{"gene":"YY1AP1","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2004,"finding":"YY1AP1 (YY1AP) was identified as a direct binding partner and co-activator of the YY1 transcription factor. Yeast two-hybrid screening, co-immunoprecipitation, and GST pull-down assays showed that YY1AP contains two YY1-binding regions. YY1AP co-localizes with YY1 in the nucleus and enhances transcriptional activation from a YY1-responsive promoter. The transactivation domain of YY1AP was mapped to amino acids 260–345.","method":"Yeast two-hybrid screen, GST pull-down assay, co-immunoprecipitation, immunostaining, luciferase reporter assay","journal":"The Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal biochemical methods (Y2H, GST pulldown, co-IP, reporter assay) in a single focused study; domain mapping performed","pmids":["14744866"],"is_preprint":false},{"year":2004,"finding":"YY1AP1 protein localizes to the nucleus and is ubiquitously expressed across human tissues and cancer cell lines. The chromosomal gene maps to chromosome 1q21.3 and encodes a 750 amino acid protein.","method":"Northern blot, immunostaining, 5'-RACE and cDNA cloning","journal":"The Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — direct localization by immunostaining with co-localization data, single lab, multiple methods","pmids":["14744866"],"is_preprint":false},{"year":2015,"finding":"YY1AP1 cooperates with YY1 to alter the chromatin landscape and activate transcription of stemness regulators in EpCAM+AFP+ hepatocellular carcinoma (HCC). YY1AP1 silencing eliminated oncogene addiction, triggered massive apoptosis in vitro, and suppressed tumor growth in vivo. YY1AP1 expression is required for maintenance of stem cell features in this HCC subtype.","method":"siRNA knockdown, in vitro apoptosis assays, in vivo xenograft tumor suppression, transcriptomic/chromatin landscape analysis, integrative genomics (copy number + expression)","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function with defined cellular and in vivo phenotypes, chromatin landscape analysis, multiple orthogonal methods in a focused study","pmids":["25597408"],"is_preprint":false},{"year":2016,"finding":"Loss-of-function mutations in YY1AP1 cause Grange syndrome and a fibromuscular dysplasia-like vascular disease. YY1AP1 localizes to the nucleus and is a component of the INO80 chromatin remodeling complex. Loss of YY1AP1 in vascular smooth muscle cells causes cell cycle arrest with decreased proliferation, increased p21/WAF/CDKN1A levels, and disrupts TGF-β-driven differentiation of smooth muscle cells.","method":"Exome sequencing, cellular fractionation/nuclear localization assay, co-immunoprecipitation with INO80 complex components, siRNA knockdown in vascular smooth muscle cells, cell cycle and proliferation assays, p21 protein level measurement, TGF-β differentiation assay","journal":"American Journal of Human Genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP establishing INO80 complex membership, direct nuclear localization, loss-of-function with defined molecular (p21 upregulation, cell cycle arrest) and differentiation phenotypes; replicated across multiple patient families","pmids":["27939641"],"is_preprint":false},{"year":2019,"finding":"Nobiletin treatment increases phosphorylation of YY1AP1 and decreases its nuclear localization in renal carcinoma cells, as part of a signaling axis involving SRC/AKT/STAT3/YY1AP1. IGF1 reversed the nobiletin-induced changes in phospho-YY1AP1 levels and antitumor effects, suggesting YY1AP1 activity is regulated by AKT signaling in this context.","method":"Western blot (phospho-YY1AP1), immunofluorescence (nuclear localization), pharmacological rescue with IGF1, in vivo xenograft","journal":"Frontiers in Pharmacology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, pharmacological study with limited mechanistic dissection of YY1AP1 specifically; pathway placement is indirect","pmids":["31354472"],"is_preprint":false}],"current_model":"YY1AP1 is a nuclear protein and co-activator of the YY1 transcription factor that contains two YY1-binding regions and an intrinsic transactivation domain (aa 260–345); it is also a component of the INO80 chromatin remodeling complex, and its loss in vascular smooth muscle cells causes cell cycle arrest (via p21 upregulation) and impaired TGF-β-driven differentiation, while in hepatocellular carcinoma it cooperates with YY1 to remodel chromatin and activate stemness gene programs."},"narrative":{"mechanistic_narrative":"YY1AP1 is a nuclear transcriptional co-activator that couples the YY1 transcription factor to chromatin remodeling machinery to control cell proliferation and lineage differentiation [PMID:14744866, PMID:27939641]. It binds YY1 directly through two YY1-binding regions and carries an intrinsic transactivation domain mapped to residues 260–345, enhancing transcription from YY1-responsive promoters [PMID:14744866]. YY1AP1 is a component of the INO80 chromatin remodeling complex, and its loss in vascular smooth muscle cells drives cell cycle arrest with p21/CDKN1A upregulation and impairs TGF-β-driven smooth muscle differentiation; biallelic loss-of-function mutations in YY1AP1 cause Grange syndrome and a fibromuscular dysplasia-like vascular disease [PMID:27939641]. In EpCAM+AFP+ hepatocellular carcinoma, YY1AP1 cooperates with YY1 to remodel the chromatin landscape and activate stemness gene programs, and its silencing eliminates oncogene addiction, triggering apoptosis and suppressing tumor growth [PMID:25597408]. Beyond these contexts, the upstream signals regulating YY1AP1 activity remain largely uncharacterized in the available corpus.","teleology":[{"year":2004,"claim":"Established that YY1AP1 is a direct physical partner and co-activator of YY1, defining its core molecular function as transcriptional enhancement rather than an independent activity.","evidence":"Yeast two-hybrid, GST pull-down, co-IP, immunostaining, and luciferase reporter assays, with transactivation domain mapped to aa 260–345","pmids":["14744866"],"confidence":"High","gaps":["Does not identify the chromatin or co-factor machinery recruited by YY1AP1","Endogenous target genes not defined","Mechanism of transactivation by the 260–345 domain unresolved"]},{"year":2004,"claim":"Defined YY1AP1 as a ubiquitously expressed nuclear protein, fixing its compartment of action.","evidence":"Northern blot, immunostaining, 5'-RACE/cDNA cloning placing the gene at 1q21.3 encoding a 750-aa protein","pmids":["14744866"],"confidence":"Medium","gaps":["Does not address tissue-specific functional roles despite ubiquitous expression","No sub-nuclear localization detail"]},{"year":2015,"claim":"Showed that YY1AP1, with YY1, reprograms chromatin to sustain stemness programs in a hepatocellular carcinoma subtype, linking the co-activator to oncogenic cell-state maintenance.","evidence":"siRNA knockdown, in vitro apoptosis assays, in vivo xenograft suppression, and chromatin/transcriptomic landscape analysis in EpCAM+AFP+ HCC","pmids":["25597408"],"confidence":"High","gaps":["Specific stemness target genes and direct chromatin binding sites not enumerated","Does not define the remodeling complex mediating the chromatin changes in this context"]},{"year":2016,"claim":"Identified YY1AP1 as a subunit of the INO80 chromatin remodeling complex and as a disease gene, connecting its molecular partnership to proliferation control, smooth muscle differentiation, and human vascular pathology.","evidence":"Exome sequencing of patient families, reciprocal co-IP with INO80 components, cellular fractionation, siRNA knockdown in vascular smooth muscle cells with cell cycle, p21, and TGF-β differentiation assays","pmids":["27939641"],"confidence":"High","gaps":["Structural position of YY1AP1 within INO80 not defined","Mechanistic link between INO80 membership and YY1 co-activation not directly resolved","How p21 upregulation is triggered mechanistically unclear"]},{"year":2019,"claim":"Raised the possibility that YY1AP1 nuclear activity is post-translationally regulated by AKT signaling, addressing how the co-activator's localization might be controlled.","evidence":"Western blot of phospho-YY1AP1, immunofluorescence of nuclear localization, and IGF1 pharmacological rescue within a SRC/AKT/STAT3/YY1AP1 axis in renal carcinoma cells","pmids":["31354472"],"confidence":"Low","gaps":["Phosphorylation sites and direct kinase not identified","Pathway placement of YY1AP1 is indirect","Functional consequence of altered phosphorylation on YY1 co-activation not tested"]},{"year":null,"claim":"How INO80 membership, YY1 co-activation, and post-translational regulation integrate to select target genes in a given cell type remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No direct genome-wide binding map for YY1AP1","Structural basis of complex assembly unknown","Upstream signals controlling context-specific activity uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,2]},{"term_id":"GO:0140097","term_label":"catalytic activity, acting on DNA","supporting_discovery_ids":[3]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,1,3]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[2,3]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0]}],"complexes":["INO80 chromatin remodeling complex"],"partners":["YY1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9H869","full_name":"YY1-associated protein 1","aliases":["Hepatocellular carcinoma susceptibility protein","Hepatocellular carcinoma-associated protein 2"],"length_aa":796,"mass_kda":87.9,"function":"Associates with the INO80 chromatin remodeling complex, which is responsible for transcriptional regulation, DNA repair, and replication (PubMed:27939641). Enhances transcription activation by YY1 (PubMed:14744866). Plays a role in cell cycle regulation (PubMed:17541814, PubMed:27939641)","subcellular_location":"Cytoplasm; Nucleus; Nucleus, nucleoplasm; Nucleus, nucleolus","url":"https://www.uniprot.org/uniprotkb/Q9H869/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/YY1AP1","classification":"Not Classified","n_dependent_lines":7,"n_total_lines":1208,"dependency_fraction":0.005794701986754967},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/YY1AP1","total_profiled":1310},"omim":[{"mim_id":"620119","title":"LONG NONCODING RNA CRYBG3","url":"https://www.omim.org/entry/620119"},{"mim_id":"607860","title":"YY1 ASSOCIATED PROTEIN 1; YY1AP1","url":"https://www.omim.org/entry/607860"},{"mim_id":"602531","title":"GRANGE SYNDROME; GRNG","url":"https://www.omim.org/entry/602531"},{"mim_id":"602074","title":"DEATH-ASSOCIATED PROTEIN 3; DAP3","url":"https://www.omim.org/entry/602074"},{"mim_id":"135580","title":"FIBROMUSCULAR DYSPLASIA, ARTERIAL; FMDA","url":"https://www.omim.org/entry/135580"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoli fibrillar center","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/YY1AP1"},"hgnc":{"alias_symbol":["YY1AP","HCCA2","YAP"],"prev_symbol":[]},"alphafold":{"accession":"Q9H869","domains":[{"cath_id":"-","chopping":"163-251_265-298_364-397","consensus_level":"high","plddt":89.8353,"start":163,"end":397}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H869","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H869-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H869-F1-predicted_aligned_error_v6.png","plddt_mean":53.72},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=YY1AP1","jax_strain_url":"https://www.jax.org/strain/search?query=YY1AP1"},"sequence":{"accession":"Q9H869","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9H869.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9H869/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H869"}},"corpus_meta":[{"pmid":"21654799","id":"PMC_21654799","title":"Role of YAP/TAZ in mechanotransduction.","date":"2011","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/21654799","citation_count":4604,"is_preprint":false},{"pmid":"18579750","id":"PMC_18579750","title":"TEAD mediates YAP-dependent gene induction and growth control.","date":"2008","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/18579750","citation_count":2110,"is_preprint":false},{"pmid":"27300434","id":"PMC_27300434","title":"YAP/TAZ at the Roots of Cancer.","date":"2016","source":"Cancer cell","url":"https://pubmed.ncbi.nlm.nih.gov/27300434","citation_count":1611,"is_preprint":false},{"pmid":"28951564","id":"PMC_28951564","title":"Mechanobiology of YAP and TAZ in physiology and disease.","date":"2017","source":"Nature reviews. 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volume.","date":"2019","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/31481532","citation_count":47,"is_preprint":false},{"pmid":"37080959","id":"PMC_37080959","title":"LncRNA modulates Hippo-YAP signaling to reprogram iron metabolism.","date":"2023","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/37080959","citation_count":47,"is_preprint":false},{"pmid":"38547833","id":"PMC_38547833","title":"FAK, vinculin, and talin control mechanosensitive YAP nuclear localization.","date":"2024","source":"Biomaterials","url":"https://pubmed.ncbi.nlm.nih.gov/38547833","citation_count":45,"is_preprint":false},{"pmid":"28616573","id":"PMC_28616573","title":"YAP and the Hippo pathway in pediatric cancer.","date":"2017","source":"Molecular & cellular oncology","url":"https://pubmed.ncbi.nlm.nih.gov/28616573","citation_count":45,"is_preprint":false},{"pmid":"34782888","id":"PMC_34782888","title":"Mechanisms of YAP/TAZ transcriptional control.","date":"2021","source":"Cell stress","url":"https://pubmed.ncbi.nlm.nih.gov/34782888","citation_count":45,"is_preprint":false},{"pmid":"30404826","id":"PMC_30404826","title":"Enigma proteins regulate YAP mechanotransduction.","date":"2018","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/30404826","citation_count":45,"is_preprint":false},{"pmid":"30815737","id":"PMC_30815737","title":"YAP and the Hippo pathway in cholangiocarcinoma.","date":"2019","source":"Journal of gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/30815737","citation_count":44,"is_preprint":false},{"pmid":"29532607","id":"PMC_29532607","title":"Hippo-yap signaling in ocular development and disease.","date":"2018","source":"Developmental dynamics : an official publication of the American Association of Anatomists","url":"https://pubmed.ncbi.nlm.nih.gov/29532607","citation_count":44,"is_preprint":false},{"pmid":"31354472","id":"PMC_31354472","title":"Nobiletin Inhibits Cell Viability via the SRC/AKT/STAT3/YY1AP1 Pathway in Human Renal Carcinoma Cells.","date":"2019","source":"Frontiers in pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/31354472","citation_count":44,"is_preprint":false},{"pmid":"33408779","id":"PMC_33408779","title":"YAP in pancreatic cancer: oncogenic role and therapeutic strategy.","date":"2021","source":"Theranostics","url":"https://pubmed.ncbi.nlm.nih.gov/33408779","citation_count":44,"is_preprint":false},{"pmid":"25597408","id":"PMC_25597408","title":"Integrative genomics identifies YY1AP1 as an oncogenic driver in EpCAM(+) AFP(+) hepatocellular carcinoma.","date":"2015","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/25597408","citation_count":43,"is_preprint":false},{"pmid":"26617849","id":"PMC_26617849","title":"Expression of Yes-associated protein (YAP) in metastatic breast cancer.","date":"2015","source":"International journal of clinical and experimental pathology","url":"https://pubmed.ncbi.nlm.nih.gov/26617849","citation_count":43,"is_preprint":false},{"pmid":"14744866","id":"PMC_14744866","title":"YY1AP, a novel co-activator of YY1.","date":"2004","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/14744866","citation_count":42,"is_preprint":false},{"pmid":"32642404","id":"PMC_32642404","title":"Yes-associated protein (YAP) and transcriptional coactivator with a PDZ-binding motif (TAZ): a nexus between hypoxia and cancer.","date":"2019","source":"Acta pharmaceutica Sinica. B","url":"https://pubmed.ncbi.nlm.nih.gov/32642404","citation_count":42,"is_preprint":false},{"pmid":"31929186","id":"PMC_31929186","title":"H3K27me3-mediated PGC1α gene silencing promotes melanoma invasion through WNT5A and YAP.","date":"2020","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/31929186","citation_count":41,"is_preprint":false},{"pmid":"35059398","id":"PMC_35059398","title":"YAP/TAZ in Bone and Cartilage Biology.","date":"2022","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/35059398","citation_count":39,"is_preprint":false},{"pmid":"34188130","id":"PMC_34188130","title":"Concurrent YAP/TAZ and SMAD signaling mediate vocal fold fibrosis.","date":"2021","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/34188130","citation_count":39,"is_preprint":false},{"pmid":"33422090","id":"PMC_33422090","title":"YAP and endothelin-1 signaling: an emerging alliance in cancer.","date":"2021","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/33422090","citation_count":38,"is_preprint":false},{"pmid":"30223434","id":"PMC_30223434","title":"Repurposing of Drugs Targeting YAP-TEAD Functions.","date":"2018","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/30223434","citation_count":38,"is_preprint":false},{"pmid":"35905788","id":"PMC_35905788","title":"Combined role for YAP-TEAD and YAP-RUNX2 signalling in substrate-stiffness regulation of cardiac fibroblast proliferation.","date":"2022","source":"Biochimica et biophysica acta. Molecular cell research","url":"https://pubmed.ncbi.nlm.nih.gov/35905788","citation_count":38,"is_preprint":false},{"pmid":"28415761","id":"PMC_28415761","title":"YAP promotes tumorigenesis and cisplatin resistance in neuroblastoma.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/28415761","citation_count":38,"is_preprint":false},{"pmid":"32159970","id":"PMC_32159970","title":"TBK1 regulates YAP/TAZ and fibrogenic fibroblast activation.","date":"2020","source":"American journal of physiology. Lung cellular and molecular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/32159970","citation_count":34,"is_preprint":false},{"pmid":"33798262","id":"PMC_33798262","title":"Targeting the YAP/TAZ Pathway in Uveal and Conjunctival Melanoma With Verteporfin.","date":"2021","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/33798262","citation_count":33,"is_preprint":false},{"pmid":"35790583","id":"PMC_35790583","title":"CD146 increases stemness and aggressiveness in glioblastoma and activates YAP signaling.","date":"2022","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/35790583","citation_count":33,"is_preprint":false},{"pmid":"30578787","id":"PMC_30578787","title":"YAP and TAZ are distinct effectors of corneal myofibroblast transformation.","date":"2018","source":"Experimental eye research","url":"https://pubmed.ncbi.nlm.nih.gov/30578787","citation_count":33,"is_preprint":false},{"pmid":"37397250","id":"PMC_37397250","title":"YAP at the progression of inflammation.","date":"2023","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/37397250","citation_count":32,"is_preprint":false},{"pmid":"31578200","id":"PMC_31578200","title":"MK5 Regulates YAP Stability and Is a Molecular Target in YAP-Driven Cancers.","date":"2019","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/31578200","citation_count":32,"is_preprint":false},{"pmid":"28279717","id":"PMC_28279717","title":"YAP and WWTR1: New targets for skin cancer treatment.","date":"2017","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/28279717","citation_count":31,"is_preprint":false},{"pmid":"35606801","id":"PMC_35606801","title":"The biology of YAP in programmed cell death.","date":"2022","source":"Biomarker research","url":"https://pubmed.ncbi.nlm.nih.gov/35606801","citation_count":31,"is_preprint":false},{"pmid":"38359507","id":"PMC_38359507","title":"Biomimetic nanodrug targets inflammation and suppresses YAP/TAZ to ameliorate atherosclerosis.","date":"2024","source":"Biomaterials","url":"https://pubmed.ncbi.nlm.nih.gov/38359507","citation_count":28,"is_preprint":false},{"pmid":"36317529","id":"PMC_36317529","title":"Hippo-Yap Signaling Maintains Sinoatrial Node Homeostasis.","date":"2022","source":"Circulation","url":"https://pubmed.ncbi.nlm.nih.gov/36317529","citation_count":28,"is_preprint":false},{"pmid":"38784009","id":"PMC_38784009","title":"YAP condensates are highly organized hubs.","date":"2024","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/38784009","citation_count":28,"is_preprint":false},{"pmid":"26254048","id":"PMC_26254048","title":"Yes-associated protein (YAP) expression is involved in epithelial-mesenchymal transition in hepatocellular carcinoma.","date":"2015","source":"Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico","url":"https://pubmed.ncbi.nlm.nih.gov/26254048","citation_count":28,"is_preprint":false},{"pmid":"37328193","id":"PMC_37328193","title":"Tripterygium wilfordii derivative celastrol, a YAP inhibitor, has antifibrotic effects in systemic sclerosis.","date":"2023","source":"Annals of the rheumatic diseases","url":"https://pubmed.ncbi.nlm.nih.gov/37328193","citation_count":26,"is_preprint":false},{"pmid":"34200497","id":"PMC_34200497","title":"Yes-Associated Protein (Yap) Is Up-Regulated in Heart Failure and Promotes Cardiac Fibroblast Proliferation.","date":"2021","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/34200497","citation_count":26,"is_preprint":false},{"pmid":"31066301","id":"PMC_31066301","title":"A brief review: some compounds targeting YAP against malignancies.","date":"2019","source":"Future oncology (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/31066301","citation_count":26,"is_preprint":false},{"pmid":"33800464","id":"PMC_33800464","title":"YAP and TAZ Mediators at the Crossroad between Metabolic and Cellular Reprogramming.","date":"2021","source":"Metabolites","url":"https://pubmed.ncbi.nlm.nih.gov/33800464","citation_count":25,"is_preprint":false},{"pmid":"37894323","id":"PMC_37894323","title":"Nuclear Import and Export of YAP and TAZ.","date":"2023","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/37894323","citation_count":22,"is_preprint":false},{"pmid":"34249412","id":"PMC_34249412","title":"Hippo-YAP signaling in digestive system tumors.","date":"2021","source":"American journal of cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/34249412","citation_count":22,"is_preprint":false},{"pmid":"36428972","id":"PMC_36428972","title":"YAP Activation in Promoting Negative Durotaxis and Acral Melanoma Progression.","date":"2022","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/36428972","citation_count":22,"is_preprint":false},{"pmid":"35597479","id":"PMC_35597479","title":"PDE4D binds and interacts with YAP to cooperatively promote HCC progression.","date":"2022","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/35597479","citation_count":22,"is_preprint":false},{"pmid":"38768671","id":"PMC_38768671","title":"STC1 competitively binding βPIX enhances melanoma progression via YAP nuclear translocation and M2 macrophage recruitment through the YAP/CCL2/VEGFA/AKT feedback loop.","date":"2024","source":"Pharmacological research","url":"https://pubmed.ncbi.nlm.nih.gov/38768671","citation_count":21,"is_preprint":false},{"pmid":"38380551","id":"PMC_38380551","title":"DNMT3A Cooperates with YAP/TAZ to Drive Gallbladder Cancer Metastasis.","date":"2024","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/38380551","citation_count":21,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":43159,"output_tokens":1845,"usd":0.078576,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8219,"output_tokens":2166,"usd":0.047622,"stage2_stop_reason":"end_turn"},"total_usd":0.126198,"stage1_batch_id":"msgbatch_01UT1AahFPCAyn2uVweS7A9z","stage2_batch_id":"msgbatch_01HuKWtKNT4Pqj1bc8eEP5RV","note":"batch pricing = 50% of standard"},"stage1_raw":"I need to carefully distinguish between YY1AP1 (the canonical gene, also known as YY1AP or YAP in some older nomenclature) and the much more common YAP/YAP1 (Yes-Associated Protein, encoded by the YAP1 gene). \n\nLooking at the HGNC aliases provided: YY1AP1 aliases include YY1AP and YAP. However, the vast majority of papers in this corpus clearly describe YAP1 (Yes-Associated Protein 1, the Hippo pathway effector), NOT YY1AP1 (YY1-Associated Protein 1, the YY1 transcription factor coactivator). These are completely different proteins.\n\nPapers specifically about YY1AP1 (YY1-associated protein 1):\n- PMID:14744866 (YY1AP, a novel co-activator of YY1) - directly about YY1AP1\n- PMID:27939641 (Loss-of-Function Mutations in YY1AP1 Lead to Grange Syndrome) - directly about YY1AP1\n- PMID:25597408 (Integrative genomics identifies YY1AP1 as an oncogenic driver) - directly about YY1AP1\n- PMID:31354472 (Nobiletin Inhibits Cell Viability via SRC/AKT/STAT3/YY1AP1) - mentions YY1AP1\n\nAll other papers are about YAP1 (Yes-Associated Protein), a completely different gene. I will only extract from the YY1AP1-specific papers.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2004,\n      \"finding\": \"YY1AP1 (YY1AP) was identified as a direct binding partner and co-activator of the YY1 transcription factor. Yeast two-hybrid screening, co-immunoprecipitation, and GST pull-down assays showed that YY1AP contains two YY1-binding regions. YY1AP co-localizes with YY1 in the nucleus and enhances transcriptional activation from a YY1-responsive promoter. The transactivation domain of YY1AP was mapped to amino acids 260–345.\",\n      \"method\": \"Yeast two-hybrid screen, GST pull-down assay, co-immunoprecipitation, immunostaining, luciferase reporter assay\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal biochemical methods (Y2H, GST pulldown, co-IP, reporter assay) in a single focused study; domain mapping performed\",\n      \"pmids\": [\"14744866\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"YY1AP1 protein localizes to the nucleus and is ubiquitously expressed across human tissues and cancer cell lines. The chromosomal gene maps to chromosome 1q21.3 and encodes a 750 amino acid protein.\",\n      \"method\": \"Northern blot, immunostaining, 5'-RACE and cDNA cloning\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — direct localization by immunostaining with co-localization data, single lab, multiple methods\",\n      \"pmids\": [\"14744866\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"YY1AP1 cooperates with YY1 to alter the chromatin landscape and activate transcription of stemness regulators in EpCAM+AFP+ hepatocellular carcinoma (HCC). YY1AP1 silencing eliminated oncogene addiction, triggered massive apoptosis in vitro, and suppressed tumor growth in vivo. YY1AP1 expression is required for maintenance of stem cell features in this HCC subtype.\",\n      \"method\": \"siRNA knockdown, in vitro apoptosis assays, in vivo xenograft tumor suppression, transcriptomic/chromatin landscape analysis, integrative genomics (copy number + expression)\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function with defined cellular and in vivo phenotypes, chromatin landscape analysis, multiple orthogonal methods in a focused study\",\n      \"pmids\": [\"25597408\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Loss-of-function mutations in YY1AP1 cause Grange syndrome and a fibromuscular dysplasia-like vascular disease. YY1AP1 localizes to the nucleus and is a component of the INO80 chromatin remodeling complex. Loss of YY1AP1 in vascular smooth muscle cells causes cell cycle arrest with decreased proliferation, increased p21/WAF/CDKN1A levels, and disrupts TGF-β-driven differentiation of smooth muscle cells.\",\n      \"method\": \"Exome sequencing, cellular fractionation/nuclear localization assay, co-immunoprecipitation with INO80 complex components, siRNA knockdown in vascular smooth muscle cells, cell cycle and proliferation assays, p21 protein level measurement, TGF-β differentiation assay\",\n      \"journal\": \"American Journal of Human Genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP establishing INO80 complex membership, direct nuclear localization, loss-of-function with defined molecular (p21 upregulation, cell cycle arrest) and differentiation phenotypes; replicated across multiple patient families\",\n      \"pmids\": [\"27939641\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Nobiletin treatment increases phosphorylation of YY1AP1 and decreases its nuclear localization in renal carcinoma cells, as part of a signaling axis involving SRC/AKT/STAT3/YY1AP1. IGF1 reversed the nobiletin-induced changes in phospho-YY1AP1 levels and antitumor effects, suggesting YY1AP1 activity is regulated by AKT signaling in this context.\",\n      \"method\": \"Western blot (phospho-YY1AP1), immunofluorescence (nuclear localization), pharmacological rescue with IGF1, in vivo xenograft\",\n      \"journal\": \"Frontiers in Pharmacology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, pharmacological study with limited mechanistic dissection of YY1AP1 specifically; pathway placement is indirect\",\n      \"pmids\": [\"31354472\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"YY1AP1 is a nuclear protein and co-activator of the YY1 transcription factor that contains two YY1-binding regions and an intrinsic transactivation domain (aa 260–345); it is also a component of the INO80 chromatin remodeling complex, and its loss in vascular smooth muscle cells causes cell cycle arrest (via p21 upregulation) and impaired TGF-β-driven differentiation, while in hepatocellular carcinoma it cooperates with YY1 to remodel chromatin and activate stemness gene programs.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"YY1AP1 is a nuclear transcriptional co-activator that couples the YY1 transcription factor to chromatin remodeling machinery to control cell proliferation and lineage differentiation [#0, #3]. It binds YY1 directly through two YY1-binding regions and carries an intrinsic transactivation domain mapped to residues 260–345, enhancing transcription from YY1-responsive promoters [#0]. YY1AP1 is a component of the INO80 chromatin remodeling complex, and its loss in vascular smooth muscle cells drives cell cycle arrest with p21/CDKN1A upregulation and impairs TGF-β-driven smooth muscle differentiation; biallelic loss-of-function mutations in YY1AP1 cause Grange syndrome and a fibromuscular dysplasia-like vascular disease [#3]. In EpCAM+AFP+ hepatocellular carcinoma, YY1AP1 cooperates with YY1 to remodel the chromatin landscape and activate stemness gene programs, and its silencing eliminates oncogene addiction, triggering apoptosis and suppressing tumor growth [#2]. Beyond these contexts, the upstream signals regulating YY1AP1 activity remain largely uncharacterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established that YY1AP1 is a direct physical partner and co-activator of YY1, defining its core molecular function as transcriptional enhancement rather than an independent activity.\",\n      \"evidence\": \"Yeast two-hybrid, GST pull-down, co-IP, immunostaining, and luciferase reporter assays, with transactivation domain mapped to aa 260–345\",\n      \"pmids\": [\"14744866\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not identify the chromatin or co-factor machinery recruited by YY1AP1\", \"Endogenous target genes not defined\", \"Mechanism of transactivation by the 260–345 domain unresolved\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Defined YY1AP1 as a ubiquitously expressed nuclear protein, fixing its compartment of action.\",\n      \"evidence\": \"Northern blot, immunostaining, 5'-RACE/cDNA cloning placing the gene at 1q21.3 encoding a 750-aa protein\",\n      \"pmids\": [\"14744866\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not address tissue-specific functional roles despite ubiquitous expression\", \"No sub-nuclear localization detail\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showed that YY1AP1, with YY1, reprograms chromatin to sustain stemness programs in a hepatocellular carcinoma subtype, linking the co-activator to oncogenic cell-state maintenance.\",\n      \"evidence\": \"siRNA knockdown, in vitro apoptosis assays, in vivo xenograft suppression, and chromatin/transcriptomic landscape analysis in EpCAM+AFP+ HCC\",\n      \"pmids\": [\"25597408\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific stemness target genes and direct chromatin binding sites not enumerated\", \"Does not define the remodeling complex mediating the chromatin changes in this context\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified YY1AP1 as a subunit of the INO80 chromatin remodeling complex and as a disease gene, connecting its molecular partnership to proliferation control, smooth muscle differentiation, and human vascular pathology.\",\n      \"evidence\": \"Exome sequencing of patient families, reciprocal co-IP with INO80 components, cellular fractionation, siRNA knockdown in vascular smooth muscle cells with cell cycle, p21, and TGF-β differentiation assays\",\n      \"pmids\": [\"27939641\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural position of YY1AP1 within INO80 not defined\", \"Mechanistic link between INO80 membership and YY1 co-activation not directly resolved\", \"How p21 upregulation is triggered mechanistically unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Raised the possibility that YY1AP1 nuclear activity is post-translationally regulated by AKT signaling, addressing how the co-activator's localization might be controlled.\",\n      \"evidence\": \"Western blot of phospho-YY1AP1, immunofluorescence of nuclear localization, and IGF1 pharmacological rescue within a SRC/AKT/STAT3/YY1AP1 axis in renal carcinoma cells\",\n      \"pmids\": [\"31354472\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Phosphorylation sites and direct kinase not identified\", \"Pathway placement of YY1AP1 is indirect\", \"Functional consequence of altered phosphorylation on YY1 co-activation not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How INO80 membership, YY1 co-activation, and post-translational regulation integrate to select target genes in a given cell type remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct genome-wide binding map for YY1AP1\", \"Structural basis of complex assembly unknown\", \"Upstream signals controlling context-specific activity uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0140097\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 1, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [\"INO80 chromatin remodeling complex\"],\n    \"partners\": [\"YY1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}