| 2011 |
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. |
NMR structural analysis combined with mutagenesis and functional studies in yeast |
Molecular cell |
High |
22195967
|
| 2009 |
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. |
In vitro binding assays, ChIP (Mediator recruitment in vivo), NMR chemical shift analysis, site-directed mutagenesis |
The Journal of biological chemistry |
High |
19940160
|
| 2008 |
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. |
Genetic deletion analysis, NMR spectroscopy, fatty acid growth assays |
The Journal of biological chemistry |
High |
19056732
|
| 2013 |
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. |
ChIP (chromatin immunoprecipitation), genetic deletion/truncation analysis in Saccharomyces cerevisiae |
The Journal of biological chemistry |
High |
23447536
|
| 2021 |
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. |
NMR chemical shift perturbation analysis, binding assays |
Nature communications |
High |
33850123
|
| 2006 |
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. |
Co-immunoprecipitation, ubiquitination assay, proteasome inhibitor treatment, transcriptional reporter assay |
FEBS letters |
Medium |
16904669
|
| 2013 |
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. |
Temperature-sensitive N-Degron mutants, global gene expression profiling, cell cycle analysis |
PloS one |
Medium |
23991176
|
| 2014 |
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. |
siRNA knockdown, immunostaining/co-localization, transcriptional reporter assay, ChIP |
Drug discoveries & therapeutics |
Medium |
25382556
|
| 2013 |
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. |
siRNA/shRNA knockdown, proliferation assays, immunohistochemistry, Western blot for p-SMAD3 |
International journal of cancer |
Medium |
24374838
|
| 2014 |
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. |
RNAi screen (1,420 genes), gene expression analysis, infection survival assays in C. elegans |
PLoS pathogens |
Medium |
24875643
|
| 2019 |
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. |
Yeast two-hybrid, qRT-PCR, reporter analysis, gain/loss-of-function genetics, ChIP (mammalian cells), siRNA knockdown in human cells |
PLoS genetics |
High |
31815936
|
| 2021 |
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. |
Live cell imaging, immunostaining, FRAP, optodroplet assay, domain deletion analysis, DYRK3 overexpression |
BMC biology |
Medium |
34789250
|
| 2021 |
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. |
Biophysical dimerization assays, amyloid aggregation assays, coiled-coil mutagenesis, fluorescence microscopy in human cells |
Communications biology |
Medium |
33772081
|
| 2024 |
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. |
ChIP-seq, co-immunoprecipitation, conditional knockout mouse, human ESC differentiation system |
Nature communications |
High |
39379383
|
| 2024 |
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. |
Co-immunoprecipitation, promoter binding assay (ChIP), siRNA knockdown, overexpression rescue experiments |
Cell death discovery |
Medium |
38649345
|
| 2024 |
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. |
ChIP-seq with DBD-AD fusions, direct DBD-Med15 fusions, genome-wide localization in budding yeast |
Nucleic acids research |
Medium |
39187372
|
| 2025 |
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. |
Site-directed mutagenesis (T603A/T603D), Co-immunoprecipitation, gene expression analysis, mouse knock-in model, behavioral assays |
Cell discovery |
Medium |
40825935
|
| 2024 |
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. |
Co-immunoprecipitation, ChIP, RNAi knockdown, gene expression analysis in Drosophila and human cells |
Open biology |
Medium |
39353569
|
| 2025 |
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. |
siRNA knockdown, zebrafish med15 knockout, reporter assays, lipid droplet quantification, tumor xenograft |
The Journal of biological chemistry |
Medium |
39947475
|
| 2024 |
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. |
Co-immunoprecipitation, ubiquitination assay, loss- and gain-of-function (siRNA/overexpression), migration assays, condensate imaging |
FASEB journal |
Medium |
41685983
|
| 2010 |
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. |
Loss-of-function genetic screen, mosaic clone analysis, gene expression analysis in Drosophila |
Genetics |
Medium |
20233856
|
| 2024 |
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. |
Truncation/deletion/synthetic allele analysis, phenotypic assays, gene expression analysis, transcription factor interaction assays, phase separation assays in yeast |
Molecular and cellular biology |
Medium |
39717019
|
| 2012 |
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. |
Co-immunoprecipitation, genetic suppressor analysis, gene expression analysis |
PloS one |
Low |
22291956
|
| 2000 |
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. |
Co-transfection reporter assay, Western blot, nuclear localization signal identification, cDNA library screening |
Gene |
Low |
11024300
|
| 2024 |
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. |
Multi-epitope immunocapture/co-immunoprecipitation, subcellular fractionation, mass spectrometry, Drosophila genetic modifier assays |
bioRxiv (preprint)preprint |
Low |
bio_10.1101_2024.09.07.611843
|
| 2025 |
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. |
Computational structure prediction, co-immunoprecipitation/interaction assays with domain mutants, aggregation assays, virtual screening and chemical compound validation |
bioRxiv (preprint)preprint |
Low |
bio_10.1101_2025.03.17.643445
|