{"gene":"PRAME","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":2010,"finding":"PRAME suppresses TRAIL expression in BCR-ABL-positive leukemia cells through a mechanism involving EZH2. PRAME knockdown by RNA interference restores TRAIL expression, and EZH2 binding to the TRAIL promoter is lost after PRAME knockdown, indicating PRAME acts upstream of EZH2 to repress TRAIL transcription.","method":"siRNA knockdown of PRAME and EZH2 in BCR-ABL-positive cell lines, chromatin immunoprecipitation (ChIP) of EZH2 on TRAIL promoter, RT-PCR expression analysis","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal functional epistasis (siRNA + ChIP), single lab, two orthogonal methods","pmids":["20838376"],"is_preprint":false},{"year":2021,"finding":"PRAME functions as the substrate-recognition receptor of the CRL2 E3 ubiquitin ligase complex (Cullin2-RBX1-EloB-PRAME), targeting the tumor suppressor p14/ARF for ubiquitination and proteasomal degradation. Knockdown of PRAME stabilizes p14/ARF and induces G2/M cell cycle arrest in cancer cells, which is rescued by simultaneous knockdown of p14/ARF.","method":"Proteomic analysis of RBX1-interacting proteins, co-immunoprecipitation, in vivo ubiquitination assay, siRNA screening, cell cycle analysis, genetic rescue experiment","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vivo ubiquitination assay + Co-IP + siRNA rescue epistasis, multiple orthogonal methods in single study","pmids":["33504946"],"is_preprint":false},{"year":2023,"finding":"PRAME acts as a CUL2 ubiquitin ligase subunit that, when expressed in somatic cells, upregulates meiosis/DNA repair pathways, increases DNA double-strand breaks, causes telomere dysfunction and aneuploidy. This is mediated at least partly through ubiquitination of SMC1A and altered cohesin function. PRAME expression also renders cells susceptible to PARP1/2 inhibition.","method":"PRAME overexpression in neoplastic and non-neoplastic cells, pathway analysis, SMC1A ubiquitination assay, DNA damage assays (DSB, telomere dysfunction), PARP inhibitor sensitivity assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional overexpression studies with multiple mechanistic readouts, single lab","pmids":["38030788"],"is_preprint":false},{"year":2007,"finding":"PRAME expression in chronic myeloid leukemia is regulated by DNA methylation: hypomethylation of the PRAME gene (CpG sites in exon 2) correlates with elevated PRAME transcript levels, and treatment with the demethylating agent 5-aza-2'-deoxycytidine restores PRAME expression in non-expressing cell lines.","method":"Bisulfite sequencing, methylation-specific PCR, 5-aza-2'-deoxycytidine treatment, RT-PCR","journal":"Leukemia research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacologic demethylation + bisulfite sequencing, two orthogonal methods, single lab","pmids":["17382387"],"is_preprint":false},{"year":2016,"finding":"PRAME promoter DNA hypomethylation is a key mechanism regulating PRAME expression in epithelial ovarian cancer. Pharmacologic or genetic disruption of DNA methyltransferase (DNMT) enzymes activated PRAME expression in EOC cells.","method":"DNMT inhibitor treatment, genetic DNMT knockdown, promoter methylation analysis, qPCR expression analysis","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacologic and genetic DNMT disruption with expression readout, single lab","pmids":["27322684"],"is_preprint":false},{"year":2017,"finding":"The transcription factor MZF1 upregulates PRAME expression by directly binding to MZF1 binding sites overlapping a CpG-rich region in PRAME intron 1. DNA demethylation with 5-azaC enhances MZF1 binding to PRAME DNA and further potentiates PRAME expression.","method":"In silico promoter analysis, ectopic MZF1 expression, 5-aza-2'-deoxycytidine treatment, chromatin immunoprecipitation, qRT-PCR and Western blot","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrating direct MZF1 binding + functional overexpression + demethylation, single lab","pmids":["28634046"],"is_preprint":false},{"year":2011,"finding":"siRNA-mediated knockdown of PRAME in the K562 leukemia cell line suppresses proliferation, induces G0/G1 cell cycle arrest, and causes apoptosis, indicating PRAME supports cell cycle progression and survival in leukemic cells.","method":"siRNA knockdown, flow cytometric cell cycle analysis, proliferation assays","journal":"Leukemia research","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean KD with defined cellular phenotype (cell cycle arrest + apoptosis), single lab, single method set","pmids":["21550659"],"is_preprint":false},{"year":2019,"finding":"PRAME promotes epithelial-to-mesenchymal transition (EMT) and increases migration and invasion in triple-negative breast cancer cells. PRAME overexpression upregulates SNAI1, TWIST1, TCF4, FOXC2, MMP2, MMP3, and WNT11 while downregulating BMP7, and alters expression of E-cadherin, N-cadherin, vimentin, and ZEB1.","method":"Gain- and loss-of-function TNBC cell line models, migration/invasion assays, gene expression profiling, qRT-PCR","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal gain/loss-of-function with multiple molecular and phenotypic readouts, single lab","pmids":["30602372"],"is_preprint":false},{"year":2022,"finding":"PRAME overexpression in breast cancer cells inhibits T cell activation and cytolytic potential through suppression of pro-inflammatory cytokines and mediators of T cell activation. PRAME silencing reduces expression of immune checkpoints PD-1, LAG3, PD-L1, CD86, Gal-9, and VISTA, and induces cancer cell killing comparable to anti-PD-L1 treatment.","method":"Direct and indirect T cell/cancer cell co-culture models, PRAME overexpression and silencing, immune checkpoint expression analysis, cytokine profiling","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-culture functional assays with gain/loss-of-function, multiple immune readouts, single lab","pmids":["34612587"],"is_preprint":false},{"year":2017,"finding":"PRAME-derived peptide ALYVDSLFFL (ALY, residues 300–309) is processed by the proteasome and presented on the cell surface in complex with HLA-A*02:01. The immunoproteasome (induced by IFN-γ via upregulation of β5i subunit) reduces internal destructive cleavages within the ALY epitope compared to the constitutive proteasome, increasing surface presentation of the peptide/HLA complex.","method":"TCR mimic antibody (Pr20) binding assays, IFN-γ treatment, immunoproteasome induction, HLA-A2+/PRAME+ cancer cell line experiments, mouse xenograft models","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — direct biochemical demonstration of proteasomal processing differences + functional antibody binding + in vivo xenograft, multiple orthogonal methods","pmids":["28628042"],"is_preprint":false},{"year":2022,"finding":"PRAME directly interacts with EZH2 and acts as a negative regulator of EZH2 in diffuse large B cell lymphoma. PRAME knockout in lymphoma cell lines leads to repression of PRC2-regulated genes, and EZH2 inhibition with EPZ-6438 restores PRAME expression and tumor microenvironment in vivo.","method":"Isogenic PRAME-KO lymphoma cell lines, gene expression profiling, protein-protein interaction studies (PRAME-EZH2 interaction), EZH2 inhibitor treatment in vivo","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct interaction demonstrated + isogenic KO + in vivo drug treatment, single lab","pmids":["35380993"],"is_preprint":false},{"year":2020,"finding":"Deletion of the X-linked mouse Prame gene reduces testis size and sperm count and increases germ cell apoptosis, with phenotypes including Sertoli-cell-only tubules and germ cell arrest at the spermatogonia stage, consistent with disruption of retinoic acid receptor (RAR) signaling by PRAME depletion.","method":"Conditional knockout mouse, histology, immunofluorescence with germ cell markers, TUNEL assay, sperm count","journal":"Molecular reproduction and development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO mouse with multiple phenotypic and molecular readouts, single lab","pmids":["32017313"],"is_preprint":false},{"year":2023,"finding":"PRAME promotes proliferation, migration, invasion, and EMT of laryngeal squamous cell carcinoma cells at least partially by activating the PI3K/AKT/mTOR signaling pathway. HDAC5 was identified as an upstream regulator of PRAME expression.","method":"qRT-PCR, functional in vitro assays (proliferation, migration, invasion), in vivo xenograft, PI3K/AKT/mTOR pathway analysis, HDAC5 expression manipulation","journal":"Open medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, indirect pathway activation inference without direct biochemical reconstitution","pmids":["36910848"],"is_preprint":false},{"year":2023,"finding":"PRAME promotes cervical cancer cell proliferation, migration, and invasion and prevents G0/G1 arrest and apoptosis through activation of the Wnt/β-catenin signaling pathway. PRAME-overexpressing effects are partly reversed by the Wnt inhibitor MSAB both in vitro and in vivo.","method":"siRNA knockdown and overexpression in cervical cancer cell lines, CCK-8/BrdU/scratch/transwell assays, flow cytometry, xenograft mouse model, Wnt inhibitor MSAB treatment","journal":"Cancers","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pathway inhibitor rescue single lab, no direct biochemical binding or reconstitution","pmids":["36980687"],"is_preprint":false},{"year":2023,"finding":"PRAME is a downstream target of Gas6/Axl/MAPK-ERK1/2 signaling in hepatocellular carcinoma. Axl signaling or MAPK/ERK1/2 inhibition reduces PRAME expression, and PRAME levels are associated with a mesenchymal-like phenotype promoting cell migration and invasion. PRAME interacts with pro-oncogenic protein CCAR1.","method":"RNA-seq of Gas6-stimulated Axl-proficient vs. Axl-deficient HCC cells, gain/loss-of-function, proteomics, 2D migration and 3D invasion assays","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA-seq target identification + functional gain/loss-of-function + proteomics interaction data, single lab","pmids":["37173882"],"is_preprint":false},{"year":2018,"finding":"MSX2 regulates PRAME expression as part of a transcriptional program driving mesenchymal stem cell (MSC) differentiation from human pluripotent stem cells (hPSCs). MSX2 genetic deletion impairs hPSC differentiation into MSCs, and MSX2 induces MSC formation by regulating TWIST1 and PRAME.","method":"Genetic deletion of MSX2, ectopic MSX2 expression, hPSC differentiation assays, gene expression analysis","journal":"Stem cell reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — genetic manipulation with lineage readout, but PRAME's mechanistic role is inferred rather than directly demonstrated","pmids":["30033084"],"is_preprint":false}],"current_model":"PRAME is a leucine-rich repeat protein that functions as the substrate-recognition subunit of the CRL2 ubiquitin E3 ligase complex (targeting p14/ARF for degradation), directly interacts with and negatively regulates EZH2 (thereby suppressing PRC2 target genes and TRAIL expression), promotes genomic instability through ubiquitination of cohesin subunit SMC1A, and whose expression is regulated epigenetically by DNA methylation and transcriptionally by MZF1; in cancer cells it supports proliferation and survival by inhibiting retinoic acid signaling, promoting EMT, suppressing anti-tumor immune responses via immune checkpoint upregulation, and activating Wnt/β-catenin and PI3K/AKT/mTOR pathways."},"narrative":{"mechanistic_narrative":"PRAME is a cancer-testis antigen that operates as the substrate-recognition receptor of a CRL2 ubiquitin E3 ligase complex (Cullin2–RBX1–EloB–PRAME), directing ubiquitination and proteasomal degradation of the tumor suppressor p14/ARF; loss of PRAME stabilizes p14/ARF and arrests cells at G2/M, establishing a direct route by which PRAME supports cancer cell cycle progression [PMID:33504946]. As a ubiquitin ligase subunit, PRAME also ubiquitinates the cohesin subunit SMC1A, and its ectopic expression in somatic cells drives DNA double-strand breaks, telomere dysfunction, and aneuploidy while sensitizing cells to PARP1/2 inhibition [PMID:38030788]. In parallel, PRAME directly interacts with and negatively regulates EZH2, controlling PRC2 target gene programs; in BCR-ABL-positive leukemia it acts upstream of EZH2 to repress TRAIL transcription, and in diffuse large B cell lymphoma its loss represses PRC2-regulated genes [PMID:20838376, PMID:35380993]. Functionally, PRAME promotes proliferation, survival, and epithelial-to-mesenchymal transition, and suppresses anti-tumor immunity by elevating immune checkpoints including PD-1, PD-L1, LAG3, and VISTA [PMID:21550659, PMID:30602372, PMID:34612587]. PRAME expression is governed epigenetically by promoter DNA hypomethylation and transcriptionally by the activator MZF1, which binds a CpG-rich region in intron 1 [PMID:17382387, PMID:27322684, PMID:28634046]. A proteasome-processed PRAME peptide (ALYVDSLFFL, residues 300–309) is presented on HLA-A*02:01, with immunoproteasome activity enhancing surface display, providing the basis for PRAME-directed immune targeting [PMID:28628042].","teleology":[{"year":2007,"claim":"Establishing how PRAME becomes aberrantly expressed in cancer, this work showed its silencing is enforced by DNA methylation, reframing PRAME as an epigenetically controlled cancer-testis antigen.","evidence":"bisulfite sequencing, methylation-specific PCR, and 5-aza-2'-deoxycytidine treatment in chronic myeloid leukemia lines","pmids":["17382387"],"confidence":"Medium","gaps":["Does not identify the transcription factors acting on the demethylated locus","Limited to leukemia context"]},{"year":2010,"claim":"The first mechanistic link to gene repression placed PRAME upstream of EZH2 in silencing the pro-apoptotic gene TRAIL, connecting PRAME to PRC2-mediated transcriptional control.","evidence":"siRNA knockdown of PRAME/EZH2 plus EZH2 ChIP on the TRAIL promoter in BCR-ABL-positive cells","pmids":["20838376"],"confidence":"Medium","gaps":["Did not demonstrate direct PRAME-EZH2 physical interaction","Mechanism of EZH2 recruitment to the promoter unresolved"]},{"year":2011,"claim":"Loss-of-function in leukemia cells defined PRAME's cellular role as supporting proliferation and survival, motivating mechanistic dissection of how it does so.","evidence":"siRNA knockdown with flow cytometric cell cycle and proliferation/apoptosis assays in K562 cells","pmids":["21550659"],"confidence":"Medium","gaps":["Phenotype not mechanistically linked to a molecular target","Single cell line"]},{"year":2016,"claim":"Extending the epigenetic regulation model to solid tumors confirmed promoter hypomethylation as a general driver of PRAME expression beyond leukemia.","evidence":"DNMT inhibitor treatment and genetic DNMT knockdown with methylation and expression readouts in epithelial ovarian cancer","pmids":["27322684"],"confidence":"Medium","gaps":["Does not address transcriptional activators","Correlative methylation-expression link"]},{"year":2017,"claim":"Two studies clarified how PRAME is transcriptionally activated and immunologically displayed: MZF1 was shown to directly bind and activate PRAME, and the ALY peptide was shown to be proteasome-processed and HLA-A2-presented.","evidence":"ChIP and ectopic MZF1 expression with demethylation (Cancer Letters); TCR-mimic antibody binding, immunoproteasome induction, and xenografts (JCI)","pmids":["28634046","28628042"],"confidence":"Medium","gaps":["MZF1 not shown to be sufficient for full expression independent of methylation state","Epitope presentation studied for a single HLA allele"]},{"year":2019,"claim":"Gain- and loss-of-function in triple-negative breast cancer connected PRAME to a defined EMT transcriptional program, linking it to invasion and metastatic potential.","evidence":"reciprocal TNBC cell models with migration/invasion assays and EMT gene expression profiling","pmids":["30602372"],"confidence":"Medium","gaps":["Does not identify the direct molecular mechanism upstream of the EMT genes","Correlative gene expression changes"]},{"year":2020,"claim":"An in vivo knockout established a physiological role for PRAME in spermatogenesis, tied to retinoic acid receptor signaling, supporting its broader proposed role in modulating RA pathways.","evidence":"conditional X-linked Prame knockout mouse with histology, germ cell markers, TUNEL, and sperm counts","pmids":["32017313"],"confidence":"Medium","gaps":["RAR signaling disruption inferred from phenotype rather than directly measured","Relevance to cancer RA signaling not demonstrated"]},{"year":2021,"claim":"The defining biochemical advance identified PRAME as the substrate-recognition subunit of a CRL2 E3 ligase targeting p14/ARF, providing a direct enzymatic mechanism for PRAME-driven cell cycle progression.","evidence":"RBX1 interaction proteomics, Co-IP, in vivo ubiquitination assay, and siRNA rescue epistasis with p14/ARF","pmids":["33504946"],"confidence":"High","gaps":["Full substrate repertoire of the PRAME-CRL2 complex not defined","Structural basis of substrate recognition unresolved"]},{"year":2022,"claim":"Two studies expanded PRAME's regulatory reach: a direct PRAME-EZH2 physical interaction was demonstrated in lymphoma, and PRAME was shown to suppress T cell activation by elevating immune checkpoints.","evidence":"isogenic PRAME-KO lymphoma lines with interaction studies and EZH2 inhibitor treatment in vivo (JCI); T cell/cancer co-culture with checkpoint and cytokine profiling (J Cell Mol Med)","pmids":["35380993","34612587"],"confidence":"Medium","gaps":["Domain mediating PRAME-EZH2 binding not mapped","Mechanism linking PRAME to checkpoint induction not biochemically defined"]},{"year":2023,"claim":"Multiple studies extended PRAME's oncogenic mechanism to genome instability via SMC1A ubiquitination, to growth/EMT signaling through PI3K/AKT/mTOR and Wnt/β-catenin, and to upstream control by Gas6/Axl/MAPK signaling and a CCAR1 interaction.","evidence":"PRAME overexpression with SMC1A ubiquitination and DNA damage/PARP-sensitivity assays (Oncogene); pathway inhibitor rescue in LSCC and cervical cancer; RNA-seq and proteomics in HCC","pmids":["38030788","36910848","36980687","37173882"],"confidence":"Medium","gaps":["PI3K/AKT/mTOR and Wnt activation inferred from inhibitor rescue without direct biochemical reconstitution","CCAR1 interaction not functionally validated","Whether SMC1A ubiquitination occurs via the CRL2-PRAME complex not explicitly linked"]},{"year":null,"claim":"It remains unresolved how PRAME's distinct activities—CRL2 substrate receptor, EZH2 binding partner, and signaling node—are integrated within a single protein, and which are direct versus downstream consequences.","evidence":"no single study reconciles the E3 ligase, transcriptional-regulatory, and signaling roles","pmids":[],"confidence":"Low","gaps":["No structural model of PRAME bound to substrate or EZH2","Complete substrate/interactor map of PRAME-CRL2 lacking","Causal hierarchy among p14/ARF, EZH2, SMC1A, and signaling phenotypes undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,2]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[1,2]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,10]}],"localization":[],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[1,2]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[1,6]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[8,9]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[0,10]}],"complexes":["CRL2 (Cullin2-RBX1-EloB-PRAME) E3 ubiquitin ligase"],"partners":["CUL2","RBX1","EZH2","SMC1A","CCAR1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P78395","full_name":"Melanoma antigen preferentially expressed in tumors","aliases":["Opa-interacting protein 4","OIP-4","Preferentially expressed antigen of melanoma"],"length_aa":509,"mass_kda":57.9,"function":"Substrate-recognition component of a Cul2-RING (CRL2) E3 ubiquitin-protein ligase complex, which mediates ubiquitination of target proteins, leading to their degradation (PubMed:21822215, PubMed:26138980). The CRL2(PRAME) complex mediates ubiquitination and degradation of truncated MSRB1/SEPX1 selenoproteins produced by failed UGA/Sec decoding (PubMed:26138980). In the nucleus, the CRL2(PRAME) complex is recruited to epigenetically and transcriptionally active promoter regions bound by nuclear transcription factor Y (NFY) and probably plays a role in chromstin regulation (PubMed:21822215). Functions as a transcriptional repressor, inhibiting the signaling of retinoic acid through the retinoic acid receptors RARA, RARB and RARG: prevents retinoic acid-induced cell proliferation arrest, differentiation and apoptosis (PubMed:16179254)","subcellular_location":"Nucleus; Chromosome; Cytoplasm; Golgi apparatus; Cell membrane","url":"https://www.uniprot.org/uniprotkb/P78395/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PRAME","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":[],"url":"https://opencell.sf.czbiohub.org/search/PRAME","total_profiled":1310},"omim":[{"mim_id":"608160","title":"SRY-BOX 9; SOX9","url":"https://www.omim.org/entry/608160"},{"mim_id":"606021","title":"PRAME NUCLEAR RECEPTOR TRANSCRIPTIONAL REGULATOR; PRAME","url":"https://www.omim.org/entry/606021"},{"mim_id":"606020","title":"OPA-INTERACTING PROTEIN 5; OIP5","url":"https://www.omim.org/entry/606020"},{"mim_id":"606019","title":"EXOSOME COMPONENT 8; EXOSC8","url":"https://www.omim.org/entry/606019"},{"mim_id":"180240","title":"RETINOIC ACID RECEPTOR, ALPHA; RARA","url":"https://www.omim.org/entry/180240"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Plasma membrane","reliability":"Additional"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"testis","ntpm":102.1}],"url":"https://www.proteinatlas.org/search/PRAME"},"hgnc":{"alias_symbol":["CT130"],"prev_symbol":["MAPE"]},"alphafold":{"accession":"P78395","domains":[{"cath_id":"-","chopping":"26-136","consensus_level":"high","plddt":85.7359,"start":26,"end":136},{"cath_id":"-","chopping":"179-296","consensus_level":"medium","plddt":90.1602,"start":179,"end":296}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P78395","model_url":"https://alphafold.ebi.ac.uk/files/AF-P78395-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P78395-F1-predicted_aligned_error_v6.png","plddt_mean":81.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PRAME","jax_strain_url":"https://www.jax.org/strain/search?query=PRAME"},"sequence":{"accession":"P78395","fasta_url":"https://rest.uniprot.org/uniprotkb/P78395.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P78395/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P78395"}},"corpus_meta":[{"pmid":"30045064","id":"PMC_30045064","title":"PRAME Expression in Melanocytic Tumors.","date":"2018","source":"The American journal of surgical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/30045064","citation_count":321,"is_preprint":false},{"pmid":"26933176","id":"PMC_26933176","title":"PRAME as an Independent Biomarker for Metastasis in Uveal Melanoma.","date":"2016","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/26933176","citation_count":231,"is_preprint":false},{"pmid":"18648365","id":"PMC_18648365","title":"PRAME expression and clinical outcome of breast cancer.","date":"2008","source":"British journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/18648365","citation_count":105,"is_preprint":false},{"pmid":"28448663","id":"PMC_28448663","title":"PRAME as a Potential Target for Immunotherapy in Metastatic Uveal Melanoma.","date":"2017","source":"JAMA ophthalmology","url":"https://pubmed.ncbi.nlm.nih.gov/28448663","citation_count":95,"is_preprint":false},{"pmid":"32700786","id":"PMC_32700786","title":"PRAME expression in melanocytic proliferations with intermediate histopathologic or spitzoid features.","date":"2020","source":"Journal of cutaneous pathology","url":"https://pubmed.ncbi.nlm.nih.gov/32700786","citation_count":93,"is_preprint":false},{"pmid":"27993576","id":"PMC_27993576","title":"Cancer-testis antigen expression in synovial sarcoma: NY-ESO-1, PRAME, MAGEA4, and MAGEA1.","date":"2016","source":"Human pathology","url":"https://pubmed.ncbi.nlm.nih.gov/27993576","citation_count":93,"is_preprint":false},{"pmid":"32022332","id":"PMC_32022332","title":"The role of the cancer testis antigen PRAME in tumorigenesis and immunotherapy in human cancer.","date":"2020","source":"Cell proliferation","url":"https://pubmed.ncbi.nlm.nih.gov/32022332","citation_count":93,"is_preprint":false},{"pmid":"35973038","id":"PMC_35973038","title":"PRAME Expression in Cancer. A Systematic Immunohistochemical Study of >5800 Epithelial and Nonepithelial Tumors.","date":"2022","source":"The American journal of surgical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/35973038","citation_count":90,"is_preprint":false},{"pmid":"31311081","id":"PMC_31311081","title":"Cancer Testis Antigens and Immunotherapy: Where Do We Stand in the Targeting of PRAME?","date":"2019","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/31311081","citation_count":90,"is_preprint":false},{"pmid":"27322684","id":"PMC_27322684","title":"PRAME expression and promoter hypomethylation in epithelial ovarian cancer.","date":"2016","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/27322684","citation_count":82,"is_preprint":false},{"pmid":"20799951","id":"PMC_20799951","title":"Leucine-rich repeat protein PRAME: expression, potential functions and clinical implications for leukaemia.","date":"2010","source":"Molecular 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involving EZH2. PRAME knockdown by RNA interference restores TRAIL expression, and EZH2 binding to the TRAIL promoter is lost after PRAME knockdown, indicating PRAME acts upstream of EZH2 to repress TRAIL transcription.\",\n      \"method\": \"siRNA knockdown of PRAME and EZH2 in BCR-ABL-positive cell lines, chromatin immunoprecipitation (ChIP) of EZH2 on TRAIL promoter, RT-PCR expression analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal functional epistasis (siRNA + ChIP), single lab, two orthogonal methods\",\n      \"pmids\": [\"20838376\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PRAME functions as the substrate-recognition receptor of the CRL2 E3 ubiquitin ligase complex (Cullin2-RBX1-EloB-PRAME), targeting the tumor suppressor p14/ARF for ubiquitination and proteasomal degradation. Knockdown of PRAME stabilizes p14/ARF and induces G2/M cell cycle arrest in cancer cells, which is rescued by simultaneous knockdown of p14/ARF.\",\n      \"method\": \"Proteomic analysis of RBX1-interacting proteins, co-immunoprecipitation, in vivo ubiquitination assay, siRNA screening, cell cycle analysis, genetic rescue experiment\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vivo ubiquitination assay + Co-IP + siRNA rescue epistasis, multiple orthogonal methods in single study\",\n      \"pmids\": [\"33504946\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PRAME acts as a CUL2 ubiquitin ligase subunit that, when expressed in somatic cells, upregulates meiosis/DNA repair pathways, increases DNA double-strand breaks, causes telomere dysfunction and aneuploidy. This is mediated at least partly through ubiquitination of SMC1A and altered cohesin function. PRAME expression also renders cells susceptible to PARP1/2 inhibition.\",\n      \"method\": \"PRAME overexpression in neoplastic and non-neoplastic cells, pathway analysis, SMC1A ubiquitination assay, DNA damage assays (DSB, telomere dysfunction), PARP inhibitor sensitivity assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional overexpression studies with multiple mechanistic readouts, single lab\",\n      \"pmids\": [\"38030788\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"PRAME expression in chronic myeloid leukemia is regulated by DNA methylation: hypomethylation of the PRAME gene (CpG sites in exon 2) correlates with elevated PRAME transcript levels, and treatment with the demethylating agent 5-aza-2'-deoxycytidine restores PRAME expression in non-expressing cell lines.\",\n      \"method\": \"Bisulfite sequencing, methylation-specific PCR, 5-aza-2'-deoxycytidine treatment, RT-PCR\",\n      \"journal\": \"Leukemia research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacologic demethylation + bisulfite sequencing, two orthogonal methods, single lab\",\n      \"pmids\": [\"17382387\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PRAME promoter DNA hypomethylation is a key mechanism regulating PRAME expression in epithelial ovarian cancer. Pharmacologic or genetic disruption of DNA methyltransferase (DNMT) enzymes activated PRAME expression in EOC cells.\",\n      \"method\": \"DNMT inhibitor treatment, genetic DNMT knockdown, promoter methylation analysis, qPCR expression analysis\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacologic and genetic DNMT disruption with expression readout, single lab\",\n      \"pmids\": [\"27322684\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The transcription factor MZF1 upregulates PRAME expression by directly binding to MZF1 binding sites overlapping a CpG-rich region in PRAME intron 1. DNA demethylation with 5-azaC enhances MZF1 binding to PRAME DNA and further potentiates PRAME expression.\",\n      \"method\": \"In silico promoter analysis, ectopic MZF1 expression, 5-aza-2'-deoxycytidine treatment, chromatin immunoprecipitation, qRT-PCR and Western blot\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrating direct MZF1 binding + functional overexpression + demethylation, single lab\",\n      \"pmids\": [\"28634046\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"siRNA-mediated knockdown of PRAME in the K562 leukemia cell line suppresses proliferation, induces G0/G1 cell cycle arrest, and causes apoptosis, indicating PRAME supports cell cycle progression and survival in leukemic cells.\",\n      \"method\": \"siRNA knockdown, flow cytometric cell cycle analysis, proliferation assays\",\n      \"journal\": \"Leukemia research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean KD with defined cellular phenotype (cell cycle arrest + apoptosis), single lab, single method set\",\n      \"pmids\": [\"21550659\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PRAME promotes epithelial-to-mesenchymal transition (EMT) and increases migration and invasion in triple-negative breast cancer cells. PRAME overexpression upregulates SNAI1, TWIST1, TCF4, FOXC2, MMP2, MMP3, and WNT11 while downregulating BMP7, and alters expression of E-cadherin, N-cadherin, vimentin, and ZEB1.\",\n      \"method\": \"Gain- and loss-of-function TNBC cell line models, migration/invasion assays, gene expression profiling, qRT-PCR\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal gain/loss-of-function with multiple molecular and phenotypic readouts, single lab\",\n      \"pmids\": [\"30602372\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PRAME overexpression in breast cancer cells inhibits T cell activation and cytolytic potential through suppression of pro-inflammatory cytokines and mediators of T cell activation. PRAME silencing reduces expression of immune checkpoints PD-1, LAG3, PD-L1, CD86, Gal-9, and VISTA, and induces cancer cell killing comparable to anti-PD-L1 treatment.\",\n      \"method\": \"Direct and indirect T cell/cancer cell co-culture models, PRAME overexpression and silencing, immune checkpoint expression analysis, cytokine profiling\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-culture functional assays with gain/loss-of-function, multiple immune readouts, single lab\",\n      \"pmids\": [\"34612587\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PRAME-derived peptide ALYVDSLFFL (ALY, residues 300–309) is processed by the proteasome and presented on the cell surface in complex with HLA-A*02:01. The immunoproteasome (induced by IFN-γ via upregulation of β5i subunit) reduces internal destructive cleavages within the ALY epitope compared to the constitutive proteasome, increasing surface presentation of the peptide/HLA complex.\",\n      \"method\": \"TCR mimic antibody (Pr20) binding assays, IFN-γ treatment, immunoproteasome induction, HLA-A2+/PRAME+ cancer cell line experiments, mouse xenograft models\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct biochemical demonstration of proteasomal processing differences + functional antibody binding + in vivo xenograft, multiple orthogonal methods\",\n      \"pmids\": [\"28628042\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PRAME directly interacts with EZH2 and acts as a negative regulator of EZH2 in diffuse large B cell lymphoma. PRAME knockout in lymphoma cell lines leads to repression of PRC2-regulated genes, and EZH2 inhibition with EPZ-6438 restores PRAME expression and tumor microenvironment in vivo.\",\n      \"method\": \"Isogenic PRAME-KO lymphoma cell lines, gene expression profiling, protein-protein interaction studies (PRAME-EZH2 interaction), EZH2 inhibitor treatment in vivo\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct interaction demonstrated + isogenic KO + in vivo drug treatment, single lab\",\n      \"pmids\": [\"35380993\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Deletion of the X-linked mouse Prame gene reduces testis size and sperm count and increases germ cell apoptosis, with phenotypes including Sertoli-cell-only tubules and germ cell arrest at the spermatogonia stage, consistent with disruption of retinoic acid receptor (RAR) signaling by PRAME depletion.\",\n      \"method\": \"Conditional knockout mouse, histology, immunofluorescence with germ cell markers, TUNEL assay, sperm count\",\n      \"journal\": \"Molecular reproduction and development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO mouse with multiple phenotypic and molecular readouts, single lab\",\n      \"pmids\": [\"32017313\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PRAME promotes proliferation, migration, invasion, and EMT of laryngeal squamous cell carcinoma cells at least partially by activating the PI3K/AKT/mTOR signaling pathway. HDAC5 was identified as an upstream regulator of PRAME expression.\",\n      \"method\": \"qRT-PCR, functional in vitro assays (proliferation, migration, invasion), in vivo xenograft, PI3K/AKT/mTOR pathway analysis, HDAC5 expression manipulation\",\n      \"journal\": \"Open medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, indirect pathway activation inference without direct biochemical reconstitution\",\n      \"pmids\": [\"36910848\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PRAME promotes cervical cancer cell proliferation, migration, and invasion and prevents G0/G1 arrest and apoptosis through activation of the Wnt/β-catenin signaling pathway. PRAME-overexpressing effects are partly reversed by the Wnt inhibitor MSAB both in vitro and in vivo.\",\n      \"method\": \"siRNA knockdown and overexpression in cervical cancer cell lines, CCK-8/BrdU/scratch/transwell assays, flow cytometry, xenograft mouse model, Wnt inhibitor MSAB treatment\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pathway inhibitor rescue single lab, no direct biochemical binding or reconstitution\",\n      \"pmids\": [\"36980687\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PRAME is a downstream target of Gas6/Axl/MAPK-ERK1/2 signaling in hepatocellular carcinoma. Axl signaling or MAPK/ERK1/2 inhibition reduces PRAME expression, and PRAME levels are associated with a mesenchymal-like phenotype promoting cell migration and invasion. PRAME interacts with pro-oncogenic protein CCAR1.\",\n      \"method\": \"RNA-seq of Gas6-stimulated Axl-proficient vs. Axl-deficient HCC cells, gain/loss-of-function, proteomics, 2D migration and 3D invasion assays\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA-seq target identification + functional gain/loss-of-function + proteomics interaction data, single lab\",\n      \"pmids\": [\"37173882\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"MSX2 regulates PRAME expression as part of a transcriptional program driving mesenchymal stem cell (MSC) differentiation from human pluripotent stem cells (hPSCs). MSX2 genetic deletion impairs hPSC differentiation into MSCs, and MSX2 induces MSC formation by regulating TWIST1 and PRAME.\",\n      \"method\": \"Genetic deletion of MSX2, ectopic MSX2 expression, hPSC differentiation assays, gene expression analysis\",\n      \"journal\": \"Stem cell reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — genetic manipulation with lineage readout, but PRAME's mechanistic role is inferred rather than directly demonstrated\",\n      \"pmids\": [\"30033084\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PRAME is a leucine-rich repeat protein that functions as the substrate-recognition subunit of the CRL2 ubiquitin E3 ligase complex (targeting p14/ARF for degradation), directly interacts with and negatively regulates EZH2 (thereby suppressing PRC2 target genes and TRAIL expression), promotes genomic instability through ubiquitination of cohesin subunit SMC1A, and whose expression is regulated epigenetically by DNA methylation and transcriptionally by MZF1; in cancer cells it supports proliferation and survival by inhibiting retinoic acid signaling, promoting EMT, suppressing anti-tumor immune responses via immune checkpoint upregulation, and activating Wnt/β-catenin and PI3K/AKT/mTOR pathways.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PRAME is a cancer-testis antigen that operates as the substrate-recognition receptor of a CRL2 ubiquitin E3 ligase complex (Cullin2–RBX1–EloB–PRAME), directing ubiquitination and proteasomal degradation of the tumor suppressor p14/ARF; loss of PRAME stabilizes p14/ARF and arrests cells at G2/M, establishing a direct route by which PRAME supports cancer cell cycle progression [#1]. As a ubiquitin ligase subunit, PRAME also ubiquitinates the cohesin subunit SMC1A, and its ectopic expression in somatic cells drives DNA double-strand breaks, telomere dysfunction, and aneuploidy while sensitizing cells to PARP1/2 inhibition [#2]. In parallel, PRAME directly interacts with and negatively regulates EZH2, controlling PRC2 target gene programs; in BCR-ABL-positive leukemia it acts upstream of EZH2 to repress TRAIL transcription, and in diffuse large B cell lymphoma its loss represses PRC2-regulated genes [#0, #10]. Functionally, PRAME promotes proliferation, survival, and epithelial-to-mesenchymal transition, and suppresses anti-tumor immunity by elevating immune checkpoints including PD-1, PD-L1, LAG3, and VISTA [#6, #7, #8]. PRAME expression is governed epigenetically by promoter DNA hypomethylation and transcriptionally by the activator MZF1, which binds a CpG-rich region in intron 1 [#3, #4, #5]. A proteasome-processed PRAME peptide (ALYVDSLFFL, residues 300–309) is presented on HLA-A*02:01, with immunoproteasome activity enhancing surface display, providing the basis for PRAME-directed immune targeting [#9].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Establishing how PRAME becomes aberrantly expressed in cancer, this work showed its silencing is enforced by DNA methylation, reframing PRAME as an epigenetically controlled cancer-testis antigen.\",\n      \"evidence\": \"bisulfite sequencing, methylation-specific PCR, and 5-aza-2'-deoxycytidine treatment in chronic myeloid leukemia lines\",\n      \"pmids\": [\"17382387\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not identify the transcription factors acting on the demethylated locus\", \"Limited to leukemia context\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"The first mechanistic link to gene repression placed PRAME upstream of EZH2 in silencing the pro-apoptotic gene TRAIL, connecting PRAME to PRC2-mediated transcriptional control.\",\n      \"evidence\": \"siRNA knockdown of PRAME/EZH2 plus EZH2 ChIP on the TRAIL promoter in BCR-ABL-positive cells\",\n      \"pmids\": [\"20838376\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not demonstrate direct PRAME-EZH2 physical interaction\", \"Mechanism of EZH2 recruitment to the promoter unresolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Loss-of-function in leukemia cells defined PRAME's cellular role as supporting proliferation and survival, motivating mechanistic dissection of how it does so.\",\n      \"evidence\": \"siRNA knockdown with flow cytometric cell cycle and proliferation/apoptosis assays in K562 cells\",\n      \"pmids\": [\"21550659\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Phenotype not mechanistically linked to a molecular target\", \"Single cell line\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Extending the epigenetic regulation model to solid tumors confirmed promoter hypomethylation as a general driver of PRAME expression beyond leukemia.\",\n      \"evidence\": \"DNMT inhibitor treatment and genetic DNMT knockdown with methylation and expression readouts in epithelial ovarian cancer\",\n      \"pmids\": [\"27322684\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not address transcriptional activators\", \"Correlative methylation-expression link\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Two studies clarified how PRAME is transcriptionally activated and immunologically displayed: MZF1 was shown to directly bind and activate PRAME, and the ALY peptide was shown to be proteasome-processed and HLA-A2-presented.\",\n      \"evidence\": \"ChIP and ectopic MZF1 expression with demethylation (Cancer Letters); TCR-mimic antibody binding, immunoproteasome induction, and xenografts (JCI)\",\n      \"pmids\": [\"28634046\", \"28628042\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"MZF1 not shown to be sufficient for full expression independent of methylation state\", \"Epitope presentation studied for a single HLA allele\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Gain- and loss-of-function in triple-negative breast cancer connected PRAME to a defined EMT transcriptional program, linking it to invasion and metastatic potential.\",\n      \"evidence\": \"reciprocal TNBC cell models with migration/invasion assays and EMT gene expression profiling\",\n      \"pmids\": [\"30602372\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not identify the direct molecular mechanism upstream of the EMT genes\", \"Correlative gene expression changes\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"An in vivo knockout established a physiological role for PRAME in spermatogenesis, tied to retinoic acid receptor signaling, supporting its broader proposed role in modulating RA pathways.\",\n      \"evidence\": \"conditional X-linked Prame knockout mouse with histology, germ cell markers, TUNEL, and sperm counts\",\n      \"pmids\": [\"32017313\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"RAR signaling disruption inferred from phenotype rather than directly measured\", \"Relevance to cancer RA signaling not demonstrated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"The defining biochemical advance identified PRAME as the substrate-recognition subunit of a CRL2 E3 ligase targeting p14/ARF, providing a direct enzymatic mechanism for PRAME-driven cell cycle progression.\",\n      \"evidence\": \"RBX1 interaction proteomics, Co-IP, in vivo ubiquitination assay, and siRNA rescue epistasis with p14/ARF\",\n      \"pmids\": [\"33504946\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full substrate repertoire of the PRAME-CRL2 complex not defined\", \"Structural basis of substrate recognition unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Two studies expanded PRAME's regulatory reach: a direct PRAME-EZH2 physical interaction was demonstrated in lymphoma, and PRAME was shown to suppress T cell activation by elevating immune checkpoints.\",\n      \"evidence\": \"isogenic PRAME-KO lymphoma lines with interaction studies and EZH2 inhibitor treatment in vivo (JCI); T cell/cancer co-culture with checkpoint and cytokine profiling (J Cell Mol Med)\",\n      \"pmids\": [\"35380993\", \"34612587\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Domain mediating PRAME-EZH2 binding not mapped\", \"Mechanism linking PRAME to checkpoint induction not biochemically defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Multiple studies extended PRAME's oncogenic mechanism to genome instability via SMC1A ubiquitination, to growth/EMT signaling through PI3K/AKT/mTOR and Wnt/β-catenin, and to upstream control by Gas6/Axl/MAPK signaling and a CCAR1 interaction.\",\n      \"evidence\": \"PRAME overexpression with SMC1A ubiquitination and DNA damage/PARP-sensitivity assays (Oncogene); pathway inhibitor rescue in LSCC and cervical cancer; RNA-seq and proteomics in HCC\",\n      \"pmids\": [\"38030788\", \"36910848\", \"36980687\", \"37173882\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"PI3K/AKT/mTOR and Wnt activation inferred from inhibitor rescue without direct biochemical reconstitution\", \"CCAR1 interaction not functionally validated\", \"Whether SMC1A ubiquitination occurs via the CRL2-PRAME complex not explicitly linked\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how PRAME's distinct activities—CRL2 substrate receptor, EZH2 binding partner, and signaling node—are integrated within a single protein, and which are direct versus downstream consequences.\",\n      \"evidence\": \"no single study reconciles the E3 ligase, transcriptional-regulatory, and signaling roles\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of PRAME bound to substrate or EZH2\", \"Complete substrate/interactor map of PRAME-CRL2 lacking\", \"Causal hierarchy among p14/ARF, EZH2, SMC1A, and signaling phenotypes undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 10]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [1, 6]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [8, 9]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0, 10]}\n    ],\n    \"complexes\": [\"CRL2 (Cullin2-RBX1-EloB-PRAME) E3 ubiquitin ligase\"],\n    \"partners\": [\"CUL2\", \"RBX1\", \"EZH2\", \"SMC1A\", \"CCAR1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":6,"faith_total":6,"faith_pct":100.0}}