{"gene":"MED15","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2011,"finding":"The acidic activation domain (AD) of transcription activator Gcn4 binds the Mediator subunit Gal11/Med15 activator-binding domain 1 (a four-helix fold with a shallow hydrophobic cleft) through a dynamic, 'fuzzy' protein interface involving only hydrophobic interactions; eight residues of Gcn4 adopt a helical conformation allowing three aromatic/aliphatic residues to insert into the Gal11 cleft, and the complex cannot be described by a single conformation.","method":"NMR structural analysis combined with mutagenesis and functional studies in yeast","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — NMR structure with mutagenesis and functional validation in a single rigorous study","pmids":["22195967"],"is_preprint":false},{"year":2009,"finding":"Gcn4 recruits Mediator to the ARG1 promoter in vivo through additive interactions with three distinct N-terminal segments of Gal11/Med15, including the KIX domain and a B-box motif; NMR chemical shift analysis identified the Gcn4 binding site on the Gal11 KIX surface, and mutagenesis of B-box established it as a critical determinant of Mediator recruitment.","method":"In vitro binding assays, ChIP (Mediator recruitment in vivo), NMR chemical shift analysis, site-directed mutagenesis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — NMR plus mutagenesis plus in vivo ChIP, multiple orthogonal methods in one study","pmids":["19940160"],"is_preprint":false},{"year":2008,"finding":"The yeast Mediator subunit Gal11p/MED15 and its KIX domain are required for fatty acid-dependent transcriptional activation by the PPARα analog Oaf1p; NMR spectroscopy revealed that the Oaf1p activation domain interacts with the Gal11p/MED15 KIX domain in a manner similar to the xenobiotic receptor Pdr1p.","method":"Genetic deletion analysis, NMR spectroscopy, fatty acid growth assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — NMR structural interaction plus genetic loss-of-function, multiple orthogonal methods","pmids":["19056732"],"is_preprint":false},{"year":2013,"finding":"Med15 (Tail module subunit) and Med16 cooperate to recruit holo-Mediator to HSP gene promoters in yeast in response to heat shock; Hsf1 recruits Mediator via dual N- and C-terminal activation domains through cooperative interactions with the Tail module, and loss of both Med15 and Med16 abolishes Mediator occupancy and substantially reduces RNA Pol II recruitment.","method":"ChIP (chromatin immunoprecipitation), genetic deletion/truncation analysis in Saccharomyces cerevisiae","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP with multiple deletion combinations, clear epistatic relationships, replicated across multiple gene targets","pmids":["23447536"],"is_preprint":false},{"year":2021,"finding":"Gal4 and Gcn4, two intrinsically disordered acidic activation domains of different sequence, interact nearly identically with Med15 via a 'fuzzy' protein interface; the two hydrophobic regions of the Gal4 AD each independently bind Med15 using this fuzzy mechanism, while the same Gal4 AD region binds Gal80 repressor via a distinct structured complex, indicating the structured binding partner dictates the interaction type.","method":"NMR chemical shift perturbation analysis, binding assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — NMR with two different ADs, multiple binding partners, mechanistically rigorous single study","pmids":["33850123"],"is_preprint":false},{"year":2006,"finding":"TRIM11 binds to MED15 (ARC105) and promotes its degradation through the ubiquitin-proteasome pathway; co-expression of TRIM11 increases ARC105 ubiquitination and degradation (blocked by proteasome inhibitor), and TRIM11 suppresses ARC105-mediated transcriptional activation induced by TGF-β in a reporter assay.","method":"Co-immunoprecipitation, ubiquitination assay, proteasome inhibitor treatment, transcriptional reporter assay","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP, ubiquitination assay, and functional reporter in a single lab with multiple orthogonal methods","pmids":["16904669"],"is_preprint":false},{"year":2013,"finding":"In yeast, loss of Med15 leads to down-regulation of Ace2 transcriptional activator target genes and a G1 cell cycle arrest phenotype; synthetic lethality of med5/med15 and med15/med16 double mutants indicates the Tail module performs essential functions even when separated from Head and Middle modules.","method":"Temperature-sensitive N-Degron mutants, global gene expression profiling, cell cycle analysis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Inducible protein depletion with transcriptome profiling and cell cycle phenotype, single lab","pmids":["23991176"],"is_preprint":false},{"year":2014,"finding":"Human MED15 co-localizes with general transcription factors TFIIE and TFIIH in the nucleus; MED15 knockdown reduces VP16- and SREBP1a-driven transcriptional activation, rescued by wild-type MED15 re-expression; MED15 localizes to both the p53 binding site and the p21 promoter region upon Nutlin-3 induction.","method":"siRNA knockdown, immunostaining/co-localization, transcriptional reporter assay, ChIP","journal":"Drug discoveries & therapeutics","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Multiple orthogonal methods (co-localization, knockdown/rescue, ChIP) in a single lab","pmids":["25382556"],"is_preprint":false},{"year":2013,"finding":"MED15 knockdown in prostate cancer cells reduces TGF-β-enhanced proliferation, affects phosphorylation and nuclear shuttling of p-SMAD3, and decreases both androgen-dependent and androgen-independent proliferation; TGF-β signaling activation leads to increased MED15 expression in PCa cells.","method":"siRNA/shRNA knockdown, proliferation assays, immunohistochemistry, Western blot for p-SMAD3","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Loss-of-function with defined signaling phenotype, single lab, multiple readouts","pmids":["24374838"],"is_preprint":false},{"year":2014,"finding":"C. elegans MDT-15/MED15 is required for xenobiotic-induced expression of PMK-1 p38 MAP kinase-dependent immune genes and for protection from Pseudomonas aeruginosa infection; MDT-15 also controls induction of detoxification genes and protects from phenazine toxins, linking xenobiotic detoxification and innate immunity.","method":"RNAi screen (1,420 genes), gene expression analysis, infection survival assays in C. elegans","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi loss-of-function with multiple functional readouts (gene expression, infection survival), single lab","pmids":["24875643"],"is_preprint":false},{"year":2019,"finding":"C. elegans MDT-15 physically and functionally cooperates with the nuclear hormone receptor HIZR-1 to promote induction of zinc and cadmium responsive genes; the physical interaction between MDT-15 and HIZR-1 is enhanced by zinc or cadmium in yeast two-hybrid assays; mdt-15 and hizr-1 mutants show defective zinc storage in the gut and hypersensitivity to zinc-induced reductions in egg-laying; mammalian MED15 orthologs bind genomic regulatory regions of metallothionein and zinc transporter genes in a cadmium/zinc-stimulated fashion, and human MED15 is required to induce a metallothionein gene in lung adenocarcinoma cells.","method":"Yeast two-hybrid, qRT-PCR, reporter analysis, gain/loss-of-function genetics, ChIP (mammalian cells), siRNA knockdown in human cells","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — Multiple orthogonal methods across two organisms (C. elegans genetics, yeast-two-hybrid, mammalian ChIP, human cell knockdown), replicated functional evidence","pmids":["31815936"],"is_preprint":false},{"year":2021,"finding":"Human MED15 forms nuclear condensates (foci) that are sensitive to 1,6-hexanediol and show rapid FRAP recovery; condensate formation requires both the glutamine-rich intrinsically disordered region (IDR) and a short downstream hydrophobic motif; DYRK3 kinase overexpression disrupts Med15 foci; the MED15 prion-like domain drives phase separation and can kidnap endogenous full-length MED15 into cytoplasmic/perinuclear inclusions in a prion-like manner.","method":"Live cell imaging, immunostaining, FRAP, optodroplet assay, domain deletion analysis, DYRK3 overexpression","journal":"BMC biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Multiple live-cell methods with domain mapping, single lab","pmids":["34789250"],"is_preprint":false},{"year":2021,"finding":"The human MED15 prion-like domain (PrLD) forms homodimers sustained by coiled-coil (CC) interactions; CC disruption (chemical or genetic) abolishes amyloid aggregation; the CC fold mediates transition to a β-sheet amyloid state; a GFP domain adjacent to the PrLD retains its structure in the amyloid state; MED15-PrLD expression in human cells promotes prion-like recruitment of endogenous full-length MED15 to cytoplasmic inclusions.","method":"Biophysical dimerization assays, amyloid aggregation assays, coiled-coil mutagenesis, fluorescence microscopy in human cells","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — In vitro biophysical assays plus mutagenesis plus cell imaging, single lab","pmids":["33772081"],"is_preprint":false},{"year":2024,"finding":"Mouse Med15 binds pancreatic β-cell transcription factors Nkx6-1 and NeuroD1 (by co-immunoprecipitation and ChIP-seq) to regulate key β-cell maturation genes; β-cell-specific Med15 knockout causes defects in β-cell maturation without affecting β-cell mass or insulin expression; human embryonic stem cell-derived β-like cells engineered to overexpress MED15 show increased maturation marker expression.","method":"ChIP-seq, co-immunoprecipitation, conditional knockout mouse, human ESC differentiation system","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — Reciprocal ChIP-seq and Co-IP with conditional KO and human ESC validation across multiple orthogonal methods","pmids":["39379383"],"is_preprint":false},{"year":2024,"finding":"MED15 directly interacts with SREBPs (SREBP1 and SREBP2) to promote SREBP-dependent lipid biosynthesis enzyme expression in clear cell renal cell carcinoma; MED15 also promotes SREBP1/2 activation through the PLK1/AKT axis; HIF-2α promotes MED15 transcriptional activation by directly binding the MED15 promoter.","method":"Co-immunoprecipitation, promoter binding assay (ChIP), siRNA knockdown, overexpression rescue experiments","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP with functional knockdown/overexpression, multiple pathway readouts, single lab","pmids":["38649345"],"is_preprint":false},{"year":2024,"finding":"Med15 in budding yeast can select its chromosomal binding sites (characterized by fuzzy-nucleosome architecture) independent of promoter-bound transcription factors; direct DBD-Med15 fusions shift DBD localization towards fuzzy-nucleosome promoters, indicating Med15 has inherent promoter preference and actively contributes to target gene selection.","method":"ChIP-seq with DBD-AD fusions, direct DBD-Med15 fusions, genome-wide localization in budding yeast","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Genome-wide ChIP-seq with multiple fusion constructs, single lab","pmids":["39187372"],"is_preprint":false},{"year":2025,"finding":"TGF-β selectively induces CDK1-mediated phosphorylation of MED15 at T603, which controls SASP gene expression and cellular senescence; the T603A (dephosphorylated) mutant inhibits SASP and cell senescence, while T603D (phosphomimetic) promotes them; forkhead box protein A1 (FOXA1) preferentially binds unphosphorylated MED15-T603 to suppress SASP gene expression; aging mice with T603A mutation show improved learning and memory through SASP attenuation.","method":"Site-directed mutagenesis (T603A/T603D), Co-immunoprecipitation, gene expression analysis, mouse knock-in model, behavioral assays","journal":"Cell discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Phospho-mutagenesis with Co-IP and in vivo mouse knock-in, single lab","pmids":["40825935"],"is_preprint":false},{"year":2024,"finding":"Drosophila Moesin directly interacts with the Med15 subunit of the Mediator complex in the nucleus; Moesin's presence at regulatory regions of the Hsp70Ab heat shock gene is Med15-dependent; both Moesin and Med15 bind heat shock factor (Hsf), and together with monomeric actin form a nuclear complex required for proper Hsp gene expression; direct interaction between the human orthologs of Moesin and Med15 was confirmed.","method":"Co-immunoprecipitation, ChIP, RNAi knockdown, gene expression analysis in Drosophila and human cells","journal":"Open biology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Multiple orthogonal methods (Co-IP, ChIP, RNAi) in Drosophila validated in human orthologs, single lab","pmids":["39353569"],"is_preprint":false},{"year":2025,"finding":"MED15 acts as a HIF target gene that participates in a positive feedback loop promoting HIF transcriptional activity; MED15 acts upstream of CPT1A (carnitine palmitoyltransferase 1A, a key fatty acid oxidation enzyme) to promote HIF-mediated lipid droplet accumulation; zebrafish med15 deficiency decreases HIF activity and impairs hypoxic stress tolerance.","method":"siRNA knockdown, zebrafish med15 knockout, reporter assays, lipid droplet quantification, tumor xenograft","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Loss-of-function in mammalian cells and zebrafish with defined pathway placement, single lab","pmids":["39947475"],"is_preprint":false},{"year":2024,"finding":"MED15 interacts with YAP1 and stabilizes it by attenuating TRIM11-mediated ubiquitination in bladder cancer cells; MED15 promotes EMT and cell migration in a YAP1-dependent manner; under osmotic stress, MED15 forms stress-inducible protein condensates with increased YAP1 co-localization.","method":"Co-immunoprecipitation, ubiquitination assay, loss- and gain-of-function (siRNA/overexpression), migration assays, condensate imaging","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP and ubiquitination assay with functional readouts, single lab","pmids":["41685983"],"is_preprint":false},{"year":2010,"finding":"Drosophila Med15 is required for transcription of Decapentaplegic (Dpp/BMP) target genes during wing development; loss-of-function clones in mosaic wings establish Med15 as a component needed for proper wing patterning and epithelial gene regulation.","method":"Loss-of-function genetic screen, mosaic clone analysis, gene expression analysis in Drosophila","journal":"Genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Genetic loss-of-function with defined target gene transcription phenotype, single lab","pmids":["20233856"],"is_preprint":false},{"year":2024,"finding":"Med15 KIX domain length and polyglutamine (polyQ) tract composition modulate interactions with specific transcription factors (including Msn2); reduced Msn2:Med15 interaction strength correlates with reduced Msn2-dependent transcriptional activation; intramolecular interactions between distant glutamine tracts and MED15 phosphorylation affect KIX domain activities; individual ABDs and adjacent polyQ tracts each contribute to Med15 activity in a context-dependent manner.","method":"Truncation/deletion/synthetic allele analysis, phenotypic assays, gene expression analysis, transcription factor interaction assays, phase separation assays in yeast","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Multiple allele series with interaction and functional assays, single lab","pmids":["39717019"],"is_preprint":false},{"year":2012,"finding":"Med15/Gal11 physically associates with Tel2 in yeast when transiently overproduced; overexpression of MED15/GAL11 partially suppresses tel2 temperature-sensitive mutant phenotypes including short telomeres and defective EST2 (telomerase catalytic subunit) transcription.","method":"Co-immunoprecipitation, genetic suppressor analysis, gene expression analysis","journal":"PloS one","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Single Co-IP (transient overexpression only) with genetic suppression, single lab","pmids":["22291956"],"is_preprint":false},{"year":2000,"finding":"The human MED15 (TIG-1/ARC105) protein contains a bipartite nuclear localization signal, localizes to the nucleus, and when tethered to DNA via a GAL4 fusion demonstrates transcriptional regulatory activity in co-transfection assays; the protein was identified as a component of the ARC chromatin-directed transcriptional co-activator complex.","method":"Co-transfection reporter assay, Western blot, nuclear localization signal identification, cDNA library screening","journal":"Gene","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Single tethered reporter assay, no endogenous functional validation, single lab","pmids":["11024300"],"is_preprint":false},{"year":2024,"finding":"Huntingtin (HTT) associates with MED15 preferentially in the Mediator tail domain, and HTT modulates the subcellular localization and assembly of the Mediator complex in HD and KO models.","method":"Multi-epitope immunocapture/co-immunoprecipitation, subcellular fractionation, mass spectrometry, Drosophila genetic modifier assays","journal":"bioRxiv (preprint)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP/MS interaction data for MED15 specifically, single preprint, no MED15-specific functional validation","pmids":["bio_10.1101_2024.09.07.611843"],"is_preprint":true},{"year":2025,"finding":"ATXN1 amino acids 99-163 and MED15 amino acids 548-665 are critical for their protein-protein interaction; MED15 significantly enhances aggregation of polyQ-expanded ATXN1; a small molecule (Chembridge ID: 5755483) targeting the ATXN1 aa99-163 domain inhibits both the ATXN1-MED15 interaction and dimerization of polyQ-expanded ATXN1.","method":"Computational structure prediction, co-immunoprecipitation/interaction assays with domain mutants, aggregation assays, virtual screening and chemical compound validation","journal":"bioRxiv (preprint)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Preprint, domain mapping by deletion/co-IP but limited orthogonal structural validation, single lab","pmids":["bio_10.1101_2025.03.17.643445"],"is_preprint":true}],"current_model":"MED15 is a tail-module subunit of the Mediator co-activator complex that bridges upstream transcription factors (including acidic activators Gcn4 and Gal4, nuclear receptors, SREBPs, FOXA1, and tissue-specific factors such as Nkx6-1 and NeuroD1) to RNA Polymerase II machinery through a structurally characterized 'fuzzy' KIX domain interaction; it is regulated post-translationally by CDK1-mediated phosphorylation at T603 (controlling SASP/senescence), and by TRIM11-mediated ubiquitin-proteasome degradation; it forms phase-separated nuclear condensates via its glutamine-rich intrinsically disordered region and hydrophobic motif; and it plays conserved roles in fatty acid/lipid metabolism gene regulation, innate immunity, β-cell maturation, heat shock gene expression, and cellular senescence across yeast, C. elegans, Drosophila, and mammals."},"narrative":{"mechanistic_narrative":"MED15 is a tail-module subunit of the Mediator co-activator complex that bridges sequence-specific transcription factors to the RNA Polymerase II machinery and thereby controls inducible gene-expression programs across eukaryotes [PMID:23447536, PMID:11024300]. Its defining biochemical feature is a set of activator-binding domains, including a KIX domain, that engage intrinsically disordered acidic activation domains through a dynamic 'fuzzy' interface: the activation domains of Gcn4 and Gal4 bind nearly identically using transient hydrophobic contacts rather than a single fixed conformation, and the same domains adopt structured complexes only when the partner itself is structured [PMID:22195967, PMID:33850123]. Through these adaptable surfaces MED15 integrates diverse upstream regulators — Gcn4 and Hsf1 at heat-shock and amino-acid genes, the lipid-sensing factors Oaf1p and SREBP1/2, the nuclear receptor HIZR-1, and tissue factors Nkx6-1 and NeuroD1 — to drive fatty-acid/lipid-metabolism, stress, metal-response, and cell-maturation programs [PMID:19056732, PMID:23447536, PMID:31815936, PMID:39379383, PMID:38649345]. In yeast the tail module performs essential functions, with Med15 loss down-regulating Ace2 targets and arresting cells in G1, and Med15 contributes intrinsic promoter selectivity toward fuzzy-nucleosome regulatory regions independent of activator tethering [PMID:23991176, PMID:39187372]. MED15 is regulated post-translationally by TRIM11-mediated ubiquitin-proteasome degradation and by CDK1 phosphorylation at T603, which licenses SASP gene expression and cellular senescence while unphosphorylated MED15 is bound by FOXA1 to suppress this program [PMID:16904669, PMID:40825935]. Its glutamine-rich intrinsically disordered region together with a downstream hydrophobic motif drives formation of liquid-like nuclear condensates and, in a prion-like coiled-coil-dependent manner, can recruit endogenous MED15 into amyloid inclusions [PMID:34789250, PMID:33772081].","teleology":[{"year":2000,"claim":"Establishing that the human protein is a nuclear, DNA-tethered transcriptional regulator placed MED15 within a chromatin-directed co-activator complex.","evidence":"GAL4-fusion reporter assays, NLS identification and cDNA screening identifying the ARC complex component (TIG-1/ARC105)","pmids":["11024300"],"confidence":"Low","gaps":["Single tethered reporter assay without endogenous functional validation","Native complex context and direct activator partners not defined"]},{"year":2008,"claim":"Linking the Gal11/MED15 KIX domain to fatty-acid-dependent activation by Oaf1p connected the subunit to lipid-metabolism gene regulation and showed shared use of the KIX surface by distinct activators.","evidence":"Genetic deletion, NMR spectroscopy and fatty-acid growth assays in yeast","pmids":["19056732"],"confidence":"High","gaps":["Whether the same mechanism operates at endogenous metabolic genes in metazoans not addressed here"]},{"year":2009,"claim":"Mapping Gcn4 recruitment to multiple N-terminal Gal11 segments including KIX and a B-box established that activator-Mediator recruitment is additive and multivalent in vivo.","evidence":"In vitro binding, NMR chemical-shift analysis, site-directed mutagenesis and in vivo ChIP at ARG1","pmids":["19940160"],"confidence":"High","gaps":["Relative contribution of each segment to Pol II output not fully quantified","Structural basis of B-box engagement not resolved"]},{"year":2011,"claim":"Defining the Gcn4-Gal11 interface as a 'fuzzy', dynamic, hydrophobic complex answered how a single Mediator surface accommodates diverse acidic activators without a fixed structure.","evidence":"NMR structural analysis with mutagenesis and functional validation in yeast","pmids":["22195967"],"confidence":"High","gaps":["Generality across non-acidic activators untested at this point","How fuzzy binding translates to recruitment kinetics unresolved"]},{"year":2013,"claim":"Showing cooperative recruitment of holo-Mediator to HSP promoters and essential tail-module functions defined MED15 as a critical, partly module-autonomous recruitment hub.","evidence":"ChIP and genetic deletion/truncation, plus N-Degron depletion with transcriptome profiling and cell-cycle analysis in S. cerevisiae","pmids":["23447536","23991176"],"confidence":"Medium","gaps":["Molecular basis of tail-module essentiality independent of Head/Middle modules unknown","Direct vs indirect effects on Ace2 targets not dissected"]},{"year":2014,"claim":"Loss-of-function studies extended MED15 function to mammalian SREBP/VP16 and p53/p21 activation and to xenobiotic detoxification and innate immunity in C. elegans, establishing conserved roles in metabolic and stress-response transcription.","evidence":"siRNA knockdown/rescue, co-localization and ChIP in human cells; RNAi screen and infection survival assays in C. elegans","pmids":["25382556","24875643"],"confidence":"Medium","gaps":["Whether MED15 acts directly at these promoters or via complex integrity unclear","Mechanism connecting detoxification and immunity gene programs not defined"]},{"year":2013,"claim":"Identifying MED15 as a TGF-β-responsive regulator of p-SMAD3 nuclear shuttling and proliferation tied the subunit to oncogenic signaling in prostate cancer.","evidence":"siRNA/shRNA knockdown, proliferation assays, IHC and Western blot for p-SMAD3","pmids":["24374838"],"confidence":"Medium","gaps":["Direct MED15-SMAD3 interaction not demonstrated","Whether effect is Mediator-dependent unresolved"]},{"year":2019,"claim":"Demonstrating metal-stimulated MED15/MDT-15 cooperation with HIZR-1 and conserved binding at metallothionein/zinc-transporter genes generalized the activator-bridging role to metal-responsive transcription across species.","evidence":"Yeast two-hybrid, qRT-PCR, reporter and gain/loss-of-function genetics in C. elegans plus mammalian ChIP and human cell knockdown","pmids":["31815936"],"confidence":"High","gaps":["Structural basis of metal-enhanced MDT-15/HIZR-1 binding not resolved","Whether mammalian orthologs use the same nuclear receptor interface unclear"]},{"year":2021,"claim":"Showing that Gal4 and Gcn4 use the same fuzzy mechanism while the structured partner dictates interaction type clarified that Mediator surfaces, not the activators alone, define binding mode.","evidence":"NMR chemical-shift perturbation and binding assays with multiple activation domains and the Gal80 repressor","pmids":["33850123"],"confidence":"High","gaps":["Quantitative link between fuzzy affinity and transcriptional output not established"]},{"year":2021,"claim":"Defining a glutamine-rich IDR plus hydrophobic motif as drivers of liquid-like nuclear condensates, and a coiled-coil PrLD that templates prion-like amyloid recruitment, revealed a phase-separation/aggregation axis governing MED15 behavior.","evidence":"Live-cell imaging, FRAP, optodroplet and domain-deletion assays with DYRK3 overexpression; biophysical dimerization and amyloid assays with coiled-coil mutagenesis","pmids":["34789250","33772081"],"confidence":"Medium","gaps":["Functional role of condensates in active transcription not established","Physiological triggers of prion-like conversion unknown"]},{"year":2024,"claim":"Reciprocal binding to Nkx6-1 and NeuroD1 and conditional knockout phenotypes established a tissue-specific MED15 requirement for pancreatic β-cell maturation.","evidence":"ChIP-seq, co-IP, β-cell-specific conditional knockout mouse and human ESC-derived β-like cell overexpression","pmids":["39379383"],"confidence":"High","gaps":["Which maturation genes depend directly on MED15 versus secondary effects not fully resolved","Mechanism distinguishing maturation from mass/insulin output unknown"]},{"year":2024,"claim":"Placing MED15 in SREBP and HIF lipid-metabolic circuits, including a HIF feedback loop upstream of CPT1A and SREBP activation via PLK1/AKT, defined MED15 as a node coupling hypoxia and lipid biosynthesis in cancer.","evidence":"Co-IP, ChIP, siRNA knockdown and overexpression rescue in ccRCC; zebrafish med15 knockout with reporter and lipid-droplet assays and xenografts","pmids":["38649345","39947475"],"confidence":"Medium","gaps":["Direct versus indirect contribution to SREBP and HIF target genes not fully separated","Stoichiometry and physical basis of SREBP binding undefined"]},{"year":2024,"claim":"Demonstrating intrinsic promoter selectivity toward fuzzy-nucleosome regions and a nuclear Moesin/actin/Hsf complex showed MED15 actively shapes target selection beyond passive activator recruitment.","evidence":"ChIP-seq with DBD-AD and DBD-Med15 fusions in yeast; co-IP, ChIP and RNAi in Drosophila with human ortholog validation","pmids":["39187372","39353569"],"confidence":"Medium","gaps":["Chromatin features driving intrinsic preference not mechanistically defined","Role of nuclear actin in the Moesin-Med15-Hsf complex unresolved"]},{"year":2025,"claim":"Identifying TGF-β/CDK1-driven phosphorylation at T603 as a switch controlled by FOXA1 binding established a post-translational mechanism linking MED15 to SASP gene expression, senescence and cognitive aging.","evidence":"T603A/T603D mutagenesis, co-IP, gene expression analysis and a mouse knock-in with behavioral assays","pmids":["40825935"],"confidence":"Medium","gaps":["How phosphorylation alters MED15 partner choice or condensate behavior unknown","Direct CDK1-MED15 modification in vivo not structurally defined"]},{"year":2024,"claim":"Reporting MED15 stabilization of YAP1 by attenuating TRIM11-mediated ubiquitination and stress-inducible MED15/YAP1 condensates connected MED15 protein turnover, EMT and condensate biology in bladder cancer.","evidence":"Co-IP, ubiquitination assays, loss/gain-of-function, migration assays and condensate imaging","pmids":["41685983"],"confidence":"Medium","gaps":["Mechanism by which MED15 blocks TRIM11 on YAP1 unresolved","Relationship between MED15 and YAP1 within Mediator not defined"]},{"year":null,"claim":"How MED15's fuzzy activator binding, intrinsic promoter selectivity, condensate/prion-like properties and post-translational control (phosphorylation, TRIM11 ubiquitination) are integrated into a single regulatory logic at native genes remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified structural model connecting condensate state to activator selection","Mechanism coupling T603 phosphorylation and TRIM11 turnover not established","Whether disease-associated polyQ interactions (HTT, ATXN1) reflect physiological MED15 function is unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,3,23]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,14,19]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,4,1]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[15,13]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[23,7,11]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[11,12]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,3,23]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[2,14,18]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[3,16,18]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[8,14,19]}],"complexes":["Mediator complex (tail module)"],"partners":["GCN4","GAL4","HSF1","SREBP1","NKX6-1","NEUROD1","TRIM11","FOXA1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96RN5","full_name":"Mediator of RNA polymerase II transcription subunit 15","aliases":["Activator-recruited cofactor 105 kDa component","ARC105","CTG repeat protein 7a","Mediator complex subunit 15","Positive cofactor 2 glutamine/Q-rich-associated protein","PC2 glutamine/Q-rich-associated protein","TPA-inducible gene 1 protein","TIG-1","Trinucleotide repeat-containing gene 7 protein"],"length_aa":788,"mass_kda":86.8,"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. Required for cholesterol-dependent gene regulation. Positively regulates the Nodal signaling pathway","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q96RN5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MED15","classification":"Not Classified","n_dependent_lines":230,"n_total_lines":1208,"dependency_fraction":0.19039735099337748},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000099917","cell_line_id":"CID000244","localizations":[{"compartment":"nuclear_punctae","grade":3},{"compartment":"nucleoplasm","grade":3}],"interactors":[{"gene":"MED11","stoichiometry":10.0},{"gene":"MED14","stoichiometry":10.0},{"gene":"MED19","stoichiometry":10.0},{"gene":"MED27","stoichiometry":10.0},{"gene":"MED28","stoichiometry":10.0},{"gene":"MED29","stoichiometry":10.0},{"gene":"MED31","stoichiometry":10.0},{"gene":"MED4","stoichiometry":10.0},{"gene":"MED9","stoichiometry":10.0},{"gene":"TOP2B","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000244","total_profiled":1310},"omim":[{"mim_id":"607372","title":"MEDIATOR COMPLEX SUBUNIT 15; MED15","url":"https://www.omim.org/entry/607372"},{"mim_id":"184756","title":"STEROL REGULATORY ELEMENT-BINDING TRANSCRIPTION FACTOR 1; SREBF1","url":"https://www.omim.org/entry/184756"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/MED15"},"hgnc":{"alias_symbol":["TIG-1","CAG7A","Arc105"],"prev_symbol":["TNRC7","PCQAP"]},"alphafold":{"accession":"Q96RN5","domains":[{"cath_id":"1.10.246.20","chopping":"12-75","consensus_level":"medium","plddt":87.5452,"start":12,"end":75},{"cath_id":"-","chopping":"542-600","consensus_level":"high","plddt":82.2058,"start":542,"end":600},{"cath_id":"3.10.110","chopping":"677-786","consensus_level":"high","plddt":88.7863,"start":677,"end":786}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96RN5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96RN5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96RN5-F1-predicted_aligned_error_v6.png","plddt_mean":61.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MED15","jax_strain_url":"https://www.jax.org/strain/search?query=MED15"},"sequence":{"accession":"Q96RN5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96RN5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96RN5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96RN5"}},"corpus_meta":[{"pmid":"1909121","id":"PMC_1909121","title":"Cooperative effect of antisense-Rb and antisense-p53 oligomers on the extension of life span in human diploid fibroblasts, TIG-1.","date":"1991","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/1909121","citation_count":246,"is_preprint":false},{"pmid":"22195967","id":"PMC_22195967","title":"The acidic transcription activator Gcn4 binds the mediator subunit Gal11/Med15 using a simple protein interface forming a fuzzy complex.","date":"2011","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/22195967","citation_count":167,"is_preprint":false},{"pmid":"19056732","id":"PMC_19056732","title":"Mediator subunit Gal11p/MED15 is required for fatty acid-dependent gene activation by yeast transcription factor Oaf1p.","date":"2008","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19056732","citation_count":82,"is_preprint":false},{"pmid":"23447536","id":"PMC_23447536","title":"Mediator recruitment to heat shock genes requires dual Hsf1 activation domains and mediator tail subunits Med15 and Med16.","date":"2013","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23447536","citation_count":66,"is_preprint":false},{"pmid":"31013839","id":"PMC_31013839","title":"Promoter Hypermethylation of Tumor-Suppressor Genes p16INK4a,RASSF1A,TIMP3, and PCQAP/MED15 in Salivary DNA as a Quadruple Biomarker Panel for Early Detection of Oral and Oropharyngeal Cancers.","date":"2019","source":"Biomolecules","url":"https://pubmed.ncbi.nlm.nih.gov/31013839","citation_count":61,"is_preprint":false},{"pmid":"19940160","id":"PMC_19940160","title":"Activator Gcn4 employs multiple segments of Med15/Gal11, including the KIX domain, to recruit mediator to target genes in vivo.","date":"2009","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19940160","citation_count":61,"is_preprint":false},{"pmid":"27246098","id":"PMC_27246098","title":"The Mediator Complex MED15 Subunit Mediates Activation of Downstream Lipid-Related Genes by the WRINKLED1 Transcription Factor.","date":"2016","source":"Plant physiology","url":"https://pubmed.ncbi.nlm.nih.gov/27246098","citation_count":57,"is_preprint":false},{"pmid":"1315688","id":"PMC_1315688","title":"Interleukin-1 up-regulates transcription of its own receptor in a human fibroblast cell line TIG-1: role of endogenous PGE2 and cAMP.","date":"1992","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/1315688","citation_count":52,"is_preprint":false},{"pmid":"33850123","id":"PMC_33850123","title":"Mediator subunit Med15 dictates the conserved \"fuzzy\" binding mechanism of yeast transcription activators Gal4 and Gcn4.","date":"2021","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/33850123","citation_count":45,"is_preprint":false},{"pmid":"24875643","id":"PMC_24875643","title":"The evolutionarily conserved mediator subunit MDT-15/MED15 links protective innate immune responses and xenobiotic detoxification.","date":"2014","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/24875643","citation_count":42,"is_preprint":false},{"pmid":"25057238","id":"PMC_25057238","title":"DNA Methylation at the Novel CpG Sites in the Promoter of MED15/PCQAP Gene as a Biomarker for Head and Neck Cancers.","date":"2014","source":"Biomarker insights","url":"https://pubmed.ncbi.nlm.nih.gov/25057238","citation_count":41,"is_preprint":false},{"pmid":"16904669","id":"PMC_16904669","title":"TRIM11 binds to and destabilizes a key component of the activator-mediated cofactor complex (ARC105) through the ubiquitin-proteasome system.","date":"2006","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/16904669","citation_count":32,"is_preprint":false},{"pmid":"1800129","id":"PMC_1800129","title":"A new human male diploid cell strain, TIG-7: its age-related changes and comparison with a matched female TIG-1 cell strain.","date":"1991","source":"Experimental gerontology","url":"https://pubmed.ncbi.nlm.nih.gov/1800129","citation_count":30,"is_preprint":false},{"pmid":"24374838","id":"PMC_24374838","title":"MED15, encoding a subunit of the mediator complex, is overexpressed at high frequency in castration-resistant prostate cancer.","date":"2013","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/24374838","citation_count":28,"is_preprint":false},{"pmid":"6333569","id":"PMC_6333569","title":"Loss of responsiveness in senescent human TIG-1 cells to the DNA synthesis-inducing effect of various growth factors.","date":"1984","source":"Mechanisms of ageing and development","url":"https://pubmed.ncbi.nlm.nih.gov/6333569","citation_count":28,"is_preprint":false},{"pmid":"31815936","id":"PMC_31815936","title":"Mediator subunit MDT-15/MED15 and Nuclear Receptor HIZR-1/HNF4 cooperate to regulate toxic metal stress responses in Caenorhabditis elegans.","date":"2019","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/31815936","citation_count":26,"is_preprint":false},{"pmid":"27974704","id":"PMC_27974704","title":"MED15 overexpression in prostate cancer arises during androgen deprivation therapy via PI3K/mTOR signaling.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/27974704","citation_count":23,"is_preprint":false},{"pmid":"7948430","id":"PMC_7948430","title":"Interleukin-1 down-regulates type I interleukin 1 receptor mRNA expression in a human fibroblast cell line TIG-1 in the absence of prostaglandin E2 synthesis.","date":"1994","source":"Lymphokine and cytokine research","url":"https://pubmed.ncbi.nlm.nih.gov/7948430","citation_count":23,"is_preprint":false},{"pmid":"25791637","id":"PMC_25791637","title":"Clinical and molecular implications of MED15 in head and neck squamous cell carcinoma.","date":"2015","source":"The American journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/25791637","citation_count":21,"is_preprint":false},{"pmid":"36591911","id":"PMC_36591911","title":"MED15::TFE3 Renal Cell Carcinomas: Report of Two New Cases and Review of the Literature Confirming Nearly Universal Multilocular Cystic Morphology.","date":"2023","source":"International journal of surgical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/36591911","citation_count":19,"is_preprint":false},{"pmid":"31036407","id":"PMC_31036407","title":"Med15: Glutamine-Rich Mediator Subunit with Potential for Plasticity.","date":"2019","source":"Trends in biochemical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/31036407","citation_count":19,"is_preprint":false},{"pmid":"38649345","id":"PMC_38649345","title":"MED15 is upregulated by HIF-2α and promotes proliferation and metastasis in clear cell renal cell carcinoma via activation of SREBP-dependent fatty acid synthesis.","date":"2024","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/38649345","citation_count":18,"is_preprint":false},{"pmid":"34789250","id":"PMC_34789250","title":"Formation of nuclear condensates by the Mediator complex subunit Med15 in mammalian cells.","date":"2021","source":"BMC biology","url":"https://pubmed.ncbi.nlm.nih.gov/34789250","citation_count":18,"is_preprint":false},{"pmid":"20233856","id":"PMC_20233856","title":"Identification of genes affecting wing patterning through a loss-of-function mutagenesis screen and characterization of med15 function during wing development.","date":"2010","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/20233856","citation_count":18,"is_preprint":false},{"pmid":"31828108","id":"PMC_31828108","title":"A Rare Partner of TFE3 in the Xp11 Translocation Renal Cell Carcinoma: Clinicopathological Analyses and Detection of MED15-TFE3 Fusion.","date":"2019","source":"BioMed research international","url":"https://pubmed.ncbi.nlm.nih.gov/31828108","citation_count":17,"is_preprint":false},{"pmid":"12497610","id":"PMC_12497610","title":"Association study between CAG trinucleotide repeats in the PCQAP gene (PC2 glutamine/Q-rich-associated protein) and schizophrenia.","date":"2003","source":"American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/12497610","citation_count":16,"is_preprint":false},{"pmid":"38278485","id":"PMC_38278485","title":"MED15::ATF1-Rearranged Tumor: A Novel Cutaneous Tumor With Melanocytic Differentiation.","date":"2024","source":"Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc","url":"https://pubmed.ncbi.nlm.nih.gov/38278485","citation_count":15,"is_preprint":false},{"pmid":"38696472","id":"PMC_38696472","title":"DELLA proteins recruit the Mediator complex subunit MED15 to coactivate transcription in land plants.","date":"2024","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/38696472","citation_count":15,"is_preprint":false},{"pmid":"36997032","id":"PMC_36997032","title":"Cystic MED15::TFE3 translocation renal cell carcinoma: histologic mimicker of multilocular cystic renal neoplasm of low malignant potential with review of the literature.","date":"2023","source":"Human pathology","url":"https://pubmed.ncbi.nlm.nih.gov/36997032","citation_count":14,"is_preprint":false},{"pmid":"33772081","id":"PMC_33772081","title":"MED15 prion-like domain forms a coiled-coil responsible for its amyloid conversion and propagation.","date":"2021","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/33772081","citation_count":14,"is_preprint":false},{"pmid":"32164312","id":"PMC_32164312","title":"The Polymorphic PolyQ Tail Protein of the Mediator Complex, Med15, Regulates the Variable Response to Diverse Stresses.","date":"2020","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/32164312","citation_count":14,"is_preprint":false},{"pmid":"26377566","id":"PMC_26377566","title":"Differential expression of Mediator complex subunit MED15 in testicular germ cell tumors.","date":"2015","source":"Diagnostic pathology","url":"https://pubmed.ncbi.nlm.nih.gov/26377566","citation_count":13,"is_preprint":false},{"pmid":"23991176","id":"PMC_23991176","title":"Functional studies of the yeast med5, med15 and med16 mediator tail subunits.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23991176","citation_count":13,"is_preprint":false},{"pmid":"2434812","id":"PMC_2434812","title":"Events blocked in prereplicative phase in senescent human diploid cells, TIG-1, following serum stimulation.","date":"1986","source":"Mechanisms of ageing and development","url":"https://pubmed.ncbi.nlm.nih.gov/2434812","citation_count":13,"is_preprint":false},{"pmid":"3361969","id":"PMC_3361969","title":"Changes in negative surface charge of human diploid fibroblasts, TIG-1, during in vitro aging.","date":"1988","source":"Mechanisms of ageing and development","url":"https://pubmed.ncbi.nlm.nih.gov/3361969","citation_count":13,"is_preprint":false},{"pmid":"39187372","id":"PMC_39187372","title":"Revisiting the model for coactivator recruitment: Med15 can select its target sites independent of promoter-bound transcription factors.","date":"2024","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/39187372","citation_count":12,"is_preprint":false},{"pmid":"7160447","id":"PMC_7160447","title":"Ganglioside changes during cell aging in human diploid fibroblast TIG-1.","date":"1982","source":"Experimental gerontology","url":"https://pubmed.ncbi.nlm.nih.gov/7160447","citation_count":12,"is_preprint":false},{"pmid":"8746788","id":"PMC_8746788","title":"Type I and type II interferons upregulate functional type I interleukin-1 receptor in a human fibroblast cell line TIG-1.","date":"1995","source":"Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research","url":"https://pubmed.ncbi.nlm.nih.gov/8746788","citation_count":12,"is_preprint":false},{"pmid":"29400661","id":"PMC_29400661","title":"The Mediator complex subunit MED15, a promoter of tumour progression and metastatic spread in renal cell carcinoma.","date":"2018","source":"Cancer biomarkers : section A of Disease markers","url":"https://pubmed.ncbi.nlm.nih.gov/29400661","citation_count":11,"is_preprint":false},{"pmid":"21562774","id":"PMC_21562774","title":"Establishment of human induced pluripotent stem cell lines from normal fibroblast TIG-1.","date":"2011","source":"Human cell","url":"https://pubmed.ncbi.nlm.nih.gov/21562774","citation_count":11,"is_preprint":false},{"pmid":"15318033","id":"PMC_15318033","title":"An association study of PCQAP polymorphisms and schizophrenia.","date":"2004","source":"Psychiatric genetics","url":"https://pubmed.ncbi.nlm.nih.gov/15318033","citation_count":10,"is_preprint":false},{"pmid":"25382556","id":"PMC_25382556","title":"Human mediator subunit MED15 promotes transcriptional activation.","date":"2014","source":"Drug discoveries & therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/25382556","citation_count":9,"is_preprint":false},{"pmid":"11024300","id":"PMC_11024300","title":"A novel glutamine-rich putative transcriptional adaptor protein (TIG-1), preferentially expressed in placental and bone-marrow tissues.","date":"2000","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/11024300","citation_count":8,"is_preprint":false},{"pmid":"38459940","id":"PMC_38459940","title":"Novel MED15::ATF1 fusion in a pediatric melanoma with spitzoid features and aggressive presentation.","date":"2024","source":"Genes, chromosomes & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/38459940","citation_count":6,"is_preprint":false},{"pmid":"30127891","id":"PMC_30127891","title":"The knockdown of the Mediator complex subunit MED15 restrains urothelial bladder cancer cells' malignancy.","date":"2018","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/30127891","citation_count":6,"is_preprint":false},{"pmid":"22273270","id":"PMC_22273270","title":"Establishment of ultra long-lived cell lines by transfection of TERT into normal human fibroblast TIG-1 and their characterization.","date":"2012","source":"Cell biology international","url":"https://pubmed.ncbi.nlm.nih.gov/22273270","citation_count":6,"is_preprint":false},{"pmid":"38387043","id":"PMC_38387043","title":"MED15::TFE3 fusion renal cell carcinoma with extensive cystic change: A clinicopathologic and molecular genetic study of 2 cases, with an emphasis on differential diagnosis.","date":"2024","source":"American journal of clinical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/38387043","citation_count":5,"is_preprint":false},{"pmid":"7266075","id":"PMC_7266075","title":"Effects of in vitro aging and cell growth on the viability and recovery of human diploid fibroblasts, TIG-1, after freezing and thawing.","date":"1981","source":"Mechanisms of ageing and development","url":"https://pubmed.ncbi.nlm.nih.gov/7266075","citation_count":5,"is_preprint":false},{"pmid":"3821186","id":"PMC_3821186","title":"Failure in S6 protein phosphorylation by serum stimulation of senescent human diploid fibroblasts, TIG-1.","date":"1986","source":"Mechanisms of ageing and development","url":"https://pubmed.ncbi.nlm.nih.gov/3821186","citation_count":5,"is_preprint":false},{"pmid":"39379383","id":"PMC_39379383","title":"Transcriptional coactivator MED15 is required for beta cell maturation.","date":"2024","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/39379383","citation_count":4,"is_preprint":false},{"pmid":"39947475","id":"PMC_39947475","title":"The mediator subunit complex protein MED15 promotes lipid deposition and cancer progression during hypoxia.","date":"2025","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/39947475","citation_count":4,"is_preprint":false},{"pmid":"39717019","id":"PMC_39717019","title":"The Role of Med15 Sequence Features in Transcription Factor Interactions.","date":"2024","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/39717019","citation_count":4,"is_preprint":false},{"pmid":"34733258","id":"PMC_34733258","title":"Possible Role for Allelic Variation in Yeast MED15 in Ecological Adaptation.","date":"2021","source":"Frontiers in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/34733258","citation_count":4,"is_preprint":false},{"pmid":"22291956","id":"PMC_22291956","title":"Genetic and physical interactions between Tel2 and the Med15 Mediator subunit in Saccharomyces cerevisiae.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22291956","citation_count":3,"is_preprint":false},{"pmid":"40825935","id":"PMC_40825935","title":"A phosphorylation switch in the Mediator MED15 controls cellular senescence and cognitive decline.","date":"2025","source":"Cell discovery","url":"https://pubmed.ncbi.nlm.nih.gov/40825935","citation_count":2,"is_preprint":false},{"pmid":"39353569","id":"PMC_39353569","title":"Moesin contributes to heat shock gene response through direct binding to the Med15 subunit of the Mediator complex in the nucleus.","date":"2024","source":"Open biology","url":"https://pubmed.ncbi.nlm.nih.gov/39353569","citation_count":2,"is_preprint":false},{"pmid":"30836860","id":"PMC_30836860","title":"PFG acted as an inducer of premature senescence in TIG-1 normal diploid fibroblast and an inhibitor of mitosis in the HeLa cells.","date":"2019","source":"Bioscience, biotechnology, and biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/30836860","citation_count":2,"is_preprint":false},{"pmid":"36983501","id":"PMC_36983501","title":"Mediator Subunit Med15 Regulates Cell Morphology and Mating in Candida lusitaniae.","date":"2023","source":"Journal of fungi (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/36983501","citation_count":1,"is_preprint":false},{"pmid":"39762166","id":"PMC_39762166","title":"[MED15-TFE3 renal cell carcinoma: a clinicopathological and molecular analysis].","date":"2025","source":"Zhonghua bing li xue za zhi = Chinese journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/39762166","citation_count":1,"is_preprint":false},{"pmid":"36340330","id":"PMC_36340330","title":"Clinical and Histopathological Factors Associated with the Tumoral Expression of TGF-β1, MED15, CD16, and CD57 in Oral Squamous Cell Carcinoma.","date":"2022","source":"Advances in preventive medicine","url":"https://pubmed.ncbi.nlm.nih.gov/36340330","citation_count":1,"is_preprint":false},{"pmid":"40501983","id":"PMC_40501983","title":"Box C/D snoRNPs and MDT-15/MED15 regulate mitochondrial surveillance via fatty acid metabolism.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/40501983","citation_count":0,"is_preprint":false},{"pmid":"41685983","id":"PMC_41685983","title":"Role of MED15 in Enhancing EMT and Metastasis in Bladder Cancer Through YAP1 Stabilization.","date":"2026","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/41685983","citation_count":0,"is_preprint":false},{"pmid":"42113263","id":"PMC_42113263","title":"Comprehensive analysis of six MED15::TFE3 renal cell carcinomas including two novel solid MED15::TFE3 renal cell carcinomas, highlighting their morphologic, immunohistochemical and molecular differences from their cystic counterparts.","date":"2026","source":"Virchows Archiv : an international journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/42113263","citation_count":0,"is_preprint":false},{"pmid":"41542482","id":"PMC_41542482","title":"Transcriptomic shift in ethanol and amino acid metabolic genes regulated by Med15 during alcoholic fermentation.","date":"2026","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/41542482","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.03.17.643445","title":"Chemical targeting of the ATXN1 aa99-163 interaction site suppresses polyQ-expanded protein dimerization","date":"2025-03-17","source":"bioRxiv","url":"https://doi.org/10.1101/2025.03.17.643445","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.05.26.656193","title":"Box C/D snoRNPs and MDT-15/MED15 regulate mitochondrial surveillance and mitophagy via fatty acid metabolism","date":"2025-05-28","source":"bioRxiv","url":"https://doi.org/10.1101/2025.05.26.656193","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.11.21.624739","title":"Reconciling competing models on the roles of condensates and soluble complexes in transcription factor function","date":"2024-11-22","source":"bioRxiv","url":"https://doi.org/10.1101/2024.11.21.624739","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.09.07.611843","title":"Multi-epitope immunocapture of huntingtin reveals striatum-selective molecular signatures","date":"2024-09-11","source":"bioRxiv","url":"https://doi.org/10.1101/2024.09.07.611843","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.10.28.24314051","title":"Extremely rare CNVs contributing to Alzheimer disease risk: a case-control association analysis of exome sequencing data from 22,319 individuals","date":"2024-11-01","source":"bioRxiv","url":"https://doi.org/10.1101/2024.10.28.24314051","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.12.27.630542","title":"Huntingtin interactome reveals huntingtin role in regulation of double strand break DNA damage response (DSB/DDR), chromatin remodeling and RNA processing pathways","date":"2024-12-28","source":"bioRxiv","url":"https://doi.org/10.1101/2024.12.27.630542","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":34620,"output_tokens":6407,"usd":0.099983,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":15342,"output_tokens":5071,"usd":0.101742,"stage2_stop_reason":"end_turn"},"total_usd":0.201725,"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\": 2011,\n      \"finding\": \"The acidic activation domain (AD) of transcription activator Gcn4 binds the Mediator subunit Gal11/Med15 activator-binding domain 1 (a four-helix fold with a shallow hydrophobic cleft) through a dynamic, 'fuzzy' protein interface involving only hydrophobic interactions; eight residues of Gcn4 adopt a helical conformation allowing three aromatic/aliphatic residues to insert into the Gal11 cleft, and the complex cannot be described by a single conformation.\",\n      \"method\": \"NMR structural analysis combined with mutagenesis and functional studies in yeast\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — NMR structure with mutagenesis and functional validation in a single rigorous study\",\n      \"pmids\": [\"22195967\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Gcn4 recruits Mediator to the ARG1 promoter in vivo through additive interactions with three distinct N-terminal segments of Gal11/Med15, including the KIX domain and a B-box motif; NMR chemical shift analysis identified the Gcn4 binding site on the Gal11 KIX surface, and mutagenesis of B-box established it as a critical determinant of Mediator recruitment.\",\n      \"method\": \"In vitro binding assays, ChIP (Mediator recruitment in vivo), NMR chemical shift analysis, site-directed mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — NMR plus mutagenesis plus in vivo ChIP, multiple orthogonal methods in one study\",\n      \"pmids\": [\"19940160\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The yeast Mediator subunit Gal11p/MED15 and its KIX domain are required for fatty acid-dependent transcriptional activation by the PPARα analog Oaf1p; NMR spectroscopy revealed that the Oaf1p activation domain interacts with the Gal11p/MED15 KIX domain in a manner similar to the xenobiotic receptor Pdr1p.\",\n      \"method\": \"Genetic deletion analysis, NMR spectroscopy, fatty acid growth assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — NMR structural interaction plus genetic loss-of-function, multiple orthogonal methods\",\n      \"pmids\": [\"19056732\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Med15 (Tail module subunit) and Med16 cooperate to recruit holo-Mediator to HSP gene promoters in yeast in response to heat shock; Hsf1 recruits Mediator via dual N- and C-terminal activation domains through cooperative interactions with the Tail module, and loss of both Med15 and Med16 abolishes Mediator occupancy and substantially reduces RNA Pol II recruitment.\",\n      \"method\": \"ChIP (chromatin immunoprecipitation), genetic deletion/truncation analysis in Saccharomyces cerevisiae\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP with multiple deletion combinations, clear epistatic relationships, replicated across multiple gene targets\",\n      \"pmids\": [\"23447536\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Gal4 and Gcn4, two intrinsically disordered acidic activation domains of different sequence, interact nearly identically with Med15 via a 'fuzzy' protein interface; the two hydrophobic regions of the Gal4 AD each independently bind Med15 using this fuzzy mechanism, while the same Gal4 AD region binds Gal80 repressor via a distinct structured complex, indicating the structured binding partner dictates the interaction type.\",\n      \"method\": \"NMR chemical shift perturbation analysis, binding assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — NMR with two different ADs, multiple binding partners, mechanistically rigorous single study\",\n      \"pmids\": [\"33850123\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"TRIM11 binds to MED15 (ARC105) and promotes its degradation through the ubiquitin-proteasome pathway; co-expression of TRIM11 increases ARC105 ubiquitination and degradation (blocked by proteasome inhibitor), and TRIM11 suppresses ARC105-mediated transcriptional activation induced by TGF-β in a reporter assay.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, proteasome inhibitor treatment, transcriptional reporter assay\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP, ubiquitination assay, and functional reporter in a single lab with multiple orthogonal methods\",\n      \"pmids\": [\"16904669\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"In yeast, loss of Med15 leads to down-regulation of Ace2 transcriptional activator target genes and a G1 cell cycle arrest phenotype; synthetic lethality of med5/med15 and med15/med16 double mutants indicates the Tail module performs essential functions even when separated from Head and Middle modules.\",\n      \"method\": \"Temperature-sensitive N-Degron mutants, global gene expression profiling, cell cycle analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Inducible protein depletion with transcriptome profiling and cell cycle phenotype, single lab\",\n      \"pmids\": [\"23991176\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Human MED15 co-localizes with general transcription factors TFIIE and TFIIH in the nucleus; MED15 knockdown reduces VP16- and SREBP1a-driven transcriptional activation, rescued by wild-type MED15 re-expression; MED15 localizes to both the p53 binding site and the p21 promoter region upon Nutlin-3 induction.\",\n      \"method\": \"siRNA knockdown, immunostaining/co-localization, transcriptional reporter assay, ChIP\",\n      \"journal\": \"Drug discoveries & therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Multiple orthogonal methods (co-localization, knockdown/rescue, ChIP) in a single lab\",\n      \"pmids\": [\"25382556\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"MED15 knockdown in prostate cancer cells reduces TGF-β-enhanced proliferation, affects phosphorylation and nuclear shuttling of p-SMAD3, and decreases both androgen-dependent and androgen-independent proliferation; TGF-β signaling activation leads to increased MED15 expression in PCa cells.\",\n      \"method\": \"siRNA/shRNA knockdown, proliferation assays, immunohistochemistry, Western blot for p-SMAD3\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Loss-of-function with defined signaling phenotype, single lab, multiple readouts\",\n      \"pmids\": [\"24374838\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"C. elegans MDT-15/MED15 is required for xenobiotic-induced expression of PMK-1 p38 MAP kinase-dependent immune genes and for protection from Pseudomonas aeruginosa infection; MDT-15 also controls induction of detoxification genes and protects from phenazine toxins, linking xenobiotic detoxification and innate immunity.\",\n      \"method\": \"RNAi screen (1,420 genes), gene expression analysis, infection survival assays in C. elegans\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi loss-of-function with multiple functional readouts (gene expression, infection survival), single lab\",\n      \"pmids\": [\"24875643\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"C. elegans MDT-15 physically and functionally cooperates with the nuclear hormone receptor HIZR-1 to promote induction of zinc and cadmium responsive genes; the physical interaction between MDT-15 and HIZR-1 is enhanced by zinc or cadmium in yeast two-hybrid assays; mdt-15 and hizr-1 mutants show defective zinc storage in the gut and hypersensitivity to zinc-induced reductions in egg-laying; mammalian MED15 orthologs bind genomic regulatory regions of metallothionein and zinc transporter genes in a cadmium/zinc-stimulated fashion, and human MED15 is required to induce a metallothionein gene in lung adenocarcinoma cells.\",\n      \"method\": \"Yeast two-hybrid, qRT-PCR, reporter analysis, gain/loss-of-function genetics, ChIP (mammalian cells), siRNA knockdown in human cells\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Multiple orthogonal methods across two organisms (C. elegans genetics, yeast-two-hybrid, mammalian ChIP, human cell knockdown), replicated functional evidence\",\n      \"pmids\": [\"31815936\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Human MED15 forms nuclear condensates (foci) that are sensitive to 1,6-hexanediol and show rapid FRAP recovery; condensate formation requires both the glutamine-rich intrinsically disordered region (IDR) and a short downstream hydrophobic motif; DYRK3 kinase overexpression disrupts Med15 foci; the MED15 prion-like domain drives phase separation and can kidnap endogenous full-length MED15 into cytoplasmic/perinuclear inclusions in a prion-like manner.\",\n      \"method\": \"Live cell imaging, immunostaining, FRAP, optodroplet assay, domain deletion analysis, DYRK3 overexpression\",\n      \"journal\": \"BMC biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Multiple live-cell methods with domain mapping, single lab\",\n      \"pmids\": [\"34789250\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The human MED15 prion-like domain (PrLD) forms homodimers sustained by coiled-coil (CC) interactions; CC disruption (chemical or genetic) abolishes amyloid aggregation; the CC fold mediates transition to a β-sheet amyloid state; a GFP domain adjacent to the PrLD retains its structure in the amyloid state; MED15-PrLD expression in human cells promotes prion-like recruitment of endogenous full-length MED15 to cytoplasmic inclusions.\",\n      \"method\": \"Biophysical dimerization assays, amyloid aggregation assays, coiled-coil mutagenesis, fluorescence microscopy in human cells\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — In vitro biophysical assays plus mutagenesis plus cell imaging, single lab\",\n      \"pmids\": [\"33772081\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Mouse Med15 binds pancreatic β-cell transcription factors Nkx6-1 and NeuroD1 (by co-immunoprecipitation and ChIP-seq) to regulate key β-cell maturation genes; β-cell-specific Med15 knockout causes defects in β-cell maturation without affecting β-cell mass or insulin expression; human embryonic stem cell-derived β-like cells engineered to overexpress MED15 show increased maturation marker expression.\",\n      \"method\": \"ChIP-seq, co-immunoprecipitation, conditional knockout mouse, human ESC differentiation system\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Reciprocal ChIP-seq and Co-IP with conditional KO and human ESC validation across multiple orthogonal methods\",\n      \"pmids\": [\"39379383\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MED15 directly interacts with SREBPs (SREBP1 and SREBP2) to promote SREBP-dependent lipid biosynthesis enzyme expression in clear cell renal cell carcinoma; MED15 also promotes SREBP1/2 activation through the PLK1/AKT axis; HIF-2α promotes MED15 transcriptional activation by directly binding the MED15 promoter.\",\n      \"method\": \"Co-immunoprecipitation, promoter binding assay (ChIP), siRNA knockdown, overexpression rescue experiments\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP with functional knockdown/overexpression, multiple pathway readouts, single lab\",\n      \"pmids\": [\"38649345\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Med15 in budding yeast can select its chromosomal binding sites (characterized by fuzzy-nucleosome architecture) independent of promoter-bound transcription factors; direct DBD-Med15 fusions shift DBD localization towards fuzzy-nucleosome promoters, indicating Med15 has inherent promoter preference and actively contributes to target gene selection.\",\n      \"method\": \"ChIP-seq with DBD-AD fusions, direct DBD-Med15 fusions, genome-wide localization in budding yeast\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Genome-wide ChIP-seq with multiple fusion constructs, single lab\",\n      \"pmids\": [\"39187372\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TGF-β selectively induces CDK1-mediated phosphorylation of MED15 at T603, which controls SASP gene expression and cellular senescence; the T603A (dephosphorylated) mutant inhibits SASP and cell senescence, while T603D (phosphomimetic) promotes them; forkhead box protein A1 (FOXA1) preferentially binds unphosphorylated MED15-T603 to suppress SASP gene expression; aging mice with T603A mutation show improved learning and memory through SASP attenuation.\",\n      \"method\": \"Site-directed mutagenesis (T603A/T603D), Co-immunoprecipitation, gene expression analysis, mouse knock-in model, behavioral assays\",\n      \"journal\": \"Cell discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Phospho-mutagenesis with Co-IP and in vivo mouse knock-in, single lab\",\n      \"pmids\": [\"40825935\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Drosophila Moesin directly interacts with the Med15 subunit of the Mediator complex in the nucleus; Moesin's presence at regulatory regions of the Hsp70Ab heat shock gene is Med15-dependent; both Moesin and Med15 bind heat shock factor (Hsf), and together with monomeric actin form a nuclear complex required for proper Hsp gene expression; direct interaction between the human orthologs of Moesin and Med15 was confirmed.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, RNAi knockdown, gene expression analysis in Drosophila and human cells\",\n      \"journal\": \"Open biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Multiple orthogonal methods (Co-IP, ChIP, RNAi) in Drosophila validated in human orthologs, single lab\",\n      \"pmids\": [\"39353569\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MED15 acts as a HIF target gene that participates in a positive feedback loop promoting HIF transcriptional activity; MED15 acts upstream of CPT1A (carnitine palmitoyltransferase 1A, a key fatty acid oxidation enzyme) to promote HIF-mediated lipid droplet accumulation; zebrafish med15 deficiency decreases HIF activity and impairs hypoxic stress tolerance.\",\n      \"method\": \"siRNA knockdown, zebrafish med15 knockout, reporter assays, lipid droplet quantification, tumor xenograft\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Loss-of-function in mammalian cells and zebrafish with defined pathway placement, single lab\",\n      \"pmids\": [\"39947475\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MED15 interacts with YAP1 and stabilizes it by attenuating TRIM11-mediated ubiquitination in bladder cancer cells; MED15 promotes EMT and cell migration in a YAP1-dependent manner; under osmotic stress, MED15 forms stress-inducible protein condensates with increased YAP1 co-localization.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, loss- and gain-of-function (siRNA/overexpression), migration assays, condensate imaging\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP and ubiquitination assay with functional readouts, single lab\",\n      \"pmids\": [\"41685983\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Drosophila Med15 is required for transcription of Decapentaplegic (Dpp/BMP) target genes during wing development; loss-of-function clones in mosaic wings establish Med15 as a component needed for proper wing patterning and epithelial gene regulation.\",\n      \"method\": \"Loss-of-function genetic screen, mosaic clone analysis, gene expression analysis in Drosophila\",\n      \"journal\": \"Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Genetic loss-of-function with defined target gene transcription phenotype, single lab\",\n      \"pmids\": [\"20233856\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Med15 KIX domain length and polyglutamine (polyQ) tract composition modulate interactions with specific transcription factors (including Msn2); reduced Msn2:Med15 interaction strength correlates with reduced Msn2-dependent transcriptional activation; intramolecular interactions between distant glutamine tracts and MED15 phosphorylation affect KIX domain activities; individual ABDs and adjacent polyQ tracts each contribute to Med15 activity in a context-dependent manner.\",\n      \"method\": \"Truncation/deletion/synthetic allele analysis, phenotypic assays, gene expression analysis, transcription factor interaction assays, phase separation assays in yeast\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Multiple allele series with interaction and functional assays, single lab\",\n      \"pmids\": [\"39717019\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Med15/Gal11 physically associates with Tel2 in yeast when transiently overproduced; overexpression of MED15/GAL11 partially suppresses tel2 temperature-sensitive mutant phenotypes including short telomeres and defective EST2 (telomerase catalytic subunit) transcription.\",\n      \"method\": \"Co-immunoprecipitation, genetic suppressor analysis, gene expression analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Single Co-IP (transient overexpression only) with genetic suppression, single lab\",\n      \"pmids\": [\"22291956\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"The human MED15 (TIG-1/ARC105) protein contains a bipartite nuclear localization signal, localizes to the nucleus, and when tethered to DNA via a GAL4 fusion demonstrates transcriptional regulatory activity in co-transfection assays; the protein was identified as a component of the ARC chromatin-directed transcriptional co-activator complex.\",\n      \"method\": \"Co-transfection reporter assay, Western blot, nuclear localization signal identification, cDNA library screening\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Single tethered reporter assay, no endogenous functional validation, single lab\",\n      \"pmids\": [\"11024300\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Huntingtin (HTT) associates with MED15 preferentially in the Mediator tail domain, and HTT modulates the subcellular localization and assembly of the Mediator complex in HD and KO models.\",\n      \"method\": \"Multi-epitope immunocapture/co-immunoprecipitation, subcellular fractionation, mass spectrometry, Drosophila genetic modifier assays\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP/MS interaction data for MED15 specifically, single preprint, no MED15-specific functional validation\",\n      \"pmids\": [\"bio_10.1101_2024.09.07.611843\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ATXN1 amino acids 99-163 and MED15 amino acids 548-665 are critical for their protein-protein interaction; MED15 significantly enhances aggregation of polyQ-expanded ATXN1; a small molecule (Chembridge ID: 5755483) targeting the ATXN1 aa99-163 domain inhibits both the ATXN1-MED15 interaction and dimerization of polyQ-expanded ATXN1.\",\n      \"method\": \"Computational structure prediction, co-immunoprecipitation/interaction assays with domain mutants, aggregation assays, virtual screening and chemical compound validation\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Preprint, domain mapping by deletion/co-IP but limited orthogonal structural validation, single lab\",\n      \"pmids\": [\"bio_10.1101_2025.03.17.643445\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"MED15 is a tail-module subunit of the Mediator co-activator complex that bridges upstream transcription factors (including acidic activators Gcn4 and Gal4, nuclear receptors, SREBPs, FOXA1, and tissue-specific factors such as Nkx6-1 and NeuroD1) to RNA Polymerase II machinery through a structurally characterized 'fuzzy' KIX domain interaction; it is regulated post-translationally by CDK1-mediated phosphorylation at T603 (controlling SASP/senescence), and by TRIM11-mediated ubiquitin-proteasome degradation; it forms phase-separated nuclear condensates via its glutamine-rich intrinsically disordered region and hydrophobic motif; and it plays conserved roles in fatty acid/lipid metabolism gene regulation, innate immunity, β-cell maturation, heat shock gene expression, and cellular senescence across yeast, C. elegans, Drosophila, and mammals.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MED15 is a tail-module subunit of the Mediator co-activator complex that bridges sequence-specific transcription factors to the RNA Polymerase II machinery and thereby controls inducible gene-expression programs across eukaryotes [#3, #23]. Its defining biochemical feature is a set of activator-binding domains, including a KIX domain, that engage intrinsically disordered acidic activation domains through a dynamic 'fuzzy' interface: the activation domains of Gcn4 and Gal4 bind nearly identically using transient hydrophobic contacts rather than a single fixed conformation, and the same domains adopt structured complexes only when the partner itself is structured [#0, #4]. Through these adaptable surfaces MED15 integrates diverse upstream regulators — Gcn4 and Hsf1 at heat-shock and amino-acid genes, the lipid-sensing factors Oaf1p and SREBP1/2, the nuclear receptor HIZR-1, and tissue factors Nkx6-1 and NeuroD1 — to drive fatty-acid/lipid-metabolism, stress, metal-response, and cell-maturation programs [#2, #3, #10, #13, #14]. In yeast the tail module performs essential functions, with Med15 loss down-regulating Ace2 targets and arresting cells in G1, and Med15 contributes intrinsic promoter selectivity toward fuzzy-nucleosome regulatory regions independent of activator tethering [#6, #15]. MED15 is regulated post-translationally by TRIM11-mediated ubiquitin-proteasome degradation and by CDK1 phosphorylation at T603, which licenses SASP gene expression and cellular senescence while unphosphorylated MED15 is bound by FOXA1 to suppress this program [#5, #16]. Its glutamine-rich intrinsically disordered region together with a downstream hydrophobic motif drives formation of liquid-like nuclear condensates and, in a prion-like coiled-coil-dependent manner, can recruit endogenous MED15 into amyloid inclusions [#11, #12].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Establishing that the human protein is a nuclear, DNA-tethered transcriptional regulator placed MED15 within a chromatin-directed co-activator complex.\",\n      \"evidence\": \"GAL4-fusion reporter assays, NLS identification and cDNA screening identifying the ARC complex component (TIG-1/ARC105)\",\n      \"pmids\": [\"11024300\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single tethered reporter assay without endogenous functional validation\", \"Native complex context and direct activator partners not defined\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Linking the Gal11/MED15 KIX domain to fatty-acid-dependent activation by Oaf1p connected the subunit to lipid-metabolism gene regulation and showed shared use of the KIX surface by distinct activators.\",\n      \"evidence\": \"Genetic deletion, NMR spectroscopy and fatty-acid growth assays in yeast\",\n      \"pmids\": [\"19056732\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the same mechanism operates at endogenous metabolic genes in metazoans not addressed here\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Mapping Gcn4 recruitment to multiple N-terminal Gal11 segments including KIX and a B-box established that activator-Mediator recruitment is additive and multivalent in vivo.\",\n      \"evidence\": \"In vitro binding, NMR chemical-shift analysis, site-directed mutagenesis and in vivo ChIP at ARG1\",\n      \"pmids\": [\"19940160\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of each segment to Pol II output not fully quantified\", \"Structural basis of B-box engagement not resolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defining the Gcn4-Gal11 interface as a 'fuzzy', dynamic, hydrophobic complex answered how a single Mediator surface accommodates diverse acidic activators without a fixed structure.\",\n      \"evidence\": \"NMR structural analysis with mutagenesis and functional validation in yeast\",\n      \"pmids\": [\"22195967\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality across non-acidic activators untested at this point\", \"How fuzzy binding translates to recruitment kinetics unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showing cooperative recruitment of holo-Mediator to HSP promoters and essential tail-module functions defined MED15 as a critical, partly module-autonomous recruitment hub.\",\n      \"evidence\": \"ChIP and genetic deletion/truncation, plus N-Degron depletion with transcriptome profiling and cell-cycle analysis in S. cerevisiae\",\n      \"pmids\": [\"23447536\", \"23991176\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of tail-module essentiality independent of Head/Middle modules unknown\", \"Direct vs indirect effects on Ace2 targets not dissected\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Loss-of-function studies extended MED15 function to mammalian SREBP/VP16 and p53/p21 activation and to xenobiotic detoxification and innate immunity in C. elegans, establishing conserved roles in metabolic and stress-response transcription.\",\n      \"evidence\": \"siRNA knockdown/rescue, co-localization and ChIP in human cells; RNAi screen and infection survival assays in C. elegans\",\n      \"pmids\": [\"25382556\", \"24875643\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether MED15 acts directly at these promoters or via complex integrity unclear\", \"Mechanism connecting detoxification and immunity gene programs not defined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identifying MED15 as a TGF-β-responsive regulator of p-SMAD3 nuclear shuttling and proliferation tied the subunit to oncogenic signaling in prostate cancer.\",\n      \"evidence\": \"siRNA/shRNA knockdown, proliferation assays, IHC and Western blot for p-SMAD3\",\n      \"pmids\": [\"24374838\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct MED15-SMAD3 interaction not demonstrated\", \"Whether effect is Mediator-dependent unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrating metal-stimulated MED15/MDT-15 cooperation with HIZR-1 and conserved binding at metallothionein/zinc-transporter genes generalized the activator-bridging role to metal-responsive transcription across species.\",\n      \"evidence\": \"Yeast two-hybrid, qRT-PCR, reporter and gain/loss-of-function genetics in C. elegans plus mammalian ChIP and human cell knockdown\",\n      \"pmids\": [\"31815936\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of metal-enhanced MDT-15/HIZR-1 binding not resolved\", \"Whether mammalian orthologs use the same nuclear receptor interface unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showing that Gal4 and Gcn4 use the same fuzzy mechanism while the structured partner dictates interaction type clarified that Mediator surfaces, not the activators alone, define binding mode.\",\n      \"evidence\": \"NMR chemical-shift perturbation and binding assays with multiple activation domains and the Gal80 repressor\",\n      \"pmids\": [\"33850123\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative link between fuzzy affinity and transcriptional output not established\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defining a glutamine-rich IDR plus hydrophobic motif as drivers of liquid-like nuclear condensates, and a coiled-coil PrLD that templates prion-like amyloid recruitment, revealed a phase-separation/aggregation axis governing MED15 behavior.\",\n      \"evidence\": \"Live-cell imaging, FRAP, optodroplet and domain-deletion assays with DYRK3 overexpression; biophysical dimerization and amyloid assays with coiled-coil mutagenesis\",\n      \"pmids\": [\"34789250\", \"33772081\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional role of condensates in active transcription not established\", \"Physiological triggers of prion-like conversion unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Reciprocal binding to Nkx6-1 and NeuroD1 and conditional knockout phenotypes established a tissue-specific MED15 requirement for pancreatic β-cell maturation.\",\n      \"evidence\": \"ChIP-seq, co-IP, β-cell-specific conditional knockout mouse and human ESC-derived β-like cell overexpression\",\n      \"pmids\": [\"39379383\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which maturation genes depend directly on MED15 versus secondary effects not fully resolved\", \"Mechanism distinguishing maturation from mass/insulin output unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Placing MED15 in SREBP and HIF lipid-metabolic circuits, including a HIF feedback loop upstream of CPT1A and SREBP activation via PLK1/AKT, defined MED15 as a node coupling hypoxia and lipid biosynthesis in cancer.\",\n      \"evidence\": \"Co-IP, ChIP, siRNA knockdown and overexpression rescue in ccRCC; zebrafish med15 knockout with reporter and lipid-droplet assays and xenografts\",\n      \"pmids\": [\"38649345\", \"39947475\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct versus indirect contribution to SREBP and HIF target genes not fully separated\", \"Stoichiometry and physical basis of SREBP binding undefined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrating intrinsic promoter selectivity toward fuzzy-nucleosome regions and a nuclear Moesin/actin/Hsf complex showed MED15 actively shapes target selection beyond passive activator recruitment.\",\n      \"evidence\": \"ChIP-seq with DBD-AD and DBD-Med15 fusions in yeast; co-IP, ChIP and RNAi in Drosophila with human ortholog validation\",\n      \"pmids\": [\"39187372\", \"39353569\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Chromatin features driving intrinsic preference not mechanistically defined\", \"Role of nuclear actin in the Moesin-Med15-Hsf complex unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identifying TGF-β/CDK1-driven phosphorylation at T603 as a switch controlled by FOXA1 binding established a post-translational mechanism linking MED15 to SASP gene expression, senescence and cognitive aging.\",\n      \"evidence\": \"T603A/T603D mutagenesis, co-IP, gene expression analysis and a mouse knock-in with behavioral assays\",\n      \"pmids\": [\"40825935\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How phosphorylation alters MED15 partner choice or condensate behavior unknown\", \"Direct CDK1-MED15 modification in vivo not structurally defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Reporting MED15 stabilization of YAP1 by attenuating TRIM11-mediated ubiquitination and stress-inducible MED15/YAP1 condensates connected MED15 protein turnover, EMT and condensate biology in bladder cancer.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, loss/gain-of-function, migration assays and condensate imaging\",\n      \"pmids\": [\"41685983\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which MED15 blocks TRIM11 on YAP1 unresolved\", \"Relationship between MED15 and YAP1 within Mediator not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How MED15's fuzzy activator binding, intrinsic promoter selectivity, condensate/prion-like properties and post-translational control (phosphorylation, TRIM11 ubiquitination) are integrated into a single regulatory logic at native genes remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified structural model connecting condensate state to activator selection\", \"Mechanism coupling T603 phosphorylation and TRIM11 turnover not established\", \"Whether disease-associated polyQ interactions (HTT, ATXN1) reflect physiological MED15 function is unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 3, 23]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 14, 19]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 4, 1]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [15, 13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [23, 7, 11]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [11, 12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 3, 23]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [2, 14, 18]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [3, 16, 18]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [8, 14, 19]}\n    ],\n    \"complexes\": [\"Mediator complex (tail module)\"],\n    \"partners\": [\"GCN4\", \"GAL4\", \"HSF1\", \"SREBP1\", \"NKX6-1\", \"NEUROD1\", \"TRIM11\", \"FOXA1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":6,"faith_total":6,"faith_pct":100.0}}