{"gene":"MED19","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2006,"finding":"Med19 (Rox3) in S. cerevisiae is required for stable association of the Middle module with the Mediator complex; deletion of Med19 allows the Middle module to dissociate under stringent conditions, leaving a Head-Tail complex. The Med19-deficient Mediator lacking the Middle module cannot facilitate activated transcription, cannot stimulate enhanced basal transcription, cannot enhance TFIIH phosphorylation of the RNA Pol II CTD, and cannot bind RNA Pol II/CTD, establishing Med19 as a structural linchpin that couples the Middle module to transcriptional activation.","method":"Biochemical purification of Mediator from Δmed19 yeast strains under mild and stringent conditions; in vitro transcription assays; CTD phosphorylation assays; RNA Pol II binding assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution, enzymatic assays, and multiple orthogonal biochemical methods in a single rigorous study","pmids":["17192271"],"is_preprint":false},{"year":2014,"finding":"Drosophila Med19 directly binds Hox transcription factor homeodomains both in vitro and in vivo through a conserved animal-specific motif. Loss-of-function Med19 mutations act as dose-sensitive genetic modifiers that synergistically alter Hox-directed developmental outcomes, and clonal analysis shows Med19 is required for Hox-dependent target gene activation, establishing Med19 as a direct molecular link between Hox homeodomains and the RNA Pol II machinery.","method":"In vitro binding assays (direct homeodomain-Med19 binding), in vivo co-immunoprecipitation, loss-of-function genetics and clonal analysis, targeted mutagenesis of the conserved motif, reporter gene assays for Ultrabithorax target activation","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct in vitro binding, in vivo interaction, genetic epistasis, mutagenesis, and functional reporter assays in a single study","pmids":["24786462"],"is_preprint":false},{"year":2020,"finding":"Drosophila Med19 physically interacts directly with GATA transcription factors (Pannier and Serpent) through their conserved C-zinc finger domains both in vivo and in vitro, and is required for GATA-dependent gene expression. Med19 also directly interacts with Med1 by GST pulldown, identifying Med19/Med1 as a composite GATA TF interface within the Mediator middle module.","method":"Co-immunoprecipitation in vivo, in vitro binding assays, GST pulldown (Med19-Med1 interaction), loss-of-function genetics, reporter gene assays in cellulo","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — reciprocal in vitro and in vivo binding, GST pulldown, and functional loss-of-function assays across multiple GATA targets","pmids":["32737196"],"is_preprint":false},{"year":2017,"finding":"LCMR1 (MED19) physically interacts with the DEK protein, with the interaction mediated primarily by the N-terminal region of DEK. Both proteins cooperate to suppress apoptosis in lung cancer cells via the MCL-1 pathway, as demonstrated by yeast two-hybrid screening, co-immunoprecipitation, and GST pulldown.","method":"Yeast two-hybrid screen of lung cancer cDNA library, co-immunoprecipitation (in vivo), GST pulldown (in vitro), RNA interference knockdown with apoptosis readout","journal":"Molecular medicine reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal in vitro and in vivo binding assays confirmed interaction, functional RNAi follow-up; single lab","pmids":["28765911"],"is_preprint":false},{"year":2018,"finding":"Med19 interacts with EGFR and increases EGFR expression, activating the EGFR/MEK/ERK signaling pathway to promote breast cancer cell proliferation, EMT, invasion, and migration; the oncogenic effect of Med19 is mediated through EGFR signaling, as demonstrated by co-immunoprecipitation and rescue experiments.","method":"Co-immunoprecipitation (Med19-EGFR), shRNA knockdown and overexpression, EGFR pathway inhibitor rescue, in vitro and in vivo functional assays","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP interaction plus pathway rescue experiments; single lab","pmids":["30583076"],"is_preprint":false},{"year":2018,"finding":"Med19 promotes autophagy and chemoresistance in breast cancer cells through the HMGB1 pathway; lentivirus-mediated Med19 inhibition suppressed LC3-II/LC3-I ratio, Atg3, Atg5 expression and LC3 puncta formation, and increased sensitivity to ADM, DDP, and TAX. The autophagy-promoting effect of Med19 was mediated via HMGB1 signaling.","method":"Lentivirus shRNA knockdown, autophagy markers (LC3-II/I ratio, p62, RFP-LC3 dots), Western blot for HMGB1 pathway components, cell viability assays with chemotherapeutic agents","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — multiple autophagy markers measured, pathway identified via HMGB1; single lab with several orthogonal readouts","pmids":["30161287"],"is_preprint":false},{"year":2016,"finding":"Med19 promotes breast cancer cell proliferation by suppressing CBFA2T3 expression, which in turn allows HEB expression; Med19 knockdown upregulates CBFA2T3 and downregulates HEB, while ectopic CBFA2T3 overexpression reverses the proliferative effect of Med19 overexpression, placing CBFA2T3/HEB downstream of Med19 in a regulatory axis.","method":"Lentivirus-mediated Med19 inhibition and overexpression, ectopic CBFA2T3 expression rescue, RT-PCR and Western blot for CBFA2T3 and HEB, cell proliferation and colony formation assays, correlation analysis in patient tissues","journal":"Breast cancer (Tokyo, Japan)","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — genetic epistasis via rescue experiment, multiple orthogonal assays; single lab","pmids":["27572702"],"is_preprint":false},{"year":2017,"finding":"Med19 knockdown in bladder cancer cells decreases Wnt/β-catenin pathway activity (measured by TOP/FOPflash reporter), downregulates Wnt2, β-catenin, Cyclin-D1, and MMP-9, and elevates GSK3β and E-cadherin, positioning Med19 as an upstream regulator of the Wnt/β-catenin pathway in bladder cancer proliferation and migration.","method":"shRNA knockdown, TOP/FOPflash Wnt reporter assay, Western blot, RT-PCR, in vitro proliferation and migration assays, in vivo xenograft","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Wnt reporter assay plus downstream target profiling; single lab","pmids":["28631286"],"is_preprint":false},{"year":2021,"finding":"In a large-scale RNAi screen, LCMR1 (MED19) was identified as a transcriptional activator of Tspan8 in melanoma cells; LCMR1 modulation positively regulated endogenous Tspan8 expression with concomitant changes in melanoma cell-matrix adherence and invasion, establishing Tspan8 as the first known LCMR1 transcriptional target linking MED19 to a specific invasive phenotype.","method":"Large-scale RNAi screen for Tspan8 regulators, shRNA knockdown of LCMR1, qRT-PCR and Western blot for Tspan8, in vitro invasion and adhesion assays, in vivo tumorigenicity","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — RNAi screen plus functional validation with multiple orthogonal assays; single lab","pmids":["27375018"],"is_preprint":false},{"year":2016,"finding":"FOXD3 acts as a transcription factor that activates miR-214 expression (validated by ChIP assay), and miR-214 directly targets MED19 3'UTR (validated by dual-luciferase reporter assay) to suppress MED19 translation; miR-214 mediates the inhibitory effect of FOXD3 on colorectal cancer proliferation, invasion and metastasis through MED19 suppression.","method":"ChIP assay (FOXD3 binding to miR-214 promoter), dual-luciferase reporter assay (miR-214 targeting MED19 3'UTR), bisulfite sequencing, in vitro and in vivo functional assays, Western blot and RT-PCR","journal":"British journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — direct reporter and ChIP validation of the regulatory axis; single lab","pmids":["27811858"],"is_preprint":false},{"year":2020,"finding":"SP1 activates LINC00339 expression by binding its promoter (binding validated by luciferase assay); LINC00339 acts as a miR-378a-3p sponge (validated by luciferase and RNA pulldown assay); miR-378a-3p directly targets MED19 3'UTR (validated by luciferase assay), thereby establishing a SP1/LINC00339/miR-378a-3p/MED19 regulatory axis controlling CRC proliferation and Wnt/β-catenin signaling.","method":"Dual-luciferase reporter assay, RNA pulldown assay, gain- and loss-of-function experiments, Western blot, in vivo tumor growth assay","journal":"OncoTargets and therapy","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — multiple validated interactions via reporter assay and RNA pulldown; single lab","pmids":["33235461"],"is_preprint":false},{"year":2022,"finding":"In Drosophila wing imaginal discs, auxin-inducible degradation of endogenous Med19 followed by RNA-seq shows that Med19 is not globally required for mRNA transcription but specifically regulates less than one quarter of expressed genes; Med19-dependent genes are enriched for spatially-regulated developmental genes while constitutively expressed genes are largely unaffected. Med19 is required for Notch-responsive target gene expression (wingless and E(spl)-C genes), suggesting a specific role as a transcriptional effector of developmental signaling pathways.","method":"Auxin-inducible degron system for endogenous Med19 degradation in vivo, RNA-seq, differential gene expression analysis, cross-referencing with developmental gene expression databases, in vivo reporter assays for Notch target genes","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — endogenous protein degradation coupled with transcriptome-wide analysis and multiple functional validations in vivo","pmids":["36445897"],"is_preprint":false},{"year":2025,"finding":"MED19 localizes to the nucleolus independently of the Mediator complex; this nucleolar targeting is mediated by a conserved poly-lysine motif at the MED19 C-terminus. In the nucleolus, MED19 binds ribosomal RNA and fibrillarin (FBL), a catalytic component of the 2'-O-methyltransferase complex, and facilitates rRNA processing and 2'-O-methylation. This promotes IRES-dependent translation efficiency for onco-promoting genes including c-Myc.","method":"Subcellular fractionation and imaging for nucleolar localization, C-terminal poly-lysine motif mutagenesis, co-immunoprecipitation with FBL, rRNA binding assays, rRNA 2'-O-methylation assays, IRES-reporter translation assays, Western blot for c-Myc","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (localization, mutagenesis, binding, enzymatic function, translation readout) in a single rigorous study","pmids":["41414671"],"is_preprint":false},{"year":2023,"finding":"LCMR1 (MED19) reduces RNA Pol II occupancy at the promoters of HLA-encoding genes, suppressing their transcription; lentivirus-based knockdown of LCMR1 de-repressed HLA gene expression and inhibited large-cell lung cancer proliferation, migration, and invasion in vitro and reduced xenograft tumor growth in vivo.","method":"Lentivirus-based knockdown, RNA Pol II occupancy assay at HLA gene promoters (multiple sequence-based assay), RT-PCR/Western blot for HLA gene expression, xenograft mouse model, proliferation/migration/invasion assays","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Pol II occupancy assay at target promoters plus functional assays; single lab","pmids":["38001705"],"is_preprint":false},{"year":2026,"finding":"MBD2 silences the SFRP1 tumor suppressor in CRC by blocking MED19 binding to the methylated SFRP1 promoter; when MBD2 is inhibited (genetically or by KCC07), MED19 can bind the SFRP1 promoter, which is required for RNA Pol II CTD-S7 phosphorylation and productive transcription of SFRP1, thereby activating Wnt pathway antagonism.","method":"siRNA and small molecule (KCC07) inhibition of MBD2, ChIP for MED19 binding at SFRP1 promoter, RNA Pol II CTD-S7 phosphorylation assays, SFRP1/β-catenin Western blot, Wnt reporter assay, in vivo tumor growth assay","journal":"Cancer biology & therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP binding assay with CTD phosphorylation readout and in vivo validation; single lab","pmids":["42084802"],"is_preprint":false},{"year":2011,"finding":"shRNA-mediated knockdown of MED19 in prostate cancer cells (PC-3 and DU145) induces S-phase arrest and apoptosis via modulation of Bid and Caspase 7, reducing cell proliferation and tumor growth in nude mouse xenografts.","method":"Lentivirus shRNA knockdown, flow cytometry (cell cycle), apoptosis assays, Western blot for Bid and Caspase 7, in vivo xenograft","journal":"BMB reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, KD with apoptosis pathway marker assay but no direct mechanistic link established","pmids":["21871180"],"is_preprint":false},{"year":2017,"finding":"Med19 knockdown in laryngocarcinoma HEp2 cells induces apoptosis via activation of caspases 3, 9, and Apaf-1, identifying an Apaf-1-dependent intrinsic apoptosis pathway downstream of Med19 inhibition.","method":"shRNA knockdown, Western blot and activity assays for caspase-3, caspase-9, Apaf-1, cell growth and migration assays, in vivo xenograft","journal":"American journal of translational research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, KD with downstream apoptotic marker measurement but no direct mechanistic interaction established","pmids":["28337304"],"is_preprint":false}],"current_model":"MED19 (LCMR1) is an integral Mediator complex subunit that serves as a structural linchpin connecting the Middle module to the Head and Tail modules for RNA Pol II-dependent transcription; it directly binds Hox homeodomain proteins and GATA transcription factors through conserved interaction motifs to mediate their transcriptional outputs, physically associates with Med1 within the Mediator middle module, and regulates developmental gene expression downstream of signaling pathways including Notch. Beyond its canonical Mediator role, MED19 independently localizes to the nucleolus via a C-terminal poly-lysine motif, where it binds rRNA and fibrillarin to promote rRNA 2'-O-methylation and IRES-dependent translation of oncoproteins such as c-Myc; in cancer contexts it also interacts with EGFR and DEK, modulates the Wnt/β-catenin and HMGB1/autophagy pathways, controls RNA Pol II occupancy at specific gene promoters (including HLA genes and SFRP1), and its loss arrests cell cycle progression at G0/G1 and induces apoptosis across multiple cancer cell types."},"narrative":{"mechanistic_narrative":"MED19 is an integral subunit of the Mediator complex that functions as a structural linchpin coupling the Middle module to the Head and Tail modules, an arrangement required for activated RNA Pol II transcription, stimulation of basal transcription, enhanced TFIIH phosphorylation of the Pol II CTD, and Mediator binding to Pol II [PMID:17192271]. Rather than being globally required for transcription, MED19 selectively controls a subset of genes — particularly spatially-regulated developmental genes and Notch-responsive targets such as wingless and E(spl)-C [PMID:36445897]. It provides a direct physical interface between sequence-specific activators and the Pol II machinery, binding Hox homeodomains through a conserved animal-specific motif [PMID:24786462] and GATA transcription factors through their C-zinc fingers, with the GATA interface formed together with Med1 in the Middle module [PMID:32737196]. Beyond Mediator, MED19 independently localizes to the nucleolus via a conserved C-terminal poly-lysine motif, where it binds rRNA and fibrillarin to promote rRNA 2'-O-methylation and IRES-dependent translation of oncoproteins including c-Myc [PMID:41414671]. In cancer, MED19 controls Pol II occupancy at specific promoters, suppressing HLA gene transcription [PMID:38001705] and, when freed from MBD2 blockade, binding the methylated SFRP1 promoter to drive CTD-S7 phosphorylation and SFRP1 transcription [PMID:42084802]; its loss arrests proliferation and induces apoptosis across multiple cancer types [PMID:21871180, PMID:28337304].","teleology":[{"year":2006,"claim":"Established why MED19 matters structurally: it determines whether the Mediator Middle module stays attached and whether Mediator can support activated transcription at all.","evidence":"Biochemical purification of Mediator from Δmed19 yeast, in vitro transcription, CTD phosphorylation, and Pol II binding assays","pmids":["17192271"],"confidence":"High","gaps":["Yeast system; human MED19 architecture not directly resolved here","Does not identify which activators depend on MED19","No structural model of the Middle-Head/Tail bridge"]},{"year":2014,"claim":"Resolved how MED19 connects developmental activators to Pol II by showing direct, motif-dependent binding to Hox homeodomains with functional consequences.","evidence":"In vitro binding, in vivo co-IP, loss-of-function genetics, motif mutagenesis, and Ubx reporter assays in Drosophila","pmids":["24786462"],"confidence":"High","gaps":["Conserved motif's structural basis of homeodomain recognition not solved","Generalizability beyond Hox not tested here"]},{"year":2016,"claim":"Began defining MED19 oncogenic downstream wiring in breast cancer through a CBFA2T3/HEB axis.","evidence":"Lentiviral knockdown/overexpression with CBFA2T3 rescue, expression profiling, proliferation assays, patient correlation","pmids":["27572702"],"confidence":"Medium","gaps":["No direct evidence MED19 transcriptionally controls CBFA2T3 via Mediator","Single lab"]},{"year":2016,"claim":"Placed MED19 under upstream non-coding RNA control, showing it is a translationally repressible target of a FOXD3/miR-214 tumor-suppressive axis.","evidence":"ChIP, dual-luciferase reporter of miR-214 targeting MED19 3'UTR, functional assays in colorectal cancer","pmids":["27811858"],"confidence":"Medium","gaps":["Regulation is of MED19 expression, not its mechanism of action","Single lab"]},{"year":2016,"claim":"Identified the first specific transcriptional target gene of MED19, linking it to an invasive phenotype.","evidence":"Large-scale RNAi screen for Tspan8 regulators with shRNA validation and invasion/adhesion assays in melanoma","pmids":["27375018"],"confidence":"Medium","gaps":["Direct promoter occupancy at Tspan8 not shown","Single lab"]},{"year":2017,"claim":"Extended MED19 cancer biology to physical partners and pathways beyond core Mediator, implicating DEK, Wnt/β-catenin, and apoptosis suppression.","evidence":"Y2H, co-IP, GST pulldown for DEK; TOP/FOPflash and target profiling for Wnt; RNAi with apoptosis/caspase readouts","pmids":["28765911","28631286","28337304"],"confidence":"Medium","gaps":["Whether DEK and Wnt effects depend on MED19's Mediator role unresolved","Apoptosis findings are marker-level without direct mechanistic link","Multiple single-lab studies"]},{"year":2018,"claim":"Connected MED19 to receptor signaling and stress responses via EGFR/MEK/ERK activation and HMGB1-dependent autophagy/chemoresistance.","evidence":"Co-IP with EGFR, pathway-inhibitor rescue, autophagy marker panels, chemosensitivity assays in breast cancer","pmids":["30583076","30161287"],"confidence":"Medium","gaps":["EGFR co-IP not shown to be direct/reciprocally validated","How a Mediator subunit regulates EGFR expression mechanistically unclear","Single lab"]},{"year":2020,"claim":"Defined the GATA-Mediator interface, showing MED19 and Med1 jointly form a composite docking surface for GATA factors.","evidence":"In vivo co-IP, in vitro binding, GST pulldown of Med19-Med1, loss-of-function genetics, reporter assays in Drosophila","pmids":["32737196"],"confidence":"High","gaps":["Structural model of the GATA/Med19/Med1 interface absent","Human GATA factor binding not directly tested"]},{"year":2022,"claim":"Reframed MED19 as a selective rather than global transcriptional effector, defining the gene set it controls and its role in Notch signaling output.","evidence":"Auxin-inducible degron degradation of endogenous Med19 plus RNA-seq and Notch target reporters in Drosophila wing discs","pmids":["36445897"],"confidence":"High","gaps":["Mechanism of target-gene selectivity not defined","Mammalian gene-selectivity not directly demonstrated"]},{"year":2023,"claim":"Showed MED19 can repress as well as activate by reducing Pol II occupancy at HLA promoters in lung cancer.","evidence":"Lentiviral knockdown, Pol II occupancy assays at HLA promoters, expression analysis, xenograft and invasion assays","pmids":["38001705"],"confidence":"Medium","gaps":["Mechanism of MED19-mediated repression unresolved","Single lab"]},{"year":2025,"claim":"Uncovered a Mediator-independent MED19 function in the nucleolus driving rRNA modification and oncoprotein translation.","evidence":"Fractionation/imaging, C-terminal poly-lysine motif mutagenesis, FBL co-IP, rRNA binding and 2'-O-methylation assays, IRES-reporter translation, c-Myc Western","pmids":["41414671"],"confidence":"High","gaps":["Stoichiometry/regulation of nucleolar vs Mediator pools unknown","Direct role in FBL methyltransferase catalysis not defined"]},{"year":2026,"claim":"Demonstrated MED19 promoter recruitment is gated by DNA methylation reader MBD2, controlling SFRP1 transcription and Wnt antagonism.","evidence":"MBD2 siRNA/KCC07 inhibition, ChIP for MED19 at SFRP1 promoter, CTD-S7 phosphorylation assays, Wnt reporter, in vivo tumor assays in CRC","pmids":["42084802"],"confidence":"Medium","gaps":["Whether MED19-SFRP1 promoter binding is direct vs Mediator-mediated unclear","Single lab"]},{"year":null,"claim":"How MED19 partitions between its core Mediator-bridging role and its Mediator-independent nucleolar/translation function, and what dictates its gene-selective activating versus repressive behavior, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of human MED19 within Mediator or with activators","Determinants of target-gene selectivity unknown","Regulation of nucleolar versus Mediator pool partitioning uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,1,2,11]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,2]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[12]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,1,11]},{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[12]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,11,13,14]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[1,2,11]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[12]}],"complexes":["Mediator complex"],"partners":["MED1","FBL","DEK","EGFR"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"A0JLT2","full_name":"Mediator of RNA polymerase II transcription subunit 19","aliases":["Lung cancer metastasis-related protein 1","Mediator complex subunit 19"],"length_aa":244,"mass_kda":26.3,"function":"Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/A0JLT2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MED19","classification":"Not Classified","n_dependent_lines":692,"n_total_lines":1208,"dependency_fraction":0.5728476821192053},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000156603","cell_line_id":"CID000248","localizations":[{"compartment":"nuclear_punctae","grade":3},{"compartment":"nucleoplasm","grade":3}],"interactors":[{"gene":"MED14","stoichiometry":10.0},{"gene":"MED27","stoichiometry":10.0},{"gene":"MED23","stoichiometry":10.0},{"gene":"MED4","stoichiometry":10.0},{"gene":"TADA2B","stoichiometry":10.0},{"gene":"MED1","stoichiometry":10.0},{"gene":"MED13","stoichiometry":10.0},{"gene":"MED9","stoichiometry":10.0},{"gene":"MED31","stoichiometry":10.0},{"gene":"MED16","stoichiometry":10.0}],"url":"https://opencell.sf.czbiohub.org/target/CID000248","total_profiled":1310},"omim":[{"mim_id":"612385","title":"MEDIATOR COMPLEX SUBUNIT 19; MED19","url":"https://www.omim.org/entry/612385"},{"mim_id":"612382","title":"MEDIATOR COMPLEX SUBUNIT 10; MED10","url":"https://www.omim.org/entry/612382"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nuclear bodies","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/MED19"},"hgnc":{"alias_symbol":["LCMR1"],"prev_symbol":[]},"alphafold":{"accession":"A0JLT2","domains":[{"cath_id":"-","chopping":"85-110_118-134","consensus_level":"medium","plddt":82.9023,"start":85,"end":134}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/A0JLT2","model_url":"https://alphafold.ebi.ac.uk/files/AF-A0JLT2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-A0JLT2-F1-predicted_aligned_error_v6.png","plddt_mean":64.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MED19","jax_strain_url":"https://www.jax.org/strain/search?query=MED19"},"sequence":{"accession":"A0JLT2","fasta_url":"https://rest.uniprot.org/uniprotkb/A0JLT2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/A0JLT2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/A0JLT2"}},"corpus_meta":[{"pmid":"17192271","id":"PMC_17192271","title":"Med19(Rox3) regulates Intermodule interactions in the Saccharomyces cerevisiae mediator complex.","date":"2006","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17192271","citation_count":54,"is_preprint":false},{"pmid":"30583076","id":"PMC_30583076","title":"Med19 is targeted by miR-101-3p/miR-422a and promotes breast cancer progression by regulating the EGFR/MEK/ERK signaling pathway.","date":"2018","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/30583076","citation_count":40,"is_preprint":false},{"pmid":"27811858","id":"PMC_27811858","title":"The FOXD3/miR-214/MED19 axis suppresses tumour growth and metastasis in human colorectal cancer.","date":"2016","source":"British journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/27811858","citation_count":40,"is_preprint":false},{"pmid":"24786462","id":"PMC_24786462","title":"Drosophila melanogaster Hox transcription factors access the RNA polymerase II machinery through direct homeodomain binding to a conserved motif of mediator subunit Med19.","date":"2014","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/24786462","citation_count":37,"is_preprint":false},{"pmid":"20890603","id":"PMC_20890603","title":"Lentivirus-mediated inhibition of Med19 suppresses growth of breast cancer cells in vitro.","date":"2010","source":"Cancer chemotherapy and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/20890603","citation_count":35,"is_preprint":false},{"pmid":"30161287","id":"PMC_30161287","title":"Med19 is involved in chemoresistance by mediating autophagy through HMGB1 in breast cancer.","date":"2018","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/30161287","citation_count":31,"is_preprint":false},{"pmid":"23276457","id":"PMC_23276457","title":"Med19 promotes bone metastasis and invasiveness of bladder urothelial carcinoma via bone morphogenetic protein 2.","date":"2012","source":"Annals of diagnostic pathology","url":"https://pubmed.ncbi.nlm.nih.gov/23276457","citation_count":30,"is_preprint":false},{"pmid":"29795113","id":"PMC_29795113","title":"Inhibition of LCMR1 and ATG12 by demethylation-activated miR-570-3p is involved in the anti-metastasis effects of metformin on human osteosarcoma.","date":"2018","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/29795113","citation_count":26,"is_preprint":false},{"pmid":"21478038","id":"PMC_21478038","title":"Expression of Med19 in bladder cancer tissues and its role on bladder cancer cell growth.","date":"2011","source":"Urologic oncology","url":"https://pubmed.ncbi.nlm.nih.gov/21478038","citation_count":25,"is_preprint":false},{"pmid":"21372827","id":"PMC_21372827","title":"The role of Med19 in the proliferation and tumorigenesis of human hepatocellular carcinoma cells.","date":"2011","source":"Acta pharmacologica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/21372827","citation_count":24,"is_preprint":false},{"pmid":"33235461","id":"PMC_33235461","title":"The SP1-Induced Long Noncoding RNA, LINC00339, Promotes Tumorigenesis in Colorectal Cancer via the miR-378a-3p/MED19 Axis.","date":"2020","source":"OncoTargets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/33235461","citation_count":24,"is_preprint":false},{"pmid":"21519921","id":"PMC_21519921","title":"MED19 promotes proliferation and tumorigenesis of lung cancer.","date":"2011","source":"Molecular and cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21519921","citation_count":23,"is_preprint":false},{"pmid":"30473219","id":"PMC_30473219","title":"Role and mechanism of miR-4778-3p and its targets NR2C2 and Med19 in cervical cancer radioresistance.","date":"2018","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/30473219","citation_count":22,"is_preprint":false},{"pmid":"38371458","id":"PMC_38371458","title":"Hypoxic Bone Mesenchymal Stem Cell-Derived Exosomes Direct Schwann Cells Proliferation, Migration, and Paracrine to Accelerate Facial Nerve Regeneration via circRNA_Nkd2/miR-214-3p/MED19 Axis.","date":"2024","source":"International journal of nanomedicine","url":"https://pubmed.ncbi.nlm.nih.gov/38371458","citation_count":21,"is_preprint":false},{"pmid":"28631286","id":"PMC_28631286","title":"Knockdown of mediator subunit Med19 suppresses bladder cancer cell proliferation and migration by downregulating Wnt/β-catenin signalling pathway.","date":"2017","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/28631286","citation_count":20,"is_preprint":false},{"pmid":"22565189","id":"PMC_22565189","title":"Med19 promotes gastric cancer progression and cellular 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research","url":"https://pubmed.ncbi.nlm.nih.gov/21542455","citation_count":17,"is_preprint":false},{"pmid":"21871180","id":"PMC_21871180","title":"Suppression of MED19 expression by shRNA induces inhibition of cell proliferation and tumorigenesis in human prostate cancer cells.","date":"2011","source":"BMB reports","url":"https://pubmed.ncbi.nlm.nih.gov/21871180","citation_count":16,"is_preprint":false},{"pmid":"27375018","id":"PMC_27375018","title":"A large-scale RNAi screen identifies LCMR1 as a critical regulator of Tspan8-mediated melanoma invasion.","date":"2016","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/27375018","citation_count":16,"is_preprint":false},{"pmid":"21732059","id":"PMC_21732059","title":"Suppression of lung cancer metastasis-related protein 1 (LCMR1) inhibits the growth of colorectal cancer cells.","date":"2011","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/21732059","citation_count":14,"is_preprint":false},{"pmid":"21834715","id":"PMC_21834715","title":"Knockdown of MED19 by short hairpin RNA-mediated gene silencing inhibits pancreatic cancer cell proliferation.","date":"2011","source":"Cancer biotherapy & radiopharmaceuticals","url":"https://pubmed.ncbi.nlm.nih.gov/21834715","citation_count":12,"is_preprint":false},{"pmid":"25735376","id":"PMC_25735376","title":"Knockdown of Med19 suppresses proliferation and enhances chemo-sensitivity to cisplatin in non-small cell lung cancer cells.","date":"2015","source":"Asian Pacific journal of cancer prevention : APJCP","url":"https://pubmed.ncbi.nlm.nih.gov/25735376","citation_count":12,"is_preprint":false},{"pmid":"28765911","id":"PMC_28765911","title":"LCMR1 interacts with DEK to suppress apoptosis in lung cancer cells.","date":"2017","source":"Molecular medicine 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research","url":"https://pubmed.ncbi.nlm.nih.gov/28337304","citation_count":7,"is_preprint":false},{"pmid":"37650745","id":"PMC_37650745","title":"Chloroprocaine antagonizes progression of breast cancer by regulating LINC00494/miR-3619-5p/MED19 axis.","date":"2023","source":"Journal of biochemical and molecular toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/37650745","citation_count":2,"is_preprint":false},{"pmid":"38001705","id":"PMC_38001705","title":"LCMR1 Promotes Large-Cell Lung Cancer Proliferation and Metastasis by Downregulating HLA-Encoding Genes.","date":"2023","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/38001705","citation_count":1,"is_preprint":false},{"pmid":"41414671","id":"PMC_41414671","title":"Nucleolar MED19 regulates 2'-O-methylation of rRNA in supporting cancer cell growth.","date":"2025","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/41414671","citation_count":1,"is_preprint":false},{"pmid":"40341970","id":"PMC_40341970","title":"LCMR1 deficiency exacerbates LPS‑induced lung injury in lung‑on‑a‑chip and mouse models.","date":"2025","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/40341970","citation_count":1,"is_preprint":false},{"pmid":"36445897","id":"PMC_36445897","title":"Inducible degradation of the Drosophila Mediator subunit Med19 reveals its role in regulating developmental but not constitutively-expressed genes.","date":"2022","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/36445897","citation_count":1,"is_preprint":false},{"pmid":"37065556","id":"PMC_37065556","title":"Deletion of LCMR1 in alveolar type II cells induces lethal impairment of lung structure and function in adult mice.","date":"2023","source":"Journal of thoracic disease","url":"https://pubmed.ncbi.nlm.nih.gov/37065556","citation_count":1,"is_preprint":false},{"pmid":"42084802","id":"PMC_42084802","title":"MBD2 suppresses SFRP1 expression and promotes colorectal cancer development by blocking MED19 binding to its methylated promoter.","date":"2026","source":"Cancer biology & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/42084802","citation_count":0,"is_preprint":false},{"pmid":"41866344","id":"PMC_41866344","title":"Mediator subunit MED19 modulates elf18-induced PR1 expression via TGA transcription factors.","date":"2026","source":"Plant signaling & behavior","url":"https://pubmed.ncbi.nlm.nih.gov/41866344","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.06.18.659864","title":"The Mediator complex subunit Med19 extends healthy lifespan in  <i>Drosophila</i>  by preventing cellular and organismal frailty","date":"2025-06-18","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.18.659864","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":20001,"output_tokens":4860,"usd":0.066451,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13015,"output_tokens":3717,"usd":0.079,"stage2_stop_reason":"end_turn"},"total_usd":0.145451,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2006,\n      \"finding\": \"Med19 (Rox3) in S. cerevisiae is required for stable association of the Middle module with the Mediator complex; deletion of Med19 allows the Middle module to dissociate under stringent conditions, leaving a Head-Tail complex. The Med19-deficient Mediator lacking the Middle module cannot facilitate activated transcription, cannot stimulate enhanced basal transcription, cannot enhance TFIIH phosphorylation of the RNA Pol II CTD, and cannot bind RNA Pol II/CTD, establishing Med19 as a structural linchpin that couples the Middle module to transcriptional activation.\",\n      \"method\": \"Biochemical purification of Mediator from Δmed19 yeast strains under mild and stringent conditions; in vitro transcription assays; CTD phosphorylation assays; RNA Pol II binding assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution, enzymatic assays, and multiple orthogonal biochemical methods in a single rigorous study\",\n      \"pmids\": [\"17192271\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Drosophila Med19 directly binds Hox transcription factor homeodomains both in vitro and in vivo through a conserved animal-specific motif. Loss-of-function Med19 mutations act as dose-sensitive genetic modifiers that synergistically alter Hox-directed developmental outcomes, and clonal analysis shows Med19 is required for Hox-dependent target gene activation, establishing Med19 as a direct molecular link between Hox homeodomains and the RNA Pol II machinery.\",\n      \"method\": \"In vitro binding assays (direct homeodomain-Med19 binding), in vivo co-immunoprecipitation, loss-of-function genetics and clonal analysis, targeted mutagenesis of the conserved motif, reporter gene assays for Ultrabithorax target activation\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct in vitro binding, in vivo interaction, genetic epistasis, mutagenesis, and functional reporter assays in a single study\",\n      \"pmids\": [\"24786462\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Drosophila Med19 physically interacts directly with GATA transcription factors (Pannier and Serpent) through their conserved C-zinc finger domains both in vivo and in vitro, and is required for GATA-dependent gene expression. Med19 also directly interacts with Med1 by GST pulldown, identifying Med19/Med1 as a composite GATA TF interface within the Mediator middle module.\",\n      \"method\": \"Co-immunoprecipitation in vivo, in vitro binding assays, GST pulldown (Med19-Med1 interaction), loss-of-function genetics, reporter gene assays in cellulo\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — reciprocal in vitro and in vivo binding, GST pulldown, and functional loss-of-function assays across multiple GATA targets\",\n      \"pmids\": [\"32737196\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"LCMR1 (MED19) physically interacts with the DEK protein, with the interaction mediated primarily by the N-terminal region of DEK. Both proteins cooperate to suppress apoptosis in lung cancer cells via the MCL-1 pathway, as demonstrated by yeast two-hybrid screening, co-immunoprecipitation, and GST pulldown.\",\n      \"method\": \"Yeast two-hybrid screen of lung cancer cDNA library, co-immunoprecipitation (in vivo), GST pulldown (in vitro), RNA interference knockdown with apoptosis readout\",\n      \"journal\": \"Molecular medicine reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal in vitro and in vivo binding assays confirmed interaction, functional RNAi follow-up; single lab\",\n      \"pmids\": [\"28765911\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Med19 interacts with EGFR and increases EGFR expression, activating the EGFR/MEK/ERK signaling pathway to promote breast cancer cell proliferation, EMT, invasion, and migration; the oncogenic effect of Med19 is mediated through EGFR signaling, as demonstrated by co-immunoprecipitation and rescue experiments.\",\n      \"method\": \"Co-immunoprecipitation (Med19-EGFR), shRNA knockdown and overexpression, EGFR pathway inhibitor rescue, in vitro and in vivo functional assays\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP interaction plus pathway rescue experiments; single lab\",\n      \"pmids\": [\"30583076\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Med19 promotes autophagy and chemoresistance in breast cancer cells through the HMGB1 pathway; lentivirus-mediated Med19 inhibition suppressed LC3-II/LC3-I ratio, Atg3, Atg5 expression and LC3 puncta formation, and increased sensitivity to ADM, DDP, and TAX. The autophagy-promoting effect of Med19 was mediated via HMGB1 signaling.\",\n      \"method\": \"Lentivirus shRNA knockdown, autophagy markers (LC3-II/I ratio, p62, RFP-LC3 dots), Western blot for HMGB1 pathway components, cell viability assays with chemotherapeutic agents\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — multiple autophagy markers measured, pathway identified via HMGB1; single lab with several orthogonal readouts\",\n      \"pmids\": [\"30161287\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Med19 promotes breast cancer cell proliferation by suppressing CBFA2T3 expression, which in turn allows HEB expression; Med19 knockdown upregulates CBFA2T3 and downregulates HEB, while ectopic CBFA2T3 overexpression reverses the proliferative effect of Med19 overexpression, placing CBFA2T3/HEB downstream of Med19 in a regulatory axis.\",\n      \"method\": \"Lentivirus-mediated Med19 inhibition and overexpression, ectopic CBFA2T3 expression rescue, RT-PCR and Western blot for CBFA2T3 and HEB, cell proliferation and colony formation assays, correlation analysis in patient tissues\",\n      \"journal\": \"Breast cancer (Tokyo, Japan)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — genetic epistasis via rescue experiment, multiple orthogonal assays; single lab\",\n      \"pmids\": [\"27572702\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Med19 knockdown in bladder cancer cells decreases Wnt/β-catenin pathway activity (measured by TOP/FOPflash reporter), downregulates Wnt2, β-catenin, Cyclin-D1, and MMP-9, and elevates GSK3β and E-cadherin, positioning Med19 as an upstream regulator of the Wnt/β-catenin pathway in bladder cancer proliferation and migration.\",\n      \"method\": \"shRNA knockdown, TOP/FOPflash Wnt reporter assay, Western blot, RT-PCR, in vitro proliferation and migration assays, in vivo xenograft\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Wnt reporter assay plus downstream target profiling; single lab\",\n      \"pmids\": [\"28631286\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In a large-scale RNAi screen, LCMR1 (MED19) was identified as a transcriptional activator of Tspan8 in melanoma cells; LCMR1 modulation positively regulated endogenous Tspan8 expression with concomitant changes in melanoma cell-matrix adherence and invasion, establishing Tspan8 as the first known LCMR1 transcriptional target linking MED19 to a specific invasive phenotype.\",\n      \"method\": \"Large-scale RNAi screen for Tspan8 regulators, shRNA knockdown of LCMR1, qRT-PCR and Western blot for Tspan8, in vitro invasion and adhesion assays, in vivo tumorigenicity\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — RNAi screen plus functional validation with multiple orthogonal assays; single lab\",\n      \"pmids\": [\"27375018\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"FOXD3 acts as a transcription factor that activates miR-214 expression (validated by ChIP assay), and miR-214 directly targets MED19 3'UTR (validated by dual-luciferase reporter assay) to suppress MED19 translation; miR-214 mediates the inhibitory effect of FOXD3 on colorectal cancer proliferation, invasion and metastasis through MED19 suppression.\",\n      \"method\": \"ChIP assay (FOXD3 binding to miR-214 promoter), dual-luciferase reporter assay (miR-214 targeting MED19 3'UTR), bisulfite sequencing, in vitro and in vivo functional assays, Western blot and RT-PCR\",\n      \"journal\": \"British journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — direct reporter and ChIP validation of the regulatory axis; single lab\",\n      \"pmids\": [\"27811858\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SP1 activates LINC00339 expression by binding its promoter (binding validated by luciferase assay); LINC00339 acts as a miR-378a-3p sponge (validated by luciferase and RNA pulldown assay); miR-378a-3p directly targets MED19 3'UTR (validated by luciferase assay), thereby establishing a SP1/LINC00339/miR-378a-3p/MED19 regulatory axis controlling CRC proliferation and Wnt/β-catenin signaling.\",\n      \"method\": \"Dual-luciferase reporter assay, RNA pulldown assay, gain- and loss-of-function experiments, Western blot, in vivo tumor growth assay\",\n      \"journal\": \"OncoTargets and therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — multiple validated interactions via reporter assay and RNA pulldown; single lab\",\n      \"pmids\": [\"33235461\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In Drosophila wing imaginal discs, auxin-inducible degradation of endogenous Med19 followed by RNA-seq shows that Med19 is not globally required for mRNA transcription but specifically regulates less than one quarter of expressed genes; Med19-dependent genes are enriched for spatially-regulated developmental genes while constitutively expressed genes are largely unaffected. Med19 is required for Notch-responsive target gene expression (wingless and E(spl)-C genes), suggesting a specific role as a transcriptional effector of developmental signaling pathways.\",\n      \"method\": \"Auxin-inducible degron system for endogenous Med19 degradation in vivo, RNA-seq, differential gene expression analysis, cross-referencing with developmental gene expression databases, in vivo reporter assays for Notch target genes\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — endogenous protein degradation coupled with transcriptome-wide analysis and multiple functional validations in vivo\",\n      \"pmids\": [\"36445897\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MED19 localizes to the nucleolus independently of the Mediator complex; this nucleolar targeting is mediated by a conserved poly-lysine motif at the MED19 C-terminus. In the nucleolus, MED19 binds ribosomal RNA and fibrillarin (FBL), a catalytic component of the 2'-O-methyltransferase complex, and facilitates rRNA processing and 2'-O-methylation. This promotes IRES-dependent translation efficiency for onco-promoting genes including c-Myc.\",\n      \"method\": \"Subcellular fractionation and imaging for nucleolar localization, C-terminal poly-lysine motif mutagenesis, co-immunoprecipitation with FBL, rRNA binding assays, rRNA 2'-O-methylation assays, IRES-reporter translation assays, Western blot for c-Myc\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (localization, mutagenesis, binding, enzymatic function, translation readout) in a single rigorous study\",\n      \"pmids\": [\"41414671\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"LCMR1 (MED19) reduces RNA Pol II occupancy at the promoters of HLA-encoding genes, suppressing their transcription; lentivirus-based knockdown of LCMR1 de-repressed HLA gene expression and inhibited large-cell lung cancer proliferation, migration, and invasion in vitro and reduced xenograft tumor growth in vivo.\",\n      \"method\": \"Lentivirus-based knockdown, RNA Pol II occupancy assay at HLA gene promoters (multiple sequence-based assay), RT-PCR/Western blot for HLA gene expression, xenograft mouse model, proliferation/migration/invasion assays\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Pol II occupancy assay at target promoters plus functional assays; single lab\",\n      \"pmids\": [\"38001705\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"MBD2 silences the SFRP1 tumor suppressor in CRC by blocking MED19 binding to the methylated SFRP1 promoter; when MBD2 is inhibited (genetically or by KCC07), MED19 can bind the SFRP1 promoter, which is required for RNA Pol II CTD-S7 phosphorylation and productive transcription of SFRP1, thereby activating Wnt pathway antagonism.\",\n      \"method\": \"siRNA and small molecule (KCC07) inhibition of MBD2, ChIP for MED19 binding at SFRP1 promoter, RNA Pol II CTD-S7 phosphorylation assays, SFRP1/β-catenin Western blot, Wnt reporter assay, in vivo tumor growth assay\",\n      \"journal\": \"Cancer biology & therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP binding assay with CTD phosphorylation readout and in vivo validation; single lab\",\n      \"pmids\": [\"42084802\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"shRNA-mediated knockdown of MED19 in prostate cancer cells (PC-3 and DU145) induces S-phase arrest and apoptosis via modulation of Bid and Caspase 7, reducing cell proliferation and tumor growth in nude mouse xenografts.\",\n      \"method\": \"Lentivirus shRNA knockdown, flow cytometry (cell cycle), apoptosis assays, Western blot for Bid and Caspase 7, in vivo xenograft\",\n      \"journal\": \"BMB reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, KD with apoptosis pathway marker assay but no direct mechanistic link established\",\n      \"pmids\": [\"21871180\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Med19 knockdown in laryngocarcinoma HEp2 cells induces apoptosis via activation of caspases 3, 9, and Apaf-1, identifying an Apaf-1-dependent intrinsic apoptosis pathway downstream of Med19 inhibition.\",\n      \"method\": \"shRNA knockdown, Western blot and activity assays for caspase-3, caspase-9, Apaf-1, cell growth and migration assays, in vivo xenograft\",\n      \"journal\": \"American journal of translational research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, KD with downstream apoptotic marker measurement but no direct mechanistic interaction established\",\n      \"pmids\": [\"28337304\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MED19 (LCMR1) is an integral Mediator complex subunit that serves as a structural linchpin connecting the Middle module to the Head and Tail modules for RNA Pol II-dependent transcription; it directly binds Hox homeodomain proteins and GATA transcription factors through conserved interaction motifs to mediate their transcriptional outputs, physically associates with Med1 within the Mediator middle module, and regulates developmental gene expression downstream of signaling pathways including Notch. Beyond its canonical Mediator role, MED19 independently localizes to the nucleolus via a C-terminal poly-lysine motif, where it binds rRNA and fibrillarin to promote rRNA 2'-O-methylation and IRES-dependent translation of oncoproteins such as c-Myc; in cancer contexts it also interacts with EGFR and DEK, modulates the Wnt/β-catenin and HMGB1/autophagy pathways, controls RNA Pol II occupancy at specific gene promoters (including HLA genes and SFRP1), and its loss arrests cell cycle progression at G0/G1 and induces apoptosis across multiple cancer cell types.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MED19 is an integral subunit of the Mediator complex that functions as a structural linchpin coupling the Middle module to the Head and Tail modules, an arrangement required for activated RNA Pol II transcription, stimulation of basal transcription, enhanced TFIIH phosphorylation of the Pol II CTD, and Mediator binding to Pol II [#0]. Rather than being globally required for transcription, MED19 selectively controls a subset of genes — particularly spatially-regulated developmental genes and Notch-responsive targets such as wingless and E(spl)-C [#11]. It provides a direct physical interface between sequence-specific activators and the Pol II machinery, binding Hox homeodomains through a conserved animal-specific motif [#1] and GATA transcription factors through their C-zinc fingers, with the GATA interface formed together with Med1 in the Middle module [#2]. Beyond Mediator, MED19 independently localizes to the nucleolus via a conserved C-terminal poly-lysine motif, where it binds rRNA and fibrillarin to promote rRNA 2'-O-methylation and IRES-dependent translation of oncoproteins including c-Myc [#12]. In cancer, MED19 controls Pol II occupancy at specific promoters, suppressing HLA gene transcription [#13] and, when freed from MBD2 blockade, binding the methylated SFRP1 promoter to drive CTD-S7 phosphorylation and SFRP1 transcription [#14]; its loss arrests proliferation and induces apoptosis across multiple cancer types [#15, #16].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Established why MED19 matters structurally: it determines whether the Mediator Middle module stays attached and whether Mediator can support activated transcription at all.\",\n      \"evidence\": \"Biochemical purification of Mediator from Δmed19 yeast, in vitro transcription, CTD phosphorylation, and Pol II binding assays\",\n      \"pmids\": [\"17192271\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Yeast system; human MED19 architecture not directly resolved here\", \"Does not identify which activators depend on MED19\", \"No structural model of the Middle-Head/Tail bridge\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Resolved how MED19 connects developmental activators to Pol II by showing direct, motif-dependent binding to Hox homeodomains with functional consequences.\",\n      \"evidence\": \"In vitro binding, in vivo co-IP, loss-of-function genetics, motif mutagenesis, and Ubx reporter assays in Drosophila\",\n      \"pmids\": [\"24786462\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Conserved motif's structural basis of homeodomain recognition not solved\", \"Generalizability beyond Hox not tested here\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Began defining MED19 oncogenic downstream wiring in breast cancer through a CBFA2T3/HEB axis.\",\n      \"evidence\": \"Lentiviral knockdown/overexpression with CBFA2T3 rescue, expression profiling, proliferation assays, patient correlation\",\n      \"pmids\": [\"27572702\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct evidence MED19 transcriptionally controls CBFA2T3 via Mediator\", \"Single lab\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Placed MED19 under upstream non-coding RNA control, showing it is a translationally repressible target of a FOXD3/miR-214 tumor-suppressive axis.\",\n      \"evidence\": \"ChIP, dual-luciferase reporter of miR-214 targeting MED19 3'UTR, functional assays in colorectal cancer\",\n      \"pmids\": [\"27811858\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Regulation is of MED19 expression, not its mechanism of action\", \"Single lab\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified the first specific transcriptional target gene of MED19, linking it to an invasive phenotype.\",\n      \"evidence\": \"Large-scale RNAi screen for Tspan8 regulators with shRNA validation and invasion/adhesion assays in melanoma\",\n      \"pmids\": [\"27375018\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct promoter occupancy at Tspan8 not shown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Extended MED19 cancer biology to physical partners and pathways beyond core Mediator, implicating DEK, Wnt/β-catenin, and apoptosis suppression.\",\n      \"evidence\": \"Y2H, co-IP, GST pulldown for DEK; TOP/FOPflash and target profiling for Wnt; RNAi with apoptosis/caspase readouts\",\n      \"pmids\": [\"28765911\", \"28631286\", \"28337304\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether DEK and Wnt effects depend on MED19's Mediator role unresolved\", \"Apoptosis findings are marker-level without direct mechanistic link\", \"Multiple single-lab studies\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Connected MED19 to receptor signaling and stress responses via EGFR/MEK/ERK activation and HMGB1-dependent autophagy/chemoresistance.\",\n      \"evidence\": \"Co-IP with EGFR, pathway-inhibitor rescue, autophagy marker panels, chemosensitivity assays in breast cancer\",\n      \"pmids\": [\"30583076\", \"30161287\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"EGFR co-IP not shown to be direct/reciprocally validated\", \"How a Mediator subunit regulates EGFR expression mechanistically unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined the GATA-Mediator interface, showing MED19 and Med1 jointly form a composite docking surface for GATA factors.\",\n      \"evidence\": \"In vivo co-IP, in vitro binding, GST pulldown of Med19-Med1, loss-of-function genetics, reporter assays in Drosophila\",\n      \"pmids\": [\"32737196\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural model of the GATA/Med19/Med1 interface absent\", \"Human GATA factor binding not directly tested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Reframed MED19 as a selective rather than global transcriptional effector, defining the gene set it controls and its role in Notch signaling output.\",\n      \"evidence\": \"Auxin-inducible degron degradation of endogenous Med19 plus RNA-seq and Notch target reporters in Drosophila wing discs\",\n      \"pmids\": [\"36445897\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of target-gene selectivity not defined\", \"Mammalian gene-selectivity not directly demonstrated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed MED19 can repress as well as activate by reducing Pol II occupancy at HLA promoters in lung cancer.\",\n      \"evidence\": \"Lentiviral knockdown, Pol II occupancy assays at HLA promoters, expression analysis, xenograft and invasion assays\",\n      \"pmids\": [\"38001705\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of MED19-mediated repression unresolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Uncovered a Mediator-independent MED19 function in the nucleolus driving rRNA modification and oncoprotein translation.\",\n      \"evidence\": \"Fractionation/imaging, C-terminal poly-lysine motif mutagenesis, FBL co-IP, rRNA binding and 2'-O-methylation assays, IRES-reporter translation, c-Myc Western\",\n      \"pmids\": [\"41414671\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry/regulation of nucleolar vs Mediator pools unknown\", \"Direct role in FBL methyltransferase catalysis not defined\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Demonstrated MED19 promoter recruitment is gated by DNA methylation reader MBD2, controlling SFRP1 transcription and Wnt antagonism.\",\n      \"evidence\": \"MBD2 siRNA/KCC07 inhibition, ChIP for MED19 at SFRP1 promoter, CTD-S7 phosphorylation assays, Wnt reporter, in vivo tumor assays in CRC\",\n      \"pmids\": [\"42084802\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether MED19-SFRP1 promoter binding is direct vs Mediator-mediated unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How MED19 partitions between its core Mediator-bridging role and its Mediator-independent nucleolar/translation function, and what dictates its gene-selective activating versus repressive behavior, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of human MED19 within Mediator or with activators\", \"Determinants of target-gene selectivity unknown\", \"Regulation of nucleolar versus Mediator pool partitioning uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1, 2, 11]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 1, 11]},\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 11, 13, 14]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [1, 2, 11]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"complexes\": [\"Mediator complex\"],\n    \"partners\": [\"MED1\", \"FBL\", \"DEK\", \"EGFR\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}