{"gene":"TFCP2","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":1990,"finding":"LSF (TFCP2) was purified as a 63-kDa polypeptide that binds two distinct bipartite sites within the SV40 late promoter (LSF-GC site and LSF-280 site), recognizing directly repeated GC motifs with a center-to-center spacing of 10 bp, and activates transcription from the SV40 late promoter in vitro via binding to template DNA at initiation site L325.","method":"Protein purification, DNA affinity chromatography, methylation interference, in vitro transcription assay","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro biochemical reconstitution with purified protein, multiple orthogonal methods (binding, footprinting, transcription assay)","pmids":["2159933"],"is_preprint":false},{"year":1992,"finding":"CP2 (TFCP2) was molecularly cloned; bacterial expression of the full-length 502-aa murine factor or a core region (aa 133–395) generated polypeptides with the DNA-binding specificity of CP2, delimiting the region sufficient for specific DNA sequence recognition. The factor activates transcription of alpha-globin promoter templates ~3–4 fold in vitro.","method":"cDNA cloning, bacterial expression, DNase I footprinting, EMSA, in vitro transcription","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution with bacterially expressed protein, multiple orthogonal methods, domain mapping by truncation","pmids":["1732747"],"is_preprint":false},{"year":1992,"finding":"LSF (TFCP2) activates RNA polymerase II transcription by increasing the rate of association of TFIIB with the committed template on the SV40 major late promoter; LSF has no effect on TFIID binding rate or stability, but specifically accelerates the TFIIB assembly step.","method":"In vitro transcription kinetics, band mobility shift assays, general transcription factor titration","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — mechanistic reconstitution in vitro with multiple rate measurements and factor-specific dissection","pmids":["1313810"],"is_preprint":false},{"year":1993,"finding":"CP2 (TFCP2) binds a hyphenated recognition sequence motif spanning one DNA helix turn; elevated CP2 levels (2.5–5.5-fold) in stably transformed cells increased alpha-globin promoter-driven reporter activity 3–6 fold in vivo, confirming direct transcriptional activation.","method":"DNase I footprinting, EMSA, stable/transient transfection, CAT reporter assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro and in vivo assays with purified bacterially expressed protein and stable cell lines","pmids":["8349681"],"is_preprint":false},{"year":1994,"finding":"LSF (TFCP2) binds DNA as a homodimer, as demonstrated by an epitope-counting method. The alternatively spliced isoform LSF-ID lacks two beta-strand-forming regions conserved with Drosophila Elf-1/NTF-1; double amino acid substitutions in each of these regions eliminated specific DNA-binding activity. Mutations in one homology region, but not the other, eliminated dimerization.","method":"Epitope-counting EMSA, mutagenesis, protein-protein interaction studies","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis combined with quantitative DNA-binding and dimerization assays, multiple orthogonal approaches","pmids":["8035790"],"is_preprint":false},{"year":1994,"finding":"The DNA-binding and dimerization domains of Drosophila Grainyhead are conserved in human CP2 (TFCP2). The DNA-binding domain (263 aa) contains a smaller core; the major dimerization domain is in a separate region and is required to stabilize DNA interactions. An N-terminal inhibitory domain can modulate activity.","method":"Domain deletion mapping, DNA-binding assays, dimerization assays in Drosophila and vertebrate (CP2) proteins","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — systematic domain mapping with functional validation for both Grainyhead and CP2","pmids":["8196641"],"is_preprint":false},{"year":1995,"finding":"CP2 (TFCP2) is pivotal to, but not sufficient for, the stage selector protein (SSP) complex that binds the stage selector element (SSE) in the gamma-globin promoter. CP2 requires a heterodimeric partner (~40–45 kDa) present in K562 cells to bind the SSE. The SSP complex is disrupted by anti-CP2 antiserum. The analogous chicken complex includes NF-E4, which is homologous to CP2.","method":"Biochemical purification, EMSA, UV and protein cross-linking, anti-CP2 antiserum disruption, Western blot","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — biochemical purification and reconstitution, multiple orthogonal methods including cross-linking and immunodepletion","pmids":["7828600"],"is_preprint":false},{"year":1997,"finding":"LSF (TFCP2) and YY1 cooperate to form a complex that recognizes the initiation region of the HIV-1 LTR and cooperatively repress LTR transcription and viral replication; transient expression of LSF alone has no effect, but cooperation with YY1 is required for repression in vivo.","method":"EMSA, transient transfection, viral replication assay","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 / Strong — replicated across multiple experiments; cooperative binding and functional repression demonstrated","pmids":["9371597"],"is_preprint":false},{"year":1997,"finding":"LSF (TFCP2) DNA-binding activity is rapidly and quantitatively increased (~5-fold within 15 min) by mitogenic stimulation of resting human peripheral T lymphocytes, correlating with phosphorylation-induced reduction in LSF electrophoretic mobility. ERK1 (pp44) phosphorylates LSF in vitro at the same residue phosphorylated in vivo (position 291). Phosphatase treatment in vitro increases LSF mobility and decreases DNA-binding activity, confirming that phosphorylation directly increases DNA-binding.","method":"EMSA, in vitro kinase assay, mutagenesis (S291 mutant), phosphatase treatment, primary T lymphocyte stimulation","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct phosphorylation demonstrated in vitro and in vivo with mutagenesis and phosphatase validation","pmids":["9192871"],"is_preprint":false},{"year":1998,"finding":"LSF (TFCP2) binds DNA as a tetramer (larger than a dimer) for high-affinity binding, requiring 234–320 amino acids. NTF-1 (Drosophila ortholog) can bind an LSF half-site as a dimer, whereas LSF cannot, indicating different oligomerization requirements despite shared DNA-binding domains.","method":"Truncation mutagenesis, EMSA, cross-linking experiments, mixing assays with full-length and truncation mutants","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — systematic truncation mutagenesis with quantitative DNA-binding and oligomerization analyses","pmids":["9668115"],"is_preprint":false},{"year":1998,"finding":"The Fe65 adaptor protein interacts with CP2/LSF/LBP1 (TFCP2) through its N-terminal PID1 domain, as shown by yeast two-hybrid and co-immunoprecipitation of native molecules. Different isoforms of CP2/LSF/LBP1 are distributed differently among subcellular fractions; at least one splice isoform (LSF-ID) is present outside the nucleus, while Fe65 is found in both nuclear and non-nuclear fractions.","method":"Interaction trap (yeast two-hybrid), co-immunoprecipitation, subcellular fractionation, transfection with HA-tagged constructs","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP of native proteins plus yeast two-hybrid, domain mapping, and localization data","pmids":["9685356"],"is_preprint":false},{"year":1998,"finding":"Chicken CP2 (cCP2, TFCP2) forms a tetramer as shown by EMSA and cross-linking experiments. cCP2 is essential for transcription through the alphaA-crystallin lens enhancer alphaCE1; lens-specific enhancer activity depends on a 6-bp sequence (LSE) adjacent to the CP2 binding site, suggesting cooperation between cCP2 tetramer and a lens-specific factor binding LSE.","method":"EMSA, protein cross-linking, overexpression/dominant negative transfection, element substitution experiments","journal":"Genes to cells","confidence":"High","confidence_rationale":"Tier 1 / Strong — biochemical demonstration of tetramer, loss-of-function with dominant negative, element substitution mapping","pmids":["9753426"],"is_preprint":false},{"year":2000,"finding":"LSF (TFCP2) binds sites within the thymidylate synthase (TS) promoter and intronic regions required for G1-S induction. Expression of dominant-negative LSF prevents the increase in TS enzyme levels during G1-S and induces S-phase-dependent apoptosis (thymineless death), which can be rescued by thymidine supplementation or heterologous TS expression.","method":"Reporter mutation analysis, dominant-negative expression, enzyme activity assay, apoptosis assays, rescue experiments","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function with specific phenotypic readout, two independent rescue approaches confirming mechanism","pmids":["10970859"],"is_preprint":false},{"year":2000,"finding":"YY1 and LSF (TFCP2) cooperate to recruit HDAC1 to the HIV-1 LTR; HDAC1 co-purifies with the LTR-bound YY1-LSF repressor complex. LSF recruits YY1 to the LTR via YY1's zinc fingers (first two zinc fingers sufficient in vitro). The HDAC1-interacting domain of YY1 is required for LTR repression, and HDAC inhibitor trichostatin A blocks YY1-mediated repression.","method":"Co-purification, EMSA, HDAC inhibitor (TSA) treatment, deletion mutant analysis, HDAC1 overexpression","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 / Strong — co-purification of ternary complex, domain mapping, pharmacological and genetic validation across multiple experiments","pmids":["10888618"],"is_preprint":false},{"year":2000,"finding":"Targeted disruption of CP2 (TFCP2) in mice produces viable animals with no apparent defects in hematopoiesis, globin gene expression, or immune responses. In CP2-null extracts, a slower-migrating complex bound to CP2 consensus sites is recognized by anti-NF2d9 (LBP-1a) antiserum, and recombinant LBP-1a can bind CP2 sites and form complexes with CP2 heteromeric partners, indicating functional compensation by the paralog LBP-1a/NF2d9.","method":"Gene targeting (knockout mice), EMSA with nuclear extracts, antiserum supershift, recombinant protein binding assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — knockout mouse model with comprehensive phenotypic analysis plus biochemical compensation mechanism identified","pmids":["10995745"],"is_preprint":false},{"year":2001,"finding":"Mutations in a putative CP2 (TFCP2) binding motif (-90C to A) in the uroporphyrinogen III synthase erythroid-specific promoter alter CP2 binding (EMSA) and reduce promoter activity to ~8% of wild-type in K562 cells, causing congenital erythropoietic porphyria. An adjacent -86A mutation does not alter CP2 binding.","method":"Sequencing, luciferase reporter assay, EMSA","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct binding disruption by mutation confirmed by EMSA, functional consequence confirmed by reporter assay","pmids":["11254675"],"is_preprint":false},{"year":2003,"finding":"LSF (TFCP2) is rapidly and quantitatively phosphorylated upon growth induction in NIH 3T3 cells; ERK is responsible for this phosphorylation, as shown by correlation of ERK activity with LSF phosphorylation and by specific MEK/ERK pathway inhibitors blocking LSF modification. ERK phosphorylation is necessary but not sufficient for activation of LSF DNA-binding activity (DNA-binding is not significantly altered in fibroblasts despite phosphorylation).","method":"Electrophoretic mobility shift, in vitro kinase assay, pharmacological inhibitors of Ras/Raf/MEK/ERK, cell fractionation","journal":"Journal of cellular biochemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — three independent lines of evidence (correlation, sufficiency in vitro, inhibitor abrogation) establishing ERK as the kinase","pmids":["12858339"],"is_preprint":false},{"year":2005,"finding":"CP2 (TFCP2) binds erythroid regulatory regions of the GATA-1, EKLF, and p45 NF-E2 genes and forms a ternary complex with GATA-1 and DNA at the GATA-1 HS2 enhancer. CP2 physically interacts with GATA-1 (demonstrated by co-immunoprecipitation and GST pull-down). Both factors occupy the same regulatory elements in vivo (chromatin IP). Mutation of the CP2 consensus in these elements severely impairs enhancer activity in K562 cells.","method":"EMSA, ChIP, co-immunoprecipitation, GST pull-down, transient transfection reporter assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP plus GST pull-down confirming direct interaction, ChIP confirming in vivo co-occupancy, functional validation","pmids":["16648487"],"is_preprint":false},{"year":2005,"finding":"Two HXPR-motif-containing proteins, REST and YY1, bind CP2 (TFCP2) via their HXPR sequences; GST pull-down and co-immunoprecipitation confirm this interaction. Double amino acid substitution in the HXPR sequence of YY1 abolishes binding to CP2 and eliminates YY1's suppression of CP2 transcriptional activity. At least three distinct binding regions on CP2 accommodate four different peptide motifs (HXPR, PHL, ASR, PXHXH).","method":"Peptide library screen, GST pull-down, co-immunoprecipitation, site-directed mutagenesis, transcriptional reporter assay","journal":"The FEBS journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal binding assays with mutagenesis validating the functional relevance of the interaction","pmids":["15720400"],"is_preprint":false},{"year":2005,"finding":"Erythroid cell-specific alpha-globin transactivation by CP2 (TFCP2) requires specific splice variants: CP2b (with an extra 36-aa exon) forms heteromeric complexes with CP2c; this heterodimer activates alpha-globin specifically in erythroid cells but not in non-erythroid 293T cells. Addition of PIAS1 (identified as a CP2-binding protein by yeast two-hybrid and confirmed by co-immunoprecipitation) restores alpha-globin activation in 293T cells, identifying PIAS1 as the missing erythroid cofactor.","method":"Yeast two-hybrid, co-immunoprecipitation, luciferase reporter in erythroid and non-erythroid cells, expression of recombinant isoforms","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — yeast two-hybrid confirmed by co-IP, functional reconstitution in non-erythroid cells with defined cofactors","pmids":["15988015"],"is_preprint":false},{"year":2006,"finding":"APLP2 intracellular C-terminal domain (ICD) interacts with CP2 (TFCP2) in the nucleus and induces expression of GSK-3β. Nuclear colocalization and interaction were demonstrated, and GSK-3β protein levels increased upon APLP2-ICD expression.","method":"Co-immunoprecipitation, transfection, immunofluorescence, Western blot","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab, co-IP and reporter readout; no direct mutagenesis of the interaction","pmids":["16645641"],"is_preprint":false},{"year":2009,"finding":"LSF (TFCP2) is phosphorylated by cyclin C/CDK2 (and cyclin C/CDK3 in humans) predominantly at S309 during early G1 after mitogenic stimulation of quiescent fibroblasts. This phosphorylation is mediated by cyclin C-dependent kinases (confirmed by co-immunoprecipitation and siRNA knockdown of cyclin C), and phosphorylation at S309 inhibits LSF transactivation and prevents induction of the LSF target gene Tyms at G1/S.","method":"In vitro kinase assays, mutagenesis (S309), co-immunoprecipitation, siRNA knockdown of cyclin C, transient transfection reporter, endogenous Tyms expression","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase assay with mutagenesis, confirmed in vivo by siRNA and co-IP, functional read-out with endogenous target gene","pmids":["19237534"],"is_preprint":false},{"year":2005,"finding":"LSF (TFCP2) binds the HIV-1 LTR as a tetramer; ERK phosphorylation of LSF decreases its binding to the LTR in vitro, while p38 phosphorylation increases binding. In cells, p38 agonist increases LSF occupancy at LTR chromatin; p38 inhibition decreases LSF occupancy, increases histone H4 acetylation at the adjacent nucleosome, blocks YY1-mediated LTR repression, and results in recovery of HIV from resting CD4+ T cells of aviremic donors.","method":"EMSA, ChIP, kinase assays, pharmacological p38 inhibition/agonism, HIV recovery assay from primary cells","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods including ChIP, in vitro kinase assays, and primary cell HIV recovery","pmids":["15857981"],"is_preprint":false},{"year":2010,"finding":"LSF (TFCP2) functions as an oncogene in hepatocellular carcinoma: LSF overexpression promotes aggressive, angiogenic, and multiorgan metastatic tumors in nude mice, while inhibition abrogates growth and metastasis. LSF transcriptionally upregulates osteopontin (OPN), which mediates key oncogenic functions; loss of OPN impairs LSF-driven tumorigenesis.","method":"Stable overexpression/dominant-negative, nude mouse xenograft, microarray, loss-of-function studies with siRNA/shRNA","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — xenograft gain/loss of function in vivo, target gene identified and functionally validated by loss-of-function","pmids":["20404171"],"is_preprint":false},{"year":2011,"finding":"LSF (TFCP2) transcriptionally upregulates MMP-9 to enhance angiogenesis in HCC. ChIP-on-chip identified MMP-9 as a direct LSF target; ChIP confirmed LSF binding to the MMP-9 promoter. Deletion mutation analysis identified LSF-responsive promoter regions. MMP-9 inhibition abrogated LSF-induced angiogenesis and tumorigenesis in vivo.","method":"ChIP-on-chip, ChIP-PCR, promoter deletion reporter assays, HUVEC differentiation assay, CAM assay, nude mouse xenograft","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct ChIP confirming promoter binding, functional validation in multiple angiogenesis assays and in vivo","pmids":["22167195"],"is_preprint":false},{"year":2011,"finding":"LSF (TFCP2) activates c-Met signaling in HCC through a pathway involving LSF-driven OPN secretion activating c-Met via CD44. Co-immunoprecipitation confirmed OPN-induced CD44/c-Met interaction. Chemical or genetic inhibition of c-Met abrogates LSF-mediated tumorigenesis and metastasis in vivo.","method":"Phospho-RTK array, co-immunoprecipitation, tissue microarray IHC, siRNA, chemical inhibitor, nude mouse xenograft","journal":"Journal of hepatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pathway elucidated by phospho-array, co-IP, and in vivo inhibition; indirect (via OPN) link to LSF","pmids":["21703197"],"is_preprint":false},{"year":2015,"finding":"TFCP2 directly regulates FN1 (fibronectin 1) and TJP1 (tight junction protein 1) as transcriptional targets mediating HCC metastasis. ChIP-on-chip combined with transcriptome analysis identified these targets; ChIP-PCR confirmed TFCP2 binding to the FN1 promoter, and promoter reporter identified TFCP2-binding motifs. FN1 inhibition blocks TFCP2-induced aggression; TFCP2 overexpression rescues FN1 inhibition.","method":"ChIP-on-chip, transcriptome microarray, ChIP-PCR, promoter reporter assay, siRNA rescue experiments","journal":"Journal of experimental & clinical cancer research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct ChIP confirmation, promoter reporter, and epistasis rescue experiments in single lab","pmids":["25609232"],"is_preprint":false},{"year":2016,"finding":"LSF (TFCP2) inhibits melanoma cell growth by binding within a 150-bp upstream region of the p21CIP1 transcription start site and increasing p21CIP1 expression, resulting in G1 phase arrest. EMSA and ChIP assays confirmed LSF binding to the p21CIP1 promoter.","method":"EMSA, ChIP, overexpression/depletion, cell cycle analysis, anchorage-dependent/independent growth assays, xenograft","journal":"Oncotarget","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct promoter binding by EMSA and ChIP, phenotype confirmed by in vivo xenograft","pmids":["26506241"],"is_preprint":false},{"year":2017,"finding":"TFCP2 is required for YAP-dependent transcription in liver cancer. Mechanistically, TFCP2 stimulates YAP function via a WW-PSY interaction, maintains YAP stability by inhibiting βTrCP-mediated ubiquitination, and acts as a transcription co-factor facilitating YAP binding to YBF-containing transcription factors and the YAP-TEAD interaction. Genomic co-occupancy of YAP and TFCP2 was revealed by ChIP.","method":"Co-immunoprecipitation (WW-PSY interaction), ubiquitination assays, ChIP, luciferase reporter, siRNA/overexpression","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods: protein interaction, ubiquitination, ChIP co-occupancy, and functional transcriptional assays","pmids":["29091762"],"is_preprint":false},{"year":2018,"finding":"Crystal structures of the DNA-binding domains of Grainyhead-like (Grhl) 1 and Grhl2 (close CP2/TFCP2 family members) reveal an immunoglobulin-like core fold shared with p53, with dimeric DNA binding mediated by two conserved arginine residues. A cancer-associated mutation in Grhl1 at one of these arginines completely abrogates DNA binding in biochemical assays and transcriptional activation in human cells.","method":"X-ray crystallography, in vitro DNA-binding assays, cancer-mutation analysis, transcriptional reporter assay in human cell line","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with functional mutagenesis validation in vitro and in cells; note these are Grhl1/2 family members, structurally informative for the CP2/TFCP2 family fold","pmids":["29309642"],"is_preprint":false},{"year":2017,"finding":"TFCP2 promotes pancreatic cancer progression by interacting with β-catenin, enhancing the β-catenin/TCF4 interaction, and activating β-catenin/TCF signaling, as demonstrated by co-immunoprecipitation and luciferase reporter assay.","method":"Co-immunoprecipitation, luciferase reporter (β-catenin/TCF), overexpression/knockdown, colony formation, in vivo metastasis model","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab, co-IP and reporter assay; mechanism not verified by mutagenesis","pmids":["29050300"],"is_preprint":false},{"year":2019,"finding":"CCT3 co-interacts with YAP and TFCP2 (confirmed by mass spectrometry co-immunoprecipitation) and prolongs their half-lives by blocking PCBP2-induced ubiquitination in a βTrCP-independent manner. PCBP2 directly interacts with YAP via a WB motif-WW domain interaction and indirectly with TFCP2 via YAP. CCT3 separates PCBP2-YAP interactions, preventing ubiquitination of both YAP and TFCP2.","method":"Mass spectrometry co-immunoprecipitation, ubiquitination assays, co-immunoprecipitation, Western blot half-life assay","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-identified interaction confirmed by co-IP, ubiquitination mechanism characterized; single lab","pmids":["31501420"],"is_preprint":false},{"year":2020,"finding":"TFCP2 directly bound the promoters of EGF and TGFα to regulate their expression, stimulating autocrine EGFR signaling and AKT activation in triple-negative breast cancer. This creates a positive feedback loop controlling TFCP2-mediated EMT, stemness, and metastasis.","method":"ChIP, promoter reporter assay, siRNA/overexpression, EGFR signaling assays, in vivo metastasis model","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct promoter binding confirmed by ChIP, feedback loop validated functionally; single lab","pmids":["32193292"],"is_preprint":false},{"year":2020,"finding":"LSF (TFCP2) binds α-tubulin and SET8 (KMT5A/PR-Set7), facilitating SET8-mediated methylation of α-tubulin at Lys311. LSF enhances SET8-mediated α-tubulin methylation in vitro; the LSF inhibitor FQI1 counters this facilitation. SET8 bound α-tubulin and methylated it at Lys311 as shown by in vitro radiolabeling, MS, and immunoblotting.","method":"In vitro radiolabeling, mass spectrometry, immunoblotting, co-immunoprecipitation, immunofluorescence, GST pull-down, FQI1 inhibitor","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro methylation reconstitution with MS identification of site, protein interactions confirmed by multiple orthogonal methods; single lab","pmids":["32111740"],"is_preprint":false},{"year":2020,"finding":"Inhibition of LSF (TFCP2) by either the small molecule FQI1 or siRNA causes highly similar mitotic delays with condensed, unaligned chromosomes preceding metaphase, leading to multi-nucleation, apoptosis, and senescence. The concordance between FQI1 and siRNA phenotypes confirms LSF as the specific cellular target of FQI1.","method":"Time-lapse microscopy, bulk cell synchronization, siRNA knockdown vs. FQI1 treatment comparison, cell death/senescence assays","journal":"BMC cancer","confidence":"High","confidence_rationale":"Tier 2 / Strong — two independent loss-of-function methods (small molecule + siRNA) yielding identical mitotic phenotypes","pmids":["32539694"],"is_preprint":false},{"year":2009,"finding":"TFCP2 acts as a transcription factor that directly binds the SRY promoter (demonstrated by EMSA); TFCP2 suppression by RNAi significantly reduced SRY mRNA expression in cells, while overexpression did not significantly increase SRY mRNA, indicating TFCP2 is required but not limiting for SRY expression.","method":"EMSA, RNAi knockdown, overexpression, RT-PCR","journal":"Molecular and cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — EMSA confirming direct binding, loss-of-function showing dependence; single lab, single method per claim","pmids":["19902333"],"is_preprint":false},{"year":2021,"finding":"TFCP2 interacts with SREBP2 (co-immunoprecipitation) and synergistically activates expression of HMGCR (a rate-limiting enzyme in cholesterol synthesis), enabling pancreatic cancer cells to overcome oncogene-induced senescence. Statins (which inhibit HMGCR) reversed the anti-senescence effect of TFCP2.","method":"Co-immunoprecipitation, qRT-PCR, luciferase reporter, statin treatment, senescence assays (SA-β-gal)","journal":"Frontiers in oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — co-IP confirmed interaction, pharmacological rescue validates pathway; single lab, limited mechanistic depth","pmids":["34804919"],"is_preprint":false},{"year":2022,"finding":"TFCP2 induces SMAD2 expression as a transcription factor; ITGA2 inhibits the nuclear translocation of TFCP2, thereby reducing SMAD2 transcription and suppressing TGF-β pathway activation. Co-immunoprecipitation and nuclear/cytoplasmic fractionation confirmed that ITGA2 interacts with and retains TFCP2 in the cytoplasm.","method":"Co-immunoprecipitation, nuclear/cytoplasmic fractionation, ChIP, luciferase reporter, Western blot, RT-qPCR","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and nuclear fractionation data plus co-IP; single lab","pmids":["35193647"],"is_preprint":false},{"year":2022,"finding":"TFCP2 interacts with ATF3 to cooperatively regulate de novo serine synthesis by promoting ATF3 binding to the PHGDH promoter. Knockdown of TFCP2 significantly inhibited ATF3 binding to the PHGDH promoter, as shown by ChIP.","method":"Co-immunoprecipitation, ChIP, siRNA knockdown, cell proliferation and sphere formation assays","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — co-IP and ChIP support the interaction and mechanism; single lab, no mutagenesis","pmids":["35421367"],"is_preprint":false},{"year":2024,"finding":"TRAF6 stabilizes YAP1 by K63 poly-ubiquitination, promoting formation of the YAP1/TFCP2 transcriptional complex and subsequent PD-L1 transcription in melanoma. Suppression of TRAF6 down-regulates PD-L1 on the membrane surface of melanoma cells. In vitro and in vivo assays confirmed the TRAF6→YAP1 K63-ubiquitination→YAP1/TFCP2 complex→PD-L1 transcription axis.","method":"CRISPR interference screen, ubiquitination assays (K63-specific), co-immunoprecipitation, PD-L1 flow cytometry, luciferase reporter, in vitro/in vivo tumor models","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — K63 ubiquitination specificity demonstrated, co-IP of YAP1/TFCP2 complex, PD-L1 functional readout; single lab","pmids":["38583649"],"is_preprint":false},{"year":2024,"finding":"FUS-TFCP2 fusion protein blocks myogenic differentiation, induces transcription of ALK and truncated TERT, and inhibits DNA repair in rhabdomyosarcoma. Functional studies in cell models showed genomic instability and signs of defective homologous recombination in TFCP2-rearranged tumors.","method":"Functional cell-based studies with FUS-TFCP2 expression constructs, transcriptome analysis, DNA repair assays","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional studies with fusion protein constructs establishing multiple cellular phenotypes; single study","pmids":["38168093"],"is_preprint":false},{"year":2017,"finding":"CP2 (TFCP2) upregulates miR-144 expression in mouse ovarian granulosa cells by directly binding the miR-144 promoter, as shown by luciferase reporter, ChIP, and EMSA. CP2-driven miR-144 expression suppresses COX-2 and reduces PGE2 production.","method":"Luciferase reporter, ChIP, EMSA, miR-144 inhibitor/mimic overexpression","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct promoter binding confirmed by EMSA and ChIP with functional output; single lab","pmids":["28182010"],"is_preprint":false},{"year":2012,"finding":"The small molecule FQI1 inhibits LSF (TFCP2) DNA-binding activity in vitro (EMSA) and in cells (ChIP), eliminates transcriptional stimulation of LSF-dependent reporter constructs, and induces rapid cell death in LSF-overexpressing HCC cells without affecting normal hepatocytes. Structure-activity relationships of 23 quinolinones are highly concordant between antiproliferative and LSF-inhibitory activities, confirming LSF as the specific target.","method":"EMSA, ChIP, luciferase reporter, cell viability assays, SAR analysis, xenograft mouse model","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (EMSA, ChIP, reporter, SAR) converging on LSF as the specific target with in vivo validation","pmids":["22396589"],"is_preprint":false}],"current_model":"TFCP2 (LSF/CP2/LBP-1c) is a transcription factor that binds directly-repeated GC-rich sequences as a tetramer (dimer in solution but tetramer on DNA), activates RNA Pol II transcription by accelerating TFIIB recruitment, and is regulated by post-translational phosphorylation: ERK phosphorylation at S291 activates DNA-binding in T cells (but not fibroblasts), while cyclin C/CDK2-mediated phosphorylation at S309 in early G1 inhibits transactivation until late G1; it drives S-phase progression by directly transactivating thymidylate synthase, activates erythroid gene expression through heteromeric complexes with lineage-specific partners (e.g., a 40–45 kDa partner for globin SSP, CP2b/PIAS1 for alpha-globin), cooperates with YY1 and HDAC1 to repress the HIV-1 LTR, promotes liver cancer through direct transcriptional upregulation of OPN, MMP-9, FN1, and TJP1, facilitates YAP-dependent transcription via a WW-PSY protein interaction, interacts with SET8 to facilitate alpha-tubulin methylation at Lys311, and when fused to FUS/EWSR1 in rhabdomyosarcoma drives ALK upregulation, blocks myogenic differentiation, and induces genomic instability."},"narrative":{"mechanistic_narrative":"TFCP2 (LSF/CP2/LBP-1c) is a sequence-specific RNA Pol II transcription factor that recognizes directly-repeated GC-rich bipartite motifs and activates transcription by accelerating TFIIB recruitment to committed templates [PMID:2159933, PMID:1313810]. It engages DNA as a higher-order oligomer—a dimer in solution that assembles into a tetramer for high-affinity binding—through DNA-binding and dimerization domains conserved with the Grainyhead/Elf-1/NTF-1 family, whose immunoglobulin-like fold and arginine-mediated DNA contacts are defined structurally in related Grhl proteins [PMID:8035790, PMID:9668115, PMID:9753426, PMID:29309642]. Its activity is gated by mitogen-driven phosphorylation: ERK modifies S291 and rapidly increases DNA binding in stimulated T lymphocytes, though this modification is necessary but not sufficient for activation in fibroblasts, while cyclin C/CDK2 (CDK3) phosphorylation at S309 in early G1 inhibits transactivation [PMID:9192871, PMID:12858339, PMID:19237534]. TFCP2 drives the G1/S transition by directly transactivating thymidylate synthase, and its inhibition triggers thymineless death or mitotic catastrophe with chromosome misalignment, multinucleation, and apoptosis [PMID:10970859, PMID:32539694]. It functions combinatorially with lineage- and context-specific partners: it requires a ~40–45 kDa partner and CP2b/PIAS1 to form the erythroid stage-selector and alpha-globin activating complexes, cooperates with GATA-1 at erythroid regulatory elements, and partners with YY1 to recruit HDAC1 and repress the HIV-1 LTR [PMID:7828600, PMID:16648487, PMID:10888618, PMID:15988015, PMID:10995745]. TFCP2 acts as an oncogene in hepatocellular carcinoma by directly upregulating osteopontin, MMP-9, FN1, and TJP1 to drive angiogenesis and metastasis, and stabilizes and co-activates YAP through a WW-PSY interaction to support YAP-TEAD transcription [PMID:20404171, PMID:22167195, PMID:25609232, PMID:29091762]. Mutations disrupting a TFCP2 binding site in the uroporphyrinogen III synthase erythroid promoter reduce its expression and cause congenital erythropoietic porphyria, and FUS-TFCP2 fusion proteins drive rhabdomyosarcoma by upregulating ALK, blocking myogenic differentiation, and inducing genomic instability [PMID:11254675, PMID:38168093]. Beyond transcription, TFCP2 binds α-tubulin and SET8 to facilitate α-tubulin methylation at Lys311 [PMID:32111740].","teleology":[{"year":1990,"claim":"Established TFCP2 as a sequence-specific factor that binds directly-repeated GC motifs and activates RNA Pol II transcription, defining its core biochemical identity.","evidence":"Protein purification, methylation interference, and in vitro transcription on the SV40 late promoter","pmids":["2159933"],"confidence":"High","gaps":["Mechanism of transcriptional activation not yet resolved","No in vivo target genes identified"]},{"year":1992,"claim":"Cloning and reconstitution mapped the region sufficient for DNA recognition and showed the factor activates a physiological (alpha-globin) promoter, while the mechanism of activation was traced to accelerated TFIIB assembly.","evidence":"cDNA cloning, bacterial expression, domain truncation, and in vitro transcription kinetics with general factor titration","pmids":["1732747","1313810"],"confidence":"High","gaps":["How TFIIB recruitment is accelerated mechanistically unresolved","Activation domain not finely mapped"]},{"year":1994,"claim":"Resolved the oligomeric basis of DNA binding—homodimerization through one of two Grainyhead-conserved regions—separating dimerization from DNA-contact functions.","evidence":"Epitope-counting EMSA, mutagenesis, and domain mapping across CP2 and Drosophila Grainyhead","pmids":["8035790","8196641"],"confidence":"High","gaps":["No structural model of the domains","Role of N-terminal inhibitory domain not defined"]},{"year":1995,"claim":"Showed TFCP2 is combinatorial, requiring lineage-specific partners to assemble functional complexes such as the erythroid stage-selector protein.","evidence":"Biochemical purification, cross-linking, and antiserum immunodepletion of the SSP complex in K562 cells","pmids":["7828600"],"confidence":"High","gaps":["Identity of the 40–45 kDa partner not molecularly defined","How partner switching is regulated unknown"]},{"year":1998,"claim":"Demonstrated that high-affinity binding requires tetramerization (distinguishing TFCP2 from its dimer-competent Drosophila ortholog) and identified the Fe65 adaptor as a partner with isoform-specific subcellular distribution.","evidence":"Truncation mutagenesis, cross-linking, yeast two-hybrid, co-IP, and subcellular fractionation","pmids":["9668115","9685356"],"confidence":"High","gaps":["Functional consequence of Fe65 interaction unresolved","Regulation of tetramer assembly unknown"]},{"year":1997,"claim":"Defined a repressive role through cooperation with YY1 at the HIV-1 LTR, showing TFCP2 acts as both activator and repressor depending on partners.","evidence":"EMSA, transient transfection, and viral replication assays","pmids":["9371597"],"confidence":"High","gaps":["Repression mechanism not yet linked to chromatin modifiers"]},{"year":2000,"claim":"Connected TFCP2 to cell cycle control by identifying thymidylate synthase as a direct G1/S target whose loss causes thymineless death, and uncovered HDAC1 recruitment as the molecular basis of LTR repression.","evidence":"Dominant-negative expression, rescue experiments, enzyme assays, and HDAC1 co-purification with the YY1-LSF complex","pmids":["10970859","10888618"],"confidence":"High","gaps":["Full set of cell-cycle targets undefined","How activation vs. repression is partner-selected unresolved"]},{"year":2000,"claim":"Mouse knockout revealed functional redundancy, showing the paralog LBP-1a/NF2d9 compensates for TFCP2 loss in hematopoiesis and globin expression.","evidence":"Gene targeting in mice with EMSA, supershift, and recombinant protein binding","pmids":["10995745"],"confidence":"High","gaps":["Non-redundant physiological roles of TFCP2 not isolated","Degree of compensation in other tissues untested"]},{"year":2005,"claim":"Defined the erythroid transcriptional network: TFCP2 interacts directly with GATA-1, requires the CP2b isoform plus PIAS1 cofactor for alpha-globin activation, and uses discrete surface motifs to engage HXPR-containing partners REST and YY1.","evidence":"Co-IP, GST pull-down, ChIP, yeast two-hybrid, peptide-motif mutagenesis, and reporter assays","pmids":["16648487","15988015","15720400"],"confidence":"High","gaps":["Structural basis of motif recognition not resolved","How isoform choice is regulated unknown"]},{"year":1997,"claim":"Identified ERK as the kinase that phosphorylates TFCP2 at S291 to increase DNA binding upon T-cell mitogenic stimulation, establishing signal-dependent regulation, later shown to be cell-type dependent (insufficient alone in fibroblasts).","evidence":"EMSA, in vitro kinase assays, S291 mutagenesis, phosphatase treatment, and MEK/ERK inhibitors in primary cells and NIH 3T3","pmids":["9192871","12858339"],"confidence":"High","gaps":["Cell-type-specific cofactor required for activation unidentified","How phosphorylation alters DNA-binding conformation unknown"]},{"year":2005,"claim":"Linked TFCP2 to HIV latency by showing opposing kinase control—ERK reduces and p38 increases LTR binding—with pharmacological consequences for viral reactivation from resting CD4+ T cells.","evidence":"EMSA, ChIP, kinase assays, p38 inhibitor/agonist, and HIV recovery from primary patient cells","pmids":["15857981"],"confidence":"High","gaps":["p38 phosphorylation site not mapped","Therapeutic exploitation untested in vivo"]},{"year":2009,"claim":"Identified cyclin C/CDK2 (CDK3) phosphorylation at S309 in early G1 as an inhibitory brake that delays TFCP2 transactivation until G1/S, refining cell-cycle timing of its target gene induction.","evidence":"In vitro kinase assays, S309 mutagenesis, cyclin C siRNA, co-IP, and endogenous Tyms readout","pmids":["19237534"],"confidence":"High","gaps":["How S309 dephosphorylation is timed at G1/S unresolved","Crosstalk with ERK phosphorylation unclear"]},{"year":2011,"claim":"Established TFCP2 as a hepatocellular carcinoma oncogene driving angiogenesis and metastasis through direct transcriptional targets OPN, MMP-9, FN1, and TJP1, with OPN-CD44-c-Met signaling as a downstream effector.","evidence":"Xenografts, ChIP-on-chip, ChIP-PCR, promoter reporters, loss-of-function rescue, and phospho-RTK array","pmids":["20404171","22167195","25609232","21703197"],"confidence":"High","gaps":["What activates TFCP2 oncogenic program upstream unclear","Tissue-specificity of target selection unresolved"]},{"year":2012,"claim":"Provided a chemical-genetic tool (FQI1) that specifically inhibits TFCP2 DNA binding and selectively kills LSF-overexpressing HCC cells, validating TFCP2 as a druggable target.","evidence":"EMSA, ChIP, reporter assays, structure-activity analysis of 23 quinolinones, and xenografts","pmids":["22396589"],"confidence":"High","gaps":["Binding site of FQI1 on TFCP2 not structurally defined","Selectivity over paralogs untested"]},{"year":2017,"claim":"Revealed a non-genomic stabilizing role in which TFCP2 supports YAP-dependent transcription via a WW-PSY interaction, blocking βTrCP-mediated YAP ubiquitination and facilitating YAP-TEAD binding.","evidence":"Co-IP, ubiquitination assays, ChIP co-occupancy, and reporter assays in liver cancer","pmids":["29091762"],"confidence":"High","gaps":["Reciprocal regulation of TFCP2 by YAP partly addressed only later","Structural basis of WW-PSY interaction undefined"]},{"year":2020,"claim":"Extended TFCP2 function beyond transcription, showing it bridges SET8 and α-tubulin to facilitate Lys311 methylation, and demonstrated that TFCP2 loss causes mitotic catastrophe with chromosome misalignment.","evidence":"In vitro methylation reconstitution, MS, co-IP, GST pull-down, FQI1 inhibitor, and time-lapse microscopy comparing siRNA and FQI1","pmids":["32111740","32539694"],"confidence":"High","gaps":["Whether tubulin methylation explains the mitotic phenotype unestablished","Substrate scope of TFCP2-SET8 axis unknown"]},{"year":2024,"claim":"Showed that TFCP2 transcriptional complexes are stabilized by ubiquitin signaling (TRAF6 K63-ubiquitination of YAP1) to drive PD-L1, and that FUS-TFCP2 fusion proteins act as oncogenic drivers in rhabdomyosarcoma.","evidence":"CRISPRi screen, K63-specific ubiquitination assays, co-IP, PD-L1 flow cytometry, fusion-protein expression, and DNA repair assays","pmids":["38583649","38168093"],"confidence":"Medium","gaps":["Single-lab findings without independent replication","Mechanism of fusion-driven genomic instability undefined"]},{"year":null,"claim":"How TFCP2 selects between its activating, repressive, and protein-stabilizing roles in different tissues, and the high-resolution structure of human TFCP2 on DNA, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No experimental structure of human TFCP2 itself (only Grhl family members)","Rules governing partner-selective activation vs. repression unknown","In vivo non-redundant roles obscured by paralog compensation"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,1,3,4,9,11]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,2,12,23,28]},{"term_id":"GO:0140223","term_label":"general transcription initiation factor activity","supporting_discovery_ids":[2]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[13,17,19,28]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[10,20,37]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[10,37]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,2,3]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[12,21,34]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[15,23,40]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[28,30,32]}],"complexes":["stage selector protein (SSP) complex","YY1-LSF-HDAC1 repressor complex","YAP1/TFCP2 transcriptional complex"],"partners":["YY1","GATA-1","PIAS1","YAP1","SET8","FE65","REST","SREBP2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q12800","full_name":"Alpha-globin transcription factor CP2","aliases":["SAA3 enhancer factor","Transcription factor LSF"],"length_aa":502,"mass_kda":57.3,"function":"Binds a variety of cellular and viral promoters including fibrinogen, alpha-globin, SV40 and HIV-1 promoters. Activation of the alpha-globin promoter in erythroid cells is via synergistic interaction with UBP1 (By similarity). Functions as part of the SSP (stage selector protein) complex. Facilitates the interaction of the gamma-globin genes with enhancer elements contained in the locus control region in fetal erythroid cells. Interacts by binding to the stage selector element (SSE) in the proximal gamma-globin promoter","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q12800/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TFCP2","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"PARP1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/TFCP2","total_profiled":1310},"omim":[{"mim_id":"616855","title":"CYTOCHROME c OXIDASE, SUBUNIT 8C; COX8C","url":"https://www.omim.org/entry/616855"},{"mim_id":"615817","title":"INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL RECESSIVE 43; MRT43","url":"https://www.omim.org/entry/615817"},{"mim_id":"615748","title":"WASH COMPLEX, SUBUNIT 4; WASHC4","url":"https://www.omim.org/entry/615748"},{"mim_id":"612779","title":"DIHYDROPYRIMIDINE DEHYDROGENASE; DPYD","url":"https://www.omim.org/entry/612779"},{"mim_id":"612133","title":"TRANSCRIPTION FACTOR NFE4; NFE4","url":"https://www.omim.org/entry/612133"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TFCP2"},"hgnc":{"alias_symbol":["CP2","LSF","LBP-1C","TFCP2C"],"prev_symbol":[]},"alphafold":{"accession":"Q12800","domains":[{"cath_id":"2.60.40.720","chopping":"66-275","consensus_level":"high","plddt":92.1824,"start":66,"end":275},{"cath_id":"3.10.20.90","chopping":"389-405_425-500","consensus_level":"high","plddt":86.5761,"start":389,"end":500},{"cath_id":"1.10.150","chopping":"329-381","consensus_level":"high","plddt":91.664,"start":329,"end":381}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q12800","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q12800-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q12800-F1-predicted_aligned_error_v6.png","plddt_mean":76.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TFCP2","jax_strain_url":"https://www.jax.org/strain/search?query=TFCP2"},"sequence":{"accession":"Q12800","fasta_url":"https://rest.uniprot.org/uniprotkb/Q12800.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q12800/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q12800"}},"corpus_meta":[{"pmid":"10888618","id":"PMC_10888618","title":"The human factors YY1 and LSF repress the human immunodeficiency virus type 1 long terminal repeat via recruitment of histone deacetylase 1.","date":"2000","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/10888618","citation_count":303,"is_preprint":false},{"pmid":"9685356","id":"PMC_9685356","title":"The Fe65 adaptor protein interacts through its PID1 domain with the transcription factor CP2/LSF/LBP1.","date":"1998","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9685356","citation_count":135,"is_preprint":false},{"pmid":"31383960","id":"PMC_31383960","title":"A subset of epithelioid and spindle cell rhabdomyosarcomas is associated with TFCP2 fusions and common ALK upregulation.","date":"2019","source":"Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc","url":"https://pubmed.ncbi.nlm.nih.gov/31383960","citation_count":117,"is_preprint":false},{"pmid":"7828600","id":"PMC_7828600","title":"Hemoglobin switching in man and chicken is mediated by a heteromeric complex between the ubiquitous transcription factor CP2 and a developmentally specific protein.","date":"1995","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/7828600","citation_count":101,"is_preprint":false},{"pmid":"29738762","id":"PMC_29738762","title":"Circular RNA hsa_circ_0023404 exerts an oncogenic role in cervical cancer through regulating miR-136/TFCP2/YAP pathway.","date":"2018","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/29738762","citation_count":92,"is_preprint":false},{"pmid":"1732747","id":"PMC_1732747","title":"Molecular cloning of the alpha-globin transcription factor CP2.","date":"1992","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/1732747","citation_count":90,"is_preprint":false},{"pmid":"9371597","id":"PMC_9371597","title":"Repression of human immunodeficiency virus type 1 through the novel cooperation of human factors YY1 and LSF.","date":"1997","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/9371597","citation_count":89,"is_preprint":false},{"pmid":"12888489","id":"PMC_12888489","title":"Functional conservation between members of an ancient duplicated transcription factor family, LSF/Grainyhead.","date":"2003","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/12888489","citation_count":84,"is_preprint":false},{"pmid":"33382123","id":"PMC_33382123","title":"Head and neck rhabdomyosarcoma with TFCP2 fusions and ALK overexpression: a clinicopathological and molecular analysis of 11 cases.","date":"2021","source":"Histopathology","url":"https://pubmed.ncbi.nlm.nih.gov/33382123","citation_count":76,"is_preprint":false},{"pmid":"29758589","id":"PMC_29758589","title":"Spindle cell rhabdomyosarcoma of bone with FUS-TFCP2 fusion: confirmation of a very recently described rhabdomyosarcoma subtype.","date":"2018","source":"Histopathology","url":"https://pubmed.ncbi.nlm.nih.gov/29758589","citation_count":76,"is_preprint":false},{"pmid":"29410248","id":"PMC_29410248","title":"TFCP2/TFCP2L1/UBP1 transcription factors in cancer.","date":"2018","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/29410248","citation_count":74,"is_preprint":false},{"pmid":"11254675","id":"PMC_11254675","title":"Uroporphyrinogen III synthase erythroid promoter mutations in adjacent GATA1 and CP2 elements cause congenital erythropoietic porphyria.","date":"2001","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/11254675","citation_count":73,"is_preprint":false},{"pmid":"2159933","id":"PMC_2159933","title":"Transcription factor LSF binds two variant bipartite sites within the SV40 late promoter.","date":"1990","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/2159933","citation_count":73,"is_preprint":false},{"pmid":"20404171","id":"PMC_20404171","title":"Transcription factor Late SV40 Factor (LSF) functions as an oncogene in hepatocellular carcinoma.","date":"2010","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/20404171","citation_count":70,"is_preprint":false},{"pmid":"8196641","id":"PMC_8196641","title":"The Drosophila tissue-specific factor Grainyhead contains novel DNA-binding and dimerization domains which are conserved in the human protein CP2.","date":"1994","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/8196641","citation_count":66,"is_preprint":false},{"pmid":"10970859","id":"PMC_10970859","title":"Inhibition of the mammalian transcription factor LSF induces S-phase-dependent apoptosis by downregulating thymidylate synthase expression.","date":"2000","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/10970859","citation_count":65,"is_preprint":false},{"pmid":"11001930","id":"PMC_11001930","title":"The transcriptional factor LBP-1c/CP2/LSF gene on chromosome 12 is a genetic determinant of Alzheimer's disease.","date":"2000","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/11001930","citation_count":63,"is_preprint":false},{"pmid":"32556562","id":"PMC_32556562","title":"Epithelioid and spindle cell rhabdomyosarcoma with FUS-TFCP2 or EWSR1-TFCP2 fusion: report of two cases.","date":"2020","source":"Virchows Archiv : an international journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/32556562","citation_count":59,"is_preprint":false},{"pmid":"8349681","id":"PMC_8349681","title":"Characterization of the molecularly cloned murine alpha-globin transcription factor CP2.","date":"1993","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8349681","citation_count":59,"is_preprint":false},{"pmid":"7869985","id":"PMC_7869985","title":"An analytical edge spread function model for computer fitting and subsequent calculation of the LSF and MTF.","date":"1994","source":"Medical physics","url":"https://pubmed.ncbi.nlm.nih.gov/7869985","citation_count":58,"is_preprint":false},{"pmid":"15563829","id":"PMC_15563829","title":"Lineage-specific and ubiquitous biological roles of the mammalian transcription factor LSF.","date":"2004","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/15563829","citation_count":55,"is_preprint":false},{"pmid":"8035790","id":"PMC_8035790","title":"One exon of the human LSF gene includes conserved regions involved in novel DNA-binding and dimerization motifs.","date":"1994","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/8035790","citation_count":54,"is_preprint":false},{"pmid":"26723877","id":"PMC_26723877","title":"Complement proteins C7 and CFH control the stemness of liver cancer cells via LSF-1.","date":"2015","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/26723877","citation_count":54,"is_preprint":false},{"pmid":"31501420","id":"PMC_31501420","title":"CCT3 acts upstream of YAP and TFCP2 as a potential target and tumour biomarker in liver cancer.","date":"2019","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/31501420","citation_count":53,"is_preprint":false},{"pmid":"9192871","id":"PMC_9192871","title":"Mitogenic stimulation of resting T cells causes rapid phosphorylation of the transcription factor LSF and increased DNA-binding activity.","date":"1997","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/9192871","citation_count":53,"is_preprint":false},{"pmid":"29091762","id":"PMC_29091762","title":"TFCP2 Is Required for YAP-Dependent Transcription to Stimulate Liver Malignancy.","date":"2017","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/29091762","citation_count":47,"is_preprint":false},{"pmid":"9668115","id":"PMC_9668115","title":"LSF and NTF-1 share a conserved DNA recognition motif yet require different oligomerization states to form a stable protein-DNA complex.","date":"1998","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9668115","citation_count":47,"is_preprint":false},{"pmid":"12555245","id":"PMC_12555245","title":"Association of the 3' UTR transcription factor LBP-1c/CP2/LSF polymorphism with late-onset Alzheimer's disease.","date":"2003","source":"American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/12555245","citation_count":44,"is_preprint":false},{"pmid":"8157699","id":"PMC_8157699","title":"Characterization of the genomic structure, chromosomal location, promoter, and development expression of the alpha-globin transcription factor CP2.","date":"1994","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8157699","citation_count":44,"is_preprint":false},{"pmid":"7582456","id":"PMC_7582456","title":"Dose-response comparisons of five lung surfactant factor (LSF) preparations in an animal model of adult respiratory distress syndrome (ARDS).","date":"1995","source":"British journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/7582456","citation_count":44,"is_preprint":false},{"pmid":"16347859","id":"PMC_16347859","title":"Hydroxylation and Dechlorination of Tetrachlorohydroquinone by Rhodococcus sp. Strain CP-2 Cell Extracts.","date":"1989","source":"Applied and environmental microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/16347859","citation_count":44,"is_preprint":false},{"pmid":"22679558","id":"PMC_22679558","title":"The transcription factor LSF: a novel oncogene for hepatocellular carcinoma.","date":"2012","source":"American journal of cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/22679558","citation_count":43,"is_preprint":false},{"pmid":"29309642","id":"PMC_29309642","title":"Structural basis of gene regulation by the Grainyhead/CP2 transcription factor family.","date":"2018","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/29309642","citation_count":42,"is_preprint":false},{"pmid":"1313810","id":"PMC_1313810","title":"Activation of RNA polymerase II transcription by the specific DNA-binding protein LSF. Increased rate of binding of the basal promoter factor TFIIB.","date":"1992","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/1313810","citation_count":41,"is_preprint":false},{"pmid":"11073954","id":"PMC_11073954","title":"CRTR-1, a developmentally regulated transcriptional repressor related to the CP2 family of transcription factors.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11073954","citation_count":41,"is_preprint":false},{"pmid":"9753426","id":"PMC_9753426","title":"Transcription factor CP2 is essential for lens-specific expression of the chicken alphaA-crystallin gene.","date":"1998","source":"Genes to cells : devoted to molecular & cellular mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/9753426","citation_count":40,"is_preprint":false},{"pmid":"22396589","id":"PMC_22396589","title":"Antiproliferative small-molecule inhibitors of transcription factor LSF reveal oncogene addiction to LSF in hepatocellular carcinoma.","date":"2012","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/22396589","citation_count":37,"is_preprint":false},{"pmid":"18787404","id":"PMC_18787404","title":"The fold recognition of CP2 transcription factors gives new insights into the function and evolution of tumor suppressor protein p53.","date":"2008","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/18787404","citation_count":37,"is_preprint":false},{"pmid":"22167195","id":"PMC_22167195","title":"Late SV40 factor (LSF) enhances angiogenesis by transcriptionally up-regulating matrix metalloproteinase-9 (MMP-9).","date":"2011","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22167195","citation_count":36,"is_preprint":false},{"pmid":"20398424","id":"PMC_20398424","title":"The evolutionary diversification of LSF and Grainyhead transcription factors preceded the radiation of basal animal lineages.","date":"2010","source":"BMC evolutionary biology","url":"https://pubmed.ncbi.nlm.nih.gov/20398424","citation_count":35,"is_preprint":false},{"pmid":"10973979","id":"PMC_10973979","title":"Identification and characterization of a critical CP2-binding element in the human interleukin-4 promoter.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10973979","citation_count":35,"is_preprint":false},{"pmid":"25609232","id":"PMC_25609232","title":"Characterization of genome-wide TFCP2 targets in hepatocellular carcinoma: implication of targets FN1 and TJP1 in metastasis.","date":"2015","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/25609232","citation_count":33,"is_preprint":false},{"pmid":"16645641","id":"PMC_16645641","title":"Intracellular domains of amyloid precursor-like protein 2 interact with CP2 transcription factor in the nucleus and induce glycogen synthase kinase-3beta expression.","date":"2006","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/16645641","citation_count":33,"is_preprint":false},{"pmid":"21703197","id":"PMC_21703197","title":"c-Met activation through a novel pathway involving osteopontin mediates oncogenesis by the transcription factor LSF.","date":"2011","source":"Journal of hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/21703197","citation_count":33,"is_preprint":false},{"pmid":"2847787","id":"PMC_2847787","title":"Hydrogen-1 nuclear magnetic resonance of the nitrogenase iron protein (Cp2) from Clostridium pasteurianum.","date":"1988","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/2847787","citation_count":32,"is_preprint":false},{"pmid":"30241344","id":"PMC_30241344","title":"Neglected Functions of TFCP2/TFCP2L1/UBP1 Transcription Factors May Offer Valuable Insights into Their Mechanisms of Action.","date":"2018","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/30241344","citation_count":31,"is_preprint":false},{"pmid":"10995745","id":"PMC_10995745","title":"Targeted disruption of the CP2 gene, a member of the NTF family of transcription factors.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10995745","citation_count":31,"is_preprint":false},{"pmid":"19902333","id":"PMC_19902333","title":"The male-determining gene SRY is a hybrid of DGCR8 and SOX3, and is regulated by the transcription factor CP2.","date":"2009","source":"Molecular and cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19902333","citation_count":30,"is_preprint":false},{"pmid":"16648487","id":"PMC_16648487","title":"Functional interaction of CP2 with GATA-1 in the regulation of erythroid promoters.","date":"2006","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/16648487","citation_count":30,"is_preprint":false},{"pmid":"11786187","id":"PMC_11786187","title":"Cloning, expression and processing of the CP2 neuropeptide precursor of Aplysia.","date":"2001","source":"Peptides","url":"https://pubmed.ncbi.nlm.nih.gov/11786187","citation_count":30,"is_preprint":false},{"pmid":"28182010","id":"PMC_28182010","title":"MicroRNA-144 is regulated by CP2 and decreases COX-2 expression and PGE2 production in mouse ovarian granulosa cells.","date":"2017","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/28182010","citation_count":30,"is_preprint":false},{"pmid":"11283204","id":"PMC_11283204","title":"Genetic association of an LBP-1c/CP2/LSF gene polymorphism with late onset Alzheimer's disease.","date":"2001","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/11283204","citation_count":29,"is_preprint":false},{"pmid":"15988015","id":"PMC_15988015","title":"Erythroid cell-specific alpha-globin gene regulation by the CP2 transcription factor family.","date":"2005","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/15988015","citation_count":28,"is_preprint":false},{"pmid":"19556876","id":"PMC_19556876","title":"Transcription factors LSF and E2Fs: tandem cyclists driving G0 to S?","date":"2009","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/19556876","citation_count":27,"is_preprint":false},{"pmid":"30948206","id":"PMC_30948206","title":"Spindle cell rhabdomyosarcoma in a lumbar vertebra with FUS-TFCP2 fusion.","date":"2019","source":"Pathology, research and practice","url":"https://pubmed.ncbi.nlm.nih.gov/30948206","citation_count":27,"is_preprint":false},{"pmid":"14727189","id":"PMC_14727189","title":"A novel Cryptosporidium parvum antigen, CP2, preferentially associates with membranous structures.","date":"2004","source":"Parasitology research","url":"https://pubmed.ncbi.nlm.nih.gov/14727189","citation_count":27,"is_preprint":false},{"pmid":"29050300","id":"PMC_29050300","title":"TFCP2 activates beta-catenin/TCF signaling in the progression of pancreatic cancer.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/29050300","citation_count":26,"is_preprint":false},{"pmid":"12858339","id":"PMC_12858339","title":"Mammalian transcription factor LSF is a target of ERK signaling.","date":"2003","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12858339","citation_count":26,"is_preprint":false},{"pmid":"38583649","id":"PMC_38583649","title":"TRAF6 enhances PD-L1 expression through YAP1-TFCP2 signaling in melanoma.","date":"2024","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/38583649","citation_count":25,"is_preprint":false},{"pmid":"26506241","id":"PMC_26506241","title":"Transcription factor LSF (TFCP2) inhibits melanoma growth.","date":"2016","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/26506241","citation_count":25,"is_preprint":false},{"pmid":"32193292","id":"PMC_32193292","title":"A Feedback Loop Comprising EGF/TGFα Sustains TFCP2-Mediated Breast Cancer Progression.","date":"2020","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/32193292","citation_count":25,"is_preprint":false},{"pmid":"33892791","id":"PMC_33892791","title":"DNA hypermethylation contributes to colorectal cancer metastasis by regulating the binding of CEBPB and TFCP2 to the CPEB1 promoter.","date":"2021","source":"Clinical epigenetics","url":"https://pubmed.ncbi.nlm.nih.gov/33892791","citation_count":25,"is_preprint":false},{"pmid":"24123743","id":"PMC_24123743","title":"Characterization of bacteriophages Cp1 and Cp2, the strain-typing agents for Xanthomonas axonopodis pv. citri.","date":"2013","source":"Applied and environmental microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/24123743","citation_count":25,"is_preprint":false},{"pmid":"7626919","id":"PMC_7626919","title":"Effects of lung surfactant factor (LSF) treatment on gas exchange and histopathological changes in an animal model of adult respiratory distress syndrome (ARDS): comparison of recombinant LSF with bovine LSF.","date":"1994","source":"Pulmonary pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/7626919","citation_count":25,"is_preprint":false},{"pmid":"35193647","id":"PMC_35193647","title":"Overexpressed integrin alpha 2 inhibits the activation of the transforming growth factor β pathway in pancreatic cancer via the TFCP2-SMAD2 axis.","date":"2022","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/35193647","citation_count":25,"is_preprint":false},{"pmid":"8972558","id":"PMC_8972558","title":"Allograft acceptance and rejection, mediated by a liver suppressor factor, LSF-1, purified from serum of liver transplanted rats.","date":"1996","source":"Transplant immunology","url":"https://pubmed.ncbi.nlm.nih.gov/8972558","citation_count":25,"is_preprint":false},{"pmid":"12661759","id":"PMC_12661759","title":"CP2 binding to the promoter is essential for the enhanced transcription of globin genes in erythroid cells.","date":"2003","source":"Molecules and cells","url":"https://pubmed.ncbi.nlm.nih.gov/12661759","citation_count":24,"is_preprint":false},{"pmid":"16650991","id":"PMC_16650991","title":"Synthesis and biological evaluation of lisofylline (LSF) analogs as a potential treatment for Type 1 diabetes.","date":"2006","source":"Bioorganic & medicinal chemistry letters","url":"https://pubmed.ncbi.nlm.nih.gov/16650991","citation_count":24,"is_preprint":false},{"pmid":"21739942","id":"PMC_21739942","title":"Total synthesis of (-)-CP2-disorazole C1.","date":"2011","source":"Organic letters","url":"https://pubmed.ncbi.nlm.nih.gov/21739942","citation_count":23,"is_preprint":false},{"pmid":"8063751","id":"PMC_8063751","title":"Evidence that levels of the dimeric cellular transcription factor CP2 play little role in the activation of the HIV-1 long terminal repeat in vivo or following superinfection with herpes simplex virus type 1.","date":"1994","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8063751","citation_count":23,"is_preprint":false},{"pmid":"38168093","id":"PMC_38168093","title":"Multi-omic and functional analysis for classification and treatment of sarcomas with FUS-TFCP2 or EWSR1-TFCP2 fusions.","date":"2024","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/38168093","citation_count":22,"is_preprint":false},{"pmid":"35768243","id":"PMC_35768243","title":"EWSR1-TFCP2 in an adolescent represents an extremely rare and aggressive form of intraosseous spindle cell rhabdomyosarcomas.","date":"2022","source":"Cold Spring Harbor molecular case studies","url":"https://pubmed.ncbi.nlm.nih.gov/35768243","citation_count":22,"is_preprint":false},{"pmid":"36688410","id":"PMC_36688410","title":"C. elegans molting requires rhythmic accumulation of the Grainyhead/LSF transcription factor GRH-1.","date":"2023","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/36688410","citation_count":22,"is_preprint":false},{"pmid":"26378040","id":"PMC_26378040","title":"GRP78 confers the resistance to 5-FU by activating the c-Src/LSF/TS axis in hepatocellular carcinoma.","date":"2015","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/26378040","citation_count":22,"is_preprint":false},{"pmid":"32111740","id":"PMC_32111740","title":"The microtubule-associated histone methyltransferase SET8, facilitated by transcription factor LSF, methylates α-tubulin.","date":"2020","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/32111740","citation_count":21,"is_preprint":false},{"pmid":"18060431","id":"PMC_18060431","title":"CP2 gene as a useful viability marker for Cryptosporidium parvum.","date":"2007","source":"Parasitology research","url":"https://pubmed.ncbi.nlm.nih.gov/18060431","citation_count":21,"is_preprint":false},{"pmid":"36374445","id":"PMC_36374445","title":"Rhabdomyosarcoma with TFCP2 Rearrangement or Typical Co-expression of AE1/AE3 and ALK: Report of Three New Cases in the Head and Neck Region and Literature Review.","date":"2022","source":"Head and neck pathology","url":"https://pubmed.ncbi.nlm.nih.gov/36374445","citation_count":20,"is_preprint":false},{"pmid":"19237534","id":"PMC_19237534","title":"Phosphorylation by cyclin C/cyclin-dependent kinase 2 following mitogenic stimulation of murine fibroblasts inhibits transcriptional activity of LSF during G1 progression.","date":"2009","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/19237534","citation_count":19,"is_preprint":false},{"pmid":"15857981","id":"PMC_15857981","title":"Mitogen-activated protein kinases regulate LSF occupancy at the human immunodeficiency virus type 1 promoter.","date":"2005","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/15857981","citation_count":18,"is_preprint":false},{"pmid":"15720400","id":"PMC_15720400","title":"Identification and characterization of four novel peptide motifs that recognize distinct regions of the transcription factor CP2.","date":"2005","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/15720400","citation_count":18,"is_preprint":false},{"pmid":"29423052","id":"PMC_29423052","title":"MAGE-A11 is activated through TFCP2/ZEB1 binding sites de-methylation as well as histone modification and facilitates ESCC tumor growth.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/29423052","citation_count":17,"is_preprint":false},{"pmid":"10491335","id":"PMC_10491335","title":"Transcription factor CP2 is crucial in hemoglobin synthesis during erythroid terminal differentiation in vitro.","date":"1999","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/10491335","citation_count":16,"is_preprint":false},{"pmid":"36350070","id":"PMC_36350070","title":"Clinicopathological features of rhabdomyosarcoma with novel FET::TFCP2 and TIMP3::ALK fusion: report of two cases and literature review.","date":"2022","source":"Histopathology","url":"https://pubmed.ncbi.nlm.nih.gov/36350070","citation_count":15,"is_preprint":false},{"pmid":"9354187","id":"PMC_9354187","title":"Regulation of the secretion and synthesis of rat Sertoli cell SGP-1, SGP-2 and CP-2 by elongate spermatids.","date":"1997","source":"International journal of andrology","url":"https://pubmed.ncbi.nlm.nih.gov/9354187","citation_count":15,"is_preprint":false},{"pmid":"38114270","id":"PMC_38114270","title":"Spindle cell rhabdomyosarcomas: With TFCP2 rearrangements, and novel EWSR1::ZBTB41 and PLOD2::RBM6 gene fusions. A study of five cases and review of the literature.","date":"2023","source":"Histopathology","url":"https://pubmed.ncbi.nlm.nih.gov/38114270","citation_count":14,"is_preprint":false},{"pmid":"16272261","id":"PMC_16272261","title":"Further evidence for LBP-1c/CP2/LSF association in Alzheimer's disease families.","date":"2005","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/16272261","citation_count":14,"is_preprint":false},{"pmid":"36437645","id":"PMC_36437645","title":"Rhabdomyosarcoma With FUS::TFCP2 Fusion in the Scalp: A Rare Case Report Depicting Round and Spindle cell Morphology.","date":"2022","source":"International journal of surgical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/36437645","citation_count":14,"is_preprint":false},{"pmid":"27626695","id":"PMC_27626695","title":"Grifolin inhibits tumor cells adhesion and migration via suppressing interplay between PGC1α and Fra-1 / LSF- MMP2 / CD44 axes.","date":"2016","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/27626695","citation_count":14,"is_preprint":false},{"pmid":"34804919","id":"PMC_34804919","title":"TFCP2 Overcomes Senescence by Cooperating With SREBP2 to Activate Cholesterol Synthesis in Pancreatic Cancer.","date":"2021","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/34804919","citation_count":13,"is_preprint":false},{"pmid":"32539694","id":"PMC_32539694","title":"Targeting the oncogene LSF with either the small molecule inhibitor FQI1 or siRNA causes mitotic delays with unaligned chromosomes, resulting in cell death or senescence.","date":"2020","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/32539694","citation_count":13,"is_preprint":false},{"pmid":"36474403","id":"PMC_36474403","title":"Intraosseous Spindle Cell/Epithelioid Rhabdomyosarcoma with TFCP2 Rearrangement: A Recent Recognized Subtype with Partial Response to Alectinib.","date":"2022","source":"International journal of surgical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/36474403","citation_count":13,"is_preprint":false},{"pmid":"17902044","id":"PMC_17902044","title":"Potential interaction between the GARS-AIRS-GART Gene and CP2/LBP-1c/LSF transcription factor in Down syndrome-related Alzheimer disease.","date":"2007","source":"Cellular and molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/17902044","citation_count":12,"is_preprint":false},{"pmid":"33114487","id":"PMC_33114487","title":"Differential Analysis of Stress Tolerance and Transcriptome of Probiotic Lacticaseibacillus casei Zhang Produced from Solid-State (SSF-SW) and Liquid-State (LSF-MRS) Fermentations.","date":"2020","source":"Microorganisms","url":"https://pubmed.ncbi.nlm.nih.gov/33114487","citation_count":12,"is_preprint":false},{"pmid":"35274492","id":"PMC_35274492","title":"circITCH suppresses cell proliferation and metastasis through miR-660/TFCP2 pathway in melanoma.","date":"2022","source":"Cancer medicine","url":"https://pubmed.ncbi.nlm.nih.gov/35274492","citation_count":11,"is_preprint":false},{"pmid":"16710089","id":"PMC_16710089","title":"Association of polymorphism in the transcription factor LBP-1c/CP2/LSF gene with Alzheimer's disease and major depression.","date":"2006","source":"Dementia and geriatric cognitive disorders","url":"https://pubmed.ncbi.nlm.nih.gov/16710089","citation_count":11,"is_preprint":false},{"pmid":"35421367","id":"PMC_35421367","title":"TFCP2, a binding protein of ATF3, promotes the progression of glioma by activating the synthesis of serine.","date":"2022","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/35421367","citation_count":11,"is_preprint":false},{"pmid":"15232220","id":"PMC_15232220","title":"Transcription factor CP2 is involved in activating mBMP4 in mouse mesenchymal stem cells.","date":"2004","source":"Molecules and cells","url":"https://pubmed.ncbi.nlm.nih.gov/15232220","citation_count":11,"is_preprint":false},{"pmid":"24765146","id":"PMC_24765146","title":"Expression of TSG101 protein and LSF transcription factor in HPV-positive cervical cancer cells.","date":"2014","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/24765146","citation_count":11,"is_preprint":false},{"pmid":"37669767","id":"PMC_37669767","title":"Cutaneous rhabdomyosarcoma with FUS::TFCP2 fusion: A case report emphasizing early detection.","date":"2023","source":"Journal of cutaneous pathology","url":"https://pubmed.ncbi.nlm.nih.gov/37669767","citation_count":11,"is_preprint":false},{"pmid":"39302072","id":"PMC_39302072","title":"Diagnostic and Therapeutic Implications of a FUS::TFCP2 Fusion and ALK Activation in a Metastatic Rhabdomyosarcoma.","date":"2024","source":"Genes, chromosomes & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/39302072","citation_count":10,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":49339,"output_tokens":10846,"usd":0.155354,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":21692,"output_tokens":5623,"usd":0.124518,"stage2_stop_reason":"end_turn"},"total_usd":0.279872,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1990,\n      \"finding\": \"LSF (TFCP2) was purified as a 63-kDa polypeptide that binds two distinct bipartite sites within the SV40 late promoter (LSF-GC site and LSF-280 site), recognizing directly repeated GC motifs with a center-to-center spacing of 10 bp, and activates transcription from the SV40 late promoter in vitro via binding to template DNA at initiation site L325.\",\n      \"method\": \"Protein purification, DNA affinity chromatography, methylation interference, in vitro transcription assay\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro biochemical reconstitution with purified protein, multiple orthogonal methods (binding, footprinting, transcription assay)\",\n      \"pmids\": [\"2159933\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"CP2 (TFCP2) was molecularly cloned; bacterial expression of the full-length 502-aa murine factor or a core region (aa 133–395) generated polypeptides with the DNA-binding specificity of CP2, delimiting the region sufficient for specific DNA sequence recognition. The factor activates transcription of alpha-globin promoter templates ~3–4 fold in vitro.\",\n      \"method\": \"cDNA cloning, bacterial expression, DNase I footprinting, EMSA, in vitro transcription\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution with bacterially expressed protein, multiple orthogonal methods, domain mapping by truncation\",\n      \"pmids\": [\"1732747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"LSF (TFCP2) activates RNA polymerase II transcription by increasing the rate of association of TFIIB with the committed template on the SV40 major late promoter; LSF has no effect on TFIID binding rate or stability, but specifically accelerates the TFIIB assembly step.\",\n      \"method\": \"In vitro transcription kinetics, band mobility shift assays, general transcription factor titration\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mechanistic reconstitution in vitro with multiple rate measurements and factor-specific dissection\",\n      \"pmids\": [\"1313810\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"CP2 (TFCP2) binds a hyphenated recognition sequence motif spanning one DNA helix turn; elevated CP2 levels (2.5–5.5-fold) in stably transformed cells increased alpha-globin promoter-driven reporter activity 3–6 fold in vivo, confirming direct transcriptional activation.\",\n      \"method\": \"DNase I footprinting, EMSA, stable/transient transfection, CAT reporter assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro and in vivo assays with purified bacterially expressed protein and stable cell lines\",\n      \"pmids\": [\"8349681\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"LSF (TFCP2) binds DNA as a homodimer, as demonstrated by an epitope-counting method. The alternatively spliced isoform LSF-ID lacks two beta-strand-forming regions conserved with Drosophila Elf-1/NTF-1; double amino acid substitutions in each of these regions eliminated specific DNA-binding activity. Mutations in one homology region, but not the other, eliminated dimerization.\",\n      \"method\": \"Epitope-counting EMSA, mutagenesis, protein-protein interaction studies\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis combined with quantitative DNA-binding and dimerization assays, multiple orthogonal approaches\",\n      \"pmids\": [\"8035790\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"The DNA-binding and dimerization domains of Drosophila Grainyhead are conserved in human CP2 (TFCP2). The DNA-binding domain (263 aa) contains a smaller core; the major dimerization domain is in a separate region and is required to stabilize DNA interactions. An N-terminal inhibitory domain can modulate activity.\",\n      \"method\": \"Domain deletion mapping, DNA-binding assays, dimerization assays in Drosophila and vertebrate (CP2) proteins\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — systematic domain mapping with functional validation for both Grainyhead and CP2\",\n      \"pmids\": [\"8196641\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"CP2 (TFCP2) is pivotal to, but not sufficient for, the stage selector protein (SSP) complex that binds the stage selector element (SSE) in the gamma-globin promoter. CP2 requires a heterodimeric partner (~40–45 kDa) present in K562 cells to bind the SSE. The SSP complex is disrupted by anti-CP2 antiserum. The analogous chicken complex includes NF-E4, which is homologous to CP2.\",\n      \"method\": \"Biochemical purification, EMSA, UV and protein cross-linking, anti-CP2 antiserum disruption, Western blot\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — biochemical purification and reconstitution, multiple orthogonal methods including cross-linking and immunodepletion\",\n      \"pmids\": [\"7828600\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"LSF (TFCP2) and YY1 cooperate to form a complex that recognizes the initiation region of the HIV-1 LTR and cooperatively repress LTR transcription and viral replication; transient expression of LSF alone has no effect, but cooperation with YY1 is required for repression in vivo.\",\n      \"method\": \"EMSA, transient transfection, viral replication assay\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — replicated across multiple experiments; cooperative binding and functional repression demonstrated\",\n      \"pmids\": [\"9371597\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"LSF (TFCP2) DNA-binding activity is rapidly and quantitatively increased (~5-fold within 15 min) by mitogenic stimulation of resting human peripheral T lymphocytes, correlating with phosphorylation-induced reduction in LSF electrophoretic mobility. ERK1 (pp44) phosphorylates LSF in vitro at the same residue phosphorylated in vivo (position 291). Phosphatase treatment in vitro increases LSF mobility and decreases DNA-binding activity, confirming that phosphorylation directly increases DNA-binding.\",\n      \"method\": \"EMSA, in vitro kinase assay, mutagenesis (S291 mutant), phosphatase treatment, primary T lymphocyte stimulation\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct phosphorylation demonstrated in vitro and in vivo with mutagenesis and phosphatase validation\",\n      \"pmids\": [\"9192871\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"LSF (TFCP2) binds DNA as a tetramer (larger than a dimer) for high-affinity binding, requiring 234–320 amino acids. NTF-1 (Drosophila ortholog) can bind an LSF half-site as a dimer, whereas LSF cannot, indicating different oligomerization requirements despite shared DNA-binding domains.\",\n      \"method\": \"Truncation mutagenesis, EMSA, cross-linking experiments, mixing assays with full-length and truncation mutants\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — systematic truncation mutagenesis with quantitative DNA-binding and oligomerization analyses\",\n      \"pmids\": [\"9668115\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"The Fe65 adaptor protein interacts with CP2/LSF/LBP1 (TFCP2) through its N-terminal PID1 domain, as shown by yeast two-hybrid and co-immunoprecipitation of native molecules. Different isoforms of CP2/LSF/LBP1 are distributed differently among subcellular fractions; at least one splice isoform (LSF-ID) is present outside the nucleus, while Fe65 is found in both nuclear and non-nuclear fractions.\",\n      \"method\": \"Interaction trap (yeast two-hybrid), co-immunoprecipitation, subcellular fractionation, transfection with HA-tagged constructs\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP of native proteins plus yeast two-hybrid, domain mapping, and localization data\",\n      \"pmids\": [\"9685356\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Chicken CP2 (cCP2, TFCP2) forms a tetramer as shown by EMSA and cross-linking experiments. cCP2 is essential for transcription through the alphaA-crystallin lens enhancer alphaCE1; lens-specific enhancer activity depends on a 6-bp sequence (LSE) adjacent to the CP2 binding site, suggesting cooperation between cCP2 tetramer and a lens-specific factor binding LSE.\",\n      \"method\": \"EMSA, protein cross-linking, overexpression/dominant negative transfection, element substitution experiments\",\n      \"journal\": \"Genes to cells\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — biochemical demonstration of tetramer, loss-of-function with dominant negative, element substitution mapping\",\n      \"pmids\": [\"9753426\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"LSF (TFCP2) binds sites within the thymidylate synthase (TS) promoter and intronic regions required for G1-S induction. Expression of dominant-negative LSF prevents the increase in TS enzyme levels during G1-S and induces S-phase-dependent apoptosis (thymineless death), which can be rescued by thymidine supplementation or heterologous TS expression.\",\n      \"method\": \"Reporter mutation analysis, dominant-negative expression, enzyme activity assay, apoptosis assays, rescue experiments\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function with specific phenotypic readout, two independent rescue approaches confirming mechanism\",\n      \"pmids\": [\"10970859\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"YY1 and LSF (TFCP2) cooperate to recruit HDAC1 to the HIV-1 LTR; HDAC1 co-purifies with the LTR-bound YY1-LSF repressor complex. LSF recruits YY1 to the LTR via YY1's zinc fingers (first two zinc fingers sufficient in vitro). The HDAC1-interacting domain of YY1 is required for LTR repression, and HDAC inhibitor trichostatin A blocks YY1-mediated repression.\",\n      \"method\": \"Co-purification, EMSA, HDAC inhibitor (TSA) treatment, deletion mutant analysis, HDAC1 overexpression\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — co-purification of ternary complex, domain mapping, pharmacological and genetic validation across multiple experiments\",\n      \"pmids\": [\"10888618\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Targeted disruption of CP2 (TFCP2) in mice produces viable animals with no apparent defects in hematopoiesis, globin gene expression, or immune responses. In CP2-null extracts, a slower-migrating complex bound to CP2 consensus sites is recognized by anti-NF2d9 (LBP-1a) antiserum, and recombinant LBP-1a can bind CP2 sites and form complexes with CP2 heteromeric partners, indicating functional compensation by the paralog LBP-1a/NF2d9.\",\n      \"method\": \"Gene targeting (knockout mice), EMSA with nuclear extracts, antiserum supershift, recombinant protein binding assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — knockout mouse model with comprehensive phenotypic analysis plus biochemical compensation mechanism identified\",\n      \"pmids\": [\"10995745\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Mutations in a putative CP2 (TFCP2) binding motif (-90C to A) in the uroporphyrinogen III synthase erythroid-specific promoter alter CP2 binding (EMSA) and reduce promoter activity to ~8% of wild-type in K562 cells, causing congenital erythropoietic porphyria. An adjacent -86A mutation does not alter CP2 binding.\",\n      \"method\": \"Sequencing, luciferase reporter assay, EMSA\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct binding disruption by mutation confirmed by EMSA, functional consequence confirmed by reporter assay\",\n      \"pmids\": [\"11254675\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"LSF (TFCP2) is rapidly and quantitatively phosphorylated upon growth induction in NIH 3T3 cells; ERK is responsible for this phosphorylation, as shown by correlation of ERK activity with LSF phosphorylation and by specific MEK/ERK pathway inhibitors blocking LSF modification. ERK phosphorylation is necessary but not sufficient for activation of LSF DNA-binding activity (DNA-binding is not significantly altered in fibroblasts despite phosphorylation).\",\n      \"method\": \"Electrophoretic mobility shift, in vitro kinase assay, pharmacological inhibitors of Ras/Raf/MEK/ERK, cell fractionation\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — three independent lines of evidence (correlation, sufficiency in vitro, inhibitor abrogation) establishing ERK as the kinase\",\n      \"pmids\": [\"12858339\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"CP2 (TFCP2) binds erythroid regulatory regions of the GATA-1, EKLF, and p45 NF-E2 genes and forms a ternary complex with GATA-1 and DNA at the GATA-1 HS2 enhancer. CP2 physically interacts with GATA-1 (demonstrated by co-immunoprecipitation and GST pull-down). Both factors occupy the same regulatory elements in vivo (chromatin IP). Mutation of the CP2 consensus in these elements severely impairs enhancer activity in K562 cells.\",\n      \"method\": \"EMSA, ChIP, co-immunoprecipitation, GST pull-down, transient transfection reporter assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP plus GST pull-down confirming direct interaction, ChIP confirming in vivo co-occupancy, functional validation\",\n      \"pmids\": [\"16648487\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Two HXPR-motif-containing proteins, REST and YY1, bind CP2 (TFCP2) via their HXPR sequences; GST pull-down and co-immunoprecipitation confirm this interaction. Double amino acid substitution in the HXPR sequence of YY1 abolishes binding to CP2 and eliminates YY1's suppression of CP2 transcriptional activity. At least three distinct binding regions on CP2 accommodate four different peptide motifs (HXPR, PHL, ASR, PXHXH).\",\n      \"method\": \"Peptide library screen, GST pull-down, co-immunoprecipitation, site-directed mutagenesis, transcriptional reporter assay\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal binding assays with mutagenesis validating the functional relevance of the interaction\",\n      \"pmids\": [\"15720400\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Erythroid cell-specific alpha-globin transactivation by CP2 (TFCP2) requires specific splice variants: CP2b (with an extra 36-aa exon) forms heteromeric complexes with CP2c; this heterodimer activates alpha-globin specifically in erythroid cells but not in non-erythroid 293T cells. Addition of PIAS1 (identified as a CP2-binding protein by yeast two-hybrid and confirmed by co-immunoprecipitation) restores alpha-globin activation in 293T cells, identifying PIAS1 as the missing erythroid cofactor.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, luciferase reporter in erythroid and non-erythroid cells, expression of recombinant isoforms\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — yeast two-hybrid confirmed by co-IP, functional reconstitution in non-erythroid cells with defined cofactors\",\n      \"pmids\": [\"15988015\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"APLP2 intracellular C-terminal domain (ICD) interacts with CP2 (TFCP2) in the nucleus and induces expression of GSK-3β. Nuclear colocalization and interaction were demonstrated, and GSK-3β protein levels increased upon APLP2-ICD expression.\",\n      \"method\": \"Co-immunoprecipitation, transfection, immunofluorescence, Western blot\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab, co-IP and reporter readout; no direct mutagenesis of the interaction\",\n      \"pmids\": [\"16645641\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"LSF (TFCP2) is phosphorylated by cyclin C/CDK2 (and cyclin C/CDK3 in humans) predominantly at S309 during early G1 after mitogenic stimulation of quiescent fibroblasts. This phosphorylation is mediated by cyclin C-dependent kinases (confirmed by co-immunoprecipitation and siRNA knockdown of cyclin C), and phosphorylation at S309 inhibits LSF transactivation and prevents induction of the LSF target gene Tyms at G1/S.\",\n      \"method\": \"In vitro kinase assays, mutagenesis (S309), co-immunoprecipitation, siRNA knockdown of cyclin C, transient transfection reporter, endogenous Tyms expression\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase assay with mutagenesis, confirmed in vivo by siRNA and co-IP, functional read-out with endogenous target gene\",\n      \"pmids\": [\"19237534\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"LSF (TFCP2) binds the HIV-1 LTR as a tetramer; ERK phosphorylation of LSF decreases its binding to the LTR in vitro, while p38 phosphorylation increases binding. In cells, p38 agonist increases LSF occupancy at LTR chromatin; p38 inhibition decreases LSF occupancy, increases histone H4 acetylation at the adjacent nucleosome, blocks YY1-mediated LTR repression, and results in recovery of HIV from resting CD4+ T cells of aviremic donors.\",\n      \"method\": \"EMSA, ChIP, kinase assays, pharmacological p38 inhibition/agonism, HIV recovery assay from primary cells\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods including ChIP, in vitro kinase assays, and primary cell HIV recovery\",\n      \"pmids\": [\"15857981\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"LSF (TFCP2) functions as an oncogene in hepatocellular carcinoma: LSF overexpression promotes aggressive, angiogenic, and multiorgan metastatic tumors in nude mice, while inhibition abrogates growth and metastasis. LSF transcriptionally upregulates osteopontin (OPN), which mediates key oncogenic functions; loss of OPN impairs LSF-driven tumorigenesis.\",\n      \"method\": \"Stable overexpression/dominant-negative, nude mouse xenograft, microarray, loss-of-function studies with siRNA/shRNA\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — xenograft gain/loss of function in vivo, target gene identified and functionally validated by loss-of-function\",\n      \"pmids\": [\"20404171\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"LSF (TFCP2) transcriptionally upregulates MMP-9 to enhance angiogenesis in HCC. ChIP-on-chip identified MMP-9 as a direct LSF target; ChIP confirmed LSF binding to the MMP-9 promoter. Deletion mutation analysis identified LSF-responsive promoter regions. MMP-9 inhibition abrogated LSF-induced angiogenesis and tumorigenesis in vivo.\",\n      \"method\": \"ChIP-on-chip, ChIP-PCR, promoter deletion reporter assays, HUVEC differentiation assay, CAM assay, nude mouse xenograft\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct ChIP confirming promoter binding, functional validation in multiple angiogenesis assays and in vivo\",\n      \"pmids\": [\"22167195\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"LSF (TFCP2) activates c-Met signaling in HCC through a pathway involving LSF-driven OPN secretion activating c-Met via CD44. Co-immunoprecipitation confirmed OPN-induced CD44/c-Met interaction. Chemical or genetic inhibition of c-Met abrogates LSF-mediated tumorigenesis and metastasis in vivo.\",\n      \"method\": \"Phospho-RTK array, co-immunoprecipitation, tissue microarray IHC, siRNA, chemical inhibitor, nude mouse xenograft\",\n      \"journal\": \"Journal of hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pathway elucidated by phospho-array, co-IP, and in vivo inhibition; indirect (via OPN) link to LSF\",\n      \"pmids\": [\"21703197\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TFCP2 directly regulates FN1 (fibronectin 1) and TJP1 (tight junction protein 1) as transcriptional targets mediating HCC metastasis. ChIP-on-chip combined with transcriptome analysis identified these targets; ChIP-PCR confirmed TFCP2 binding to the FN1 promoter, and promoter reporter identified TFCP2-binding motifs. FN1 inhibition blocks TFCP2-induced aggression; TFCP2 overexpression rescues FN1 inhibition.\",\n      \"method\": \"ChIP-on-chip, transcriptome microarray, ChIP-PCR, promoter reporter assay, siRNA rescue experiments\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct ChIP confirmation, promoter reporter, and epistasis rescue experiments in single lab\",\n      \"pmids\": [\"25609232\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"LSF (TFCP2) inhibits melanoma cell growth by binding within a 150-bp upstream region of the p21CIP1 transcription start site and increasing p21CIP1 expression, resulting in G1 phase arrest. EMSA and ChIP assays confirmed LSF binding to the p21CIP1 promoter.\",\n      \"method\": \"EMSA, ChIP, overexpression/depletion, cell cycle analysis, anchorage-dependent/independent growth assays, xenograft\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct promoter binding by EMSA and ChIP, phenotype confirmed by in vivo xenograft\",\n      \"pmids\": [\"26506241\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TFCP2 is required for YAP-dependent transcription in liver cancer. Mechanistically, TFCP2 stimulates YAP function via a WW-PSY interaction, maintains YAP stability by inhibiting βTrCP-mediated ubiquitination, and acts as a transcription co-factor facilitating YAP binding to YBF-containing transcription factors and the YAP-TEAD interaction. Genomic co-occupancy of YAP and TFCP2 was revealed by ChIP.\",\n      \"method\": \"Co-immunoprecipitation (WW-PSY interaction), ubiquitination assays, ChIP, luciferase reporter, siRNA/overexpression\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods: protein interaction, ubiquitination, ChIP co-occupancy, and functional transcriptional assays\",\n      \"pmids\": [\"29091762\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Crystal structures of the DNA-binding domains of Grainyhead-like (Grhl) 1 and Grhl2 (close CP2/TFCP2 family members) reveal an immunoglobulin-like core fold shared with p53, with dimeric DNA binding mediated by two conserved arginine residues. A cancer-associated mutation in Grhl1 at one of these arginines completely abrogates DNA binding in biochemical assays and transcriptional activation in human cells.\",\n      \"method\": \"X-ray crystallography, in vitro DNA-binding assays, cancer-mutation analysis, transcriptional reporter assay in human cell line\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with functional mutagenesis validation in vitro and in cells; note these are Grhl1/2 family members, structurally informative for the CP2/TFCP2 family fold\",\n      \"pmids\": [\"29309642\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TFCP2 promotes pancreatic cancer progression by interacting with β-catenin, enhancing the β-catenin/TCF4 interaction, and activating β-catenin/TCF signaling, as demonstrated by co-immunoprecipitation and luciferase reporter assay.\",\n      \"method\": \"Co-immunoprecipitation, luciferase reporter (β-catenin/TCF), overexpression/knockdown, colony formation, in vivo metastasis model\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab, co-IP and reporter assay; mechanism not verified by mutagenesis\",\n      \"pmids\": [\"29050300\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CCT3 co-interacts with YAP and TFCP2 (confirmed by mass spectrometry co-immunoprecipitation) and prolongs their half-lives by blocking PCBP2-induced ubiquitination in a βTrCP-independent manner. PCBP2 directly interacts with YAP via a WB motif-WW domain interaction and indirectly with TFCP2 via YAP. CCT3 separates PCBP2-YAP interactions, preventing ubiquitination of both YAP and TFCP2.\",\n      \"method\": \"Mass spectrometry co-immunoprecipitation, ubiquitination assays, co-immunoprecipitation, Western blot half-life assay\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-identified interaction confirmed by co-IP, ubiquitination mechanism characterized; single lab\",\n      \"pmids\": [\"31501420\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TFCP2 directly bound the promoters of EGF and TGFα to regulate their expression, stimulating autocrine EGFR signaling and AKT activation in triple-negative breast cancer. This creates a positive feedback loop controlling TFCP2-mediated EMT, stemness, and metastasis.\",\n      \"method\": \"ChIP, promoter reporter assay, siRNA/overexpression, EGFR signaling assays, in vivo metastasis model\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct promoter binding confirmed by ChIP, feedback loop validated functionally; single lab\",\n      \"pmids\": [\"32193292\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"LSF (TFCP2) binds α-tubulin and SET8 (KMT5A/PR-Set7), facilitating SET8-mediated methylation of α-tubulin at Lys311. LSF enhances SET8-mediated α-tubulin methylation in vitro; the LSF inhibitor FQI1 counters this facilitation. SET8 bound α-tubulin and methylated it at Lys311 as shown by in vitro radiolabeling, MS, and immunoblotting.\",\n      \"method\": \"In vitro radiolabeling, mass spectrometry, immunoblotting, co-immunoprecipitation, immunofluorescence, GST pull-down, FQI1 inhibitor\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro methylation reconstitution with MS identification of site, protein interactions confirmed by multiple orthogonal methods; single lab\",\n      \"pmids\": [\"32111740\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Inhibition of LSF (TFCP2) by either the small molecule FQI1 or siRNA causes highly similar mitotic delays with condensed, unaligned chromosomes preceding metaphase, leading to multi-nucleation, apoptosis, and senescence. The concordance between FQI1 and siRNA phenotypes confirms LSF as the specific cellular target of FQI1.\",\n      \"method\": \"Time-lapse microscopy, bulk cell synchronization, siRNA knockdown vs. FQI1 treatment comparison, cell death/senescence assays\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two independent loss-of-function methods (small molecule + siRNA) yielding identical mitotic phenotypes\",\n      \"pmids\": [\"32539694\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"TFCP2 acts as a transcription factor that directly binds the SRY promoter (demonstrated by EMSA); TFCP2 suppression by RNAi significantly reduced SRY mRNA expression in cells, while overexpression did not significantly increase SRY mRNA, indicating TFCP2 is required but not limiting for SRY expression.\",\n      \"method\": \"EMSA, RNAi knockdown, overexpression, RT-PCR\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — EMSA confirming direct binding, loss-of-function showing dependence; single lab, single method per claim\",\n      \"pmids\": [\"19902333\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TFCP2 interacts with SREBP2 (co-immunoprecipitation) and synergistically activates expression of HMGCR (a rate-limiting enzyme in cholesterol synthesis), enabling pancreatic cancer cells to overcome oncogene-induced senescence. Statins (which inhibit HMGCR) reversed the anti-senescence effect of TFCP2.\",\n      \"method\": \"Co-immunoprecipitation, qRT-PCR, luciferase reporter, statin treatment, senescence assays (SA-β-gal)\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — co-IP confirmed interaction, pharmacological rescue validates pathway; single lab, limited mechanistic depth\",\n      \"pmids\": [\"34804919\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TFCP2 induces SMAD2 expression as a transcription factor; ITGA2 inhibits the nuclear translocation of TFCP2, thereby reducing SMAD2 transcription and suppressing TGF-β pathway activation. Co-immunoprecipitation and nuclear/cytoplasmic fractionation confirmed that ITGA2 interacts with and retains TFCP2 in the cytoplasm.\",\n      \"method\": \"Co-immunoprecipitation, nuclear/cytoplasmic fractionation, ChIP, luciferase reporter, Western blot, RT-qPCR\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and nuclear fractionation data plus co-IP; single lab\",\n      \"pmids\": [\"35193647\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TFCP2 interacts with ATF3 to cooperatively regulate de novo serine synthesis by promoting ATF3 binding to the PHGDH promoter. Knockdown of TFCP2 significantly inhibited ATF3 binding to the PHGDH promoter, as shown by ChIP.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, siRNA knockdown, cell proliferation and sphere formation assays\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — co-IP and ChIP support the interaction and mechanism; single lab, no mutagenesis\",\n      \"pmids\": [\"35421367\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRAF6 stabilizes YAP1 by K63 poly-ubiquitination, promoting formation of the YAP1/TFCP2 transcriptional complex and subsequent PD-L1 transcription in melanoma. Suppression of TRAF6 down-regulates PD-L1 on the membrane surface of melanoma cells. In vitro and in vivo assays confirmed the TRAF6→YAP1 K63-ubiquitination→YAP1/TFCP2 complex→PD-L1 transcription axis.\",\n      \"method\": \"CRISPR interference screen, ubiquitination assays (K63-specific), co-immunoprecipitation, PD-L1 flow cytometry, luciferase reporter, in vitro/in vivo tumor models\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — K63 ubiquitination specificity demonstrated, co-IP of YAP1/TFCP2 complex, PD-L1 functional readout; single lab\",\n      \"pmids\": [\"38583649\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FUS-TFCP2 fusion protein blocks myogenic differentiation, induces transcription of ALK and truncated TERT, and inhibits DNA repair in rhabdomyosarcoma. Functional studies in cell models showed genomic instability and signs of defective homologous recombination in TFCP2-rearranged tumors.\",\n      \"method\": \"Functional cell-based studies with FUS-TFCP2 expression constructs, transcriptome analysis, DNA repair assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional studies with fusion protein constructs establishing multiple cellular phenotypes; single study\",\n      \"pmids\": [\"38168093\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CP2 (TFCP2) upregulates miR-144 expression in mouse ovarian granulosa cells by directly binding the miR-144 promoter, as shown by luciferase reporter, ChIP, and EMSA. CP2-driven miR-144 expression suppresses COX-2 and reduces PGE2 production.\",\n      \"method\": \"Luciferase reporter, ChIP, EMSA, miR-144 inhibitor/mimic overexpression\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct promoter binding confirmed by EMSA and ChIP with functional output; single lab\",\n      \"pmids\": [\"28182010\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The small molecule FQI1 inhibits LSF (TFCP2) DNA-binding activity in vitro (EMSA) and in cells (ChIP), eliminates transcriptional stimulation of LSF-dependent reporter constructs, and induces rapid cell death in LSF-overexpressing HCC cells without affecting normal hepatocytes. Structure-activity relationships of 23 quinolinones are highly concordant between antiproliferative and LSF-inhibitory activities, confirming LSF as the specific target.\",\n      \"method\": \"EMSA, ChIP, luciferase reporter, cell viability assays, SAR analysis, xenograft mouse model\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (EMSA, ChIP, reporter, SAR) converging on LSF as the specific target with in vivo validation\",\n      \"pmids\": [\"22396589\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TFCP2 (LSF/CP2/LBP-1c) is a transcription factor that binds directly-repeated GC-rich sequences as a tetramer (dimer in solution but tetramer on DNA), activates RNA Pol II transcription by accelerating TFIIB recruitment, and is regulated by post-translational phosphorylation: ERK phosphorylation at S291 activates DNA-binding in T cells (but not fibroblasts), while cyclin C/CDK2-mediated phosphorylation at S309 in early G1 inhibits transactivation until late G1; it drives S-phase progression by directly transactivating thymidylate synthase, activates erythroid gene expression through heteromeric complexes with lineage-specific partners (e.g., a 40–45 kDa partner for globin SSP, CP2b/PIAS1 for alpha-globin), cooperates with YY1 and HDAC1 to repress the HIV-1 LTR, promotes liver cancer through direct transcriptional upregulation of OPN, MMP-9, FN1, and TJP1, facilitates YAP-dependent transcription via a WW-PSY protein interaction, interacts with SET8 to facilitate alpha-tubulin methylation at Lys311, and when fused to FUS/EWSR1 in rhabdomyosarcoma drives ALK upregulation, blocks myogenic differentiation, and induces genomic instability.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TFCP2 (LSF/CP2/LBP-1c) is a sequence-specific RNA Pol II transcription factor that recognizes directly-repeated GC-rich bipartite motifs and activates transcription by accelerating TFIIB recruitment to committed templates [#0, #2]. It engages DNA as a higher-order oligomer\\u2014a dimer in solution that assembles into a tetramer for high-affinity binding\\u2014through DNA-binding and dimerization domains conserved with the Grainyhead/Elf-1/NTF-1 family, whose immunoglobulin-like fold and arginine-mediated DNA contacts are defined structurally in related Grhl proteins [#4, #9, #11, #29]. Its activity is gated by mitogen-driven phosphorylation: ERK modifies S291 and rapidly increases DNA binding in stimulated T lymphocytes, though this modification is necessary but not sufficient for activation in fibroblasts, while cyclin C/CDK2 (CDK3) phosphorylation at S309 in early G1 inhibits transactivation [#8, #16, #21]. TFCP2 drives the G1/S transition by directly transactivating thymidylate synthase, and its inhibition triggers thymineless death or mitotic catastrophe with chromosome misalignment, multinucleation, and apoptosis [#12, #34]. It functions combinatorially with lineage- and context-specific partners: it requires a ~40\\u201345 kDa partner and CP2b/PIAS1 to form the erythroid stage-selector and alpha-globin activating complexes, cooperates with GATA-1 at erythroid regulatory elements, and partners with YY1 to recruit HDAC1 and repress the HIV-1 LTR [#6, #17, #13, #19, #17, #14]. TFCP2 acts as an oncogene in hepatocellular carcinoma by directly upregulating osteopontin, MMP-9, FN1, and TJP1 to drive angiogenesis and metastasis, and stabilizes and co-activates YAP through a WW-PSY interaction to support YAP-TEAD transcription [#23, #24, #26, #28]. Mutations disrupting a TFCP2 binding site in the uroporphyrinogen III synthase erythroid promoter reduce its expression and cause congenital erythropoietic porphyria, and FUS-TFCP2 fusion proteins drive rhabdomyosarcoma by upregulating ALK, blocking myogenic differentiation, and inducing genomic instability [#15, #40]. Beyond transcription, TFCP2 binds \\u03b1-tubulin and SET8 to facilitate \\u03b1-tubulin methylation at Lys311 [#33].\",\n  \"teleology\": [\n    {\n      \"year\": 1990,\n      \"claim\": \"Established TFCP2 as a sequence-specific factor that binds directly-repeated GC motifs and activates RNA Pol II transcription, defining its core biochemical identity.\",\n      \"evidence\": \"Protein purification, methylation interference, and in vitro transcription on the SV40 late promoter\",\n      \"pmids\": [\"2159933\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of transcriptional activation not yet resolved\", \"No in vivo target genes identified\"]\n    },\n    {\n      \"year\": 1992,\n      \"claim\": \"Cloning and reconstitution mapped the region sufficient for DNA recognition and showed the factor activates a physiological (alpha-globin) promoter, while the mechanism of activation was traced to accelerated TFIIB assembly.\",\n      \"evidence\": \"cDNA cloning, bacterial expression, domain truncation, and in vitro transcription kinetics with general factor titration\",\n      \"pmids\": [\"1732747\", \"1313810\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How TFIIB recruitment is accelerated mechanistically unresolved\", \"Activation domain not finely mapped\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Resolved the oligomeric basis of DNA binding\\u2014homodimerization through one of two Grainyhead-conserved regions\\u2014separating dimerization from DNA-contact functions.\",\n      \"evidence\": \"Epitope-counting EMSA, mutagenesis, and domain mapping across CP2 and Drosophila Grainyhead\",\n      \"pmids\": [\"8035790\", \"8196641\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural model of the domains\", \"Role of N-terminal inhibitory domain not defined\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Showed TFCP2 is combinatorial, requiring lineage-specific partners to assemble functional complexes such as the erythroid stage-selector protein.\",\n      \"evidence\": \"Biochemical purification, cross-linking, and antiserum immunodepletion of the SSP complex in K562 cells\",\n      \"pmids\": [\"7828600\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the 40\\u201345 kDa partner not molecularly defined\", \"How partner switching is regulated unknown\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Demonstrated that high-affinity binding requires tetramerization (distinguishing TFCP2 from its dimer-competent Drosophila ortholog) and identified the Fe65 adaptor as a partner with isoform-specific subcellular distribution.\",\n      \"evidence\": \"Truncation mutagenesis, cross-linking, yeast two-hybrid, co-IP, and subcellular fractionation\",\n      \"pmids\": [\"9668115\", \"9685356\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of Fe65 interaction unresolved\", \"Regulation of tetramer assembly unknown\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Defined a repressive role through cooperation with YY1 at the HIV-1 LTR, showing TFCP2 acts as both activator and repressor depending on partners.\",\n      \"evidence\": \"EMSA, transient transfection, and viral replication assays\",\n      \"pmids\": [\"9371597\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Repression mechanism not yet linked to chromatin modifiers\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Connected TFCP2 to cell cycle control by identifying thymidylate synthase as a direct G1/S target whose loss causes thymineless death, and uncovered HDAC1 recruitment as the molecular basis of LTR repression.\",\n      \"evidence\": \"Dominant-negative expression, rescue experiments, enzyme assays, and HDAC1 co-purification with the YY1-LSF complex\",\n      \"pmids\": [\"10970859\", \"10888618\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full set of cell-cycle targets undefined\", \"How activation vs. repression is partner-selected unresolved\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Mouse knockout revealed functional redundancy, showing the paralog LBP-1a/NF2d9 compensates for TFCP2 loss in hematopoiesis and globin expression.\",\n      \"evidence\": \"Gene targeting in mice with EMSA, supershift, and recombinant protein binding\",\n      \"pmids\": [\"10995745\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Non-redundant physiological roles of TFCP2 not isolated\", \"Degree of compensation in other tissues untested\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Defined the erythroid transcriptional network: TFCP2 interacts directly with GATA-1, requires the CP2b isoform plus PIAS1 cofactor for alpha-globin activation, and uses discrete surface motifs to engage HXPR-containing partners REST and YY1.\",\n      \"evidence\": \"Co-IP, GST pull-down, ChIP, yeast two-hybrid, peptide-motif mutagenesis, and reporter assays\",\n      \"pmids\": [\"16648487\", \"15988015\", \"15720400\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of motif recognition not resolved\", \"How isoform choice is regulated unknown\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Identified ERK as the kinase that phosphorylates TFCP2 at S291 to increase DNA binding upon T-cell mitogenic stimulation, establishing signal-dependent regulation, later shown to be cell-type dependent (insufficient alone in fibroblasts).\",\n      \"evidence\": \"EMSA, in vitro kinase assays, S291 mutagenesis, phosphatase treatment, and MEK/ERK inhibitors in primary cells and NIH 3T3\",\n      \"pmids\": [\"9192871\", \"12858339\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell-type-specific cofactor required for activation unidentified\", \"How phosphorylation alters DNA-binding conformation unknown\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Linked TFCP2 to HIV latency by showing opposing kinase control\\u2014ERK reduces and p38 increases LTR binding\\u2014with pharmacological consequences for viral reactivation from resting CD4+ T cells.\",\n      \"evidence\": \"EMSA, ChIP, kinase assays, p38 inhibitor/agonist, and HIV recovery from primary patient cells\",\n      \"pmids\": [\"15857981\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"p38 phosphorylation site not mapped\", \"Therapeutic exploitation untested in vivo\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identified cyclin C/CDK2 (CDK3) phosphorylation at S309 in early G1 as an inhibitory brake that delays TFCP2 transactivation until G1/S, refining cell-cycle timing of its target gene induction.\",\n      \"evidence\": \"In vitro kinase assays, S309 mutagenesis, cyclin C siRNA, co-IP, and endogenous Tyms readout\",\n      \"pmids\": [\"19237534\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How S309 dephosphorylation is timed at G1/S unresolved\", \"Crosstalk with ERK phosphorylation unclear\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Established TFCP2 as a hepatocellular carcinoma oncogene driving angiogenesis and metastasis through direct transcriptional targets OPN, MMP-9, FN1, and TJP1, with OPN-CD44-c-Met signaling as a downstream effector.\",\n      \"evidence\": \"Xenografts, ChIP-on-chip, ChIP-PCR, promoter reporters, loss-of-function rescue, and phospho-RTK array\",\n      \"pmids\": [\"20404171\", \"22167195\", \"25609232\", \"21703197\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"What activates TFCP2 oncogenic program upstream unclear\", \"Tissue-specificity of target selection unresolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Provided a chemical-genetic tool (FQI1) that specifically inhibits TFCP2 DNA binding and selectively kills LSF-overexpressing HCC cells, validating TFCP2 as a druggable target.\",\n      \"evidence\": \"EMSA, ChIP, reporter assays, structure-activity analysis of 23 quinolinones, and xenografts\",\n      \"pmids\": [\"22396589\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Binding site of FQI1 on TFCP2 not structurally defined\", \"Selectivity over paralogs untested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Revealed a non-genomic stabilizing role in which TFCP2 supports YAP-dependent transcription via a WW-PSY interaction, blocking \\u03b2TrCP-mediated YAP ubiquitination and facilitating YAP-TEAD binding.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, ChIP co-occupancy, and reporter assays in liver cancer\",\n      \"pmids\": [\"29091762\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Reciprocal regulation of TFCP2 by YAP partly addressed only later\", \"Structural basis of WW-PSY interaction undefined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Extended TFCP2 function beyond transcription, showing it bridges SET8 and \\u03b1-tubulin to facilitate Lys311 methylation, and demonstrated that TFCP2 loss causes mitotic catastrophe with chromosome misalignment.\",\n      \"evidence\": \"In vitro methylation reconstitution, MS, co-IP, GST pull-down, FQI1 inhibitor, and time-lapse microscopy comparing siRNA and FQI1\",\n      \"pmids\": [\"32111740\", \"32539694\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether tubulin methylation explains the mitotic phenotype unestablished\", \"Substrate scope of TFCP2-SET8 axis unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed that TFCP2 transcriptional complexes are stabilized by ubiquitin signaling (TRAF6 K63-ubiquitination of YAP1) to drive PD-L1, and that FUS-TFCP2 fusion proteins act as oncogenic drivers in rhabdomyosarcoma.\",\n      \"evidence\": \"CRISPRi screen, K63-specific ubiquitination assays, co-IP, PD-L1 flow cytometry, fusion-protein expression, and DNA repair assays\",\n      \"pmids\": [\"38583649\", \"38168093\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab findings without independent replication\", \"Mechanism of fusion-driven genomic instability undefined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TFCP2 selects between its activating, repressive, and protein-stabilizing roles in different tissues, and the high-resolution structure of human TFCP2 on DNA, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No experimental structure of human TFCP2 itself (only Grhl family members)\", \"Rules governing partner-selective activation vs. repression unknown\", \"In vivo non-redundant roles obscured by paralog compensation\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 1, 3, 4, 9, 11]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 2, 12, 23, 28]},\n      {\"term_id\": \"GO:0140223\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [13, 17, 19, 28]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [10, 20, 37]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [10, 37]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 2, 3]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [12, 21, 34]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [15, 23, 40]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [28, 30, 32]}\n    ],\n    \"complexes\": [\n      \"stage selector protein (SSP) complex\",\n      \"YY1-LSF-HDAC1 repressor complex\",\n      \"YAP1/TFCP2 transcriptional complex\"\n    ],\n    \"partners\": [\n      \"YY1\",\n      \"GATA-1\",\n      \"PIAS1\",\n      \"YAP1\",\n      \"SET8\",\n      \"Fe65\",\n      \"REST\",\n      \"SREBP2\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}