdown with tfap2a. Should IGI-based specification terms be propagated to TFAP2C orthologs when single-paralog data (chick) place TFAP2C before specification?
Q: Should the TFAP2A-TFAP2C heterodimer (and TFAP2A-TFAP2B) be represented as complexes, or should the partner switch be captured only as GO-CAM causal edges (TFAP2A/C activates TFAP2B; TFAP2B represses TFAP2C)?
Q: Epidermis development and mammary gland roles of AP-2gamma rest mainly on combined Tfap2a/Tfap2c mouse knockouts. Should these be annotated to TFAP2C (IGI) given the redundancy?
Q: The IMP to negative regulation of gene expression, epigenetic (PMID:24413532) needs full-text review: does TFAP2C loss cause epigenetic silencing of ESR1, or is TFAP2C the activating partner of MTA1?
Experiment: Single and combined TFAP2A/TFAP2C knockout in human pluripotent stem cell-derived neural plate border and cranial neural crest models, with CUT&RUN for each paralog, to test whether the chick TFAP2A/C to TFAP2A/B partner switch operates in human.
Experiment: Map TFAP2B occupancy and enhancer deletion at the TFAP2C locus in chick or human crest models to test whether TFAP2B repression of TFAP2C is direct.
Experiment: Test whether lamprey AP-2 paralogs show a TFAP2C-like transient border expression and a TFAP2B-like crest expression, to date the subfunctionalisation of border and crest AP-2 roles.
Loading supporting contentβ¦
Download this section (compressed HTML)Loading supporting contentβ¦
Download this section (compressed HTML)Loading supporting contentβ¦
Download this section (compressed HTML)