{"gene":"PSMD11","run_date":"2026-04-28T19:45:45","timeline":{"discoveries":[{"year":2012,"finding":"Human embryonic stem cells (hESCs) exhibit elevated proteasome activity correlated with increased PSMD11 (Rpn6) protein levels and enhanced 26S/30S proteasome assembly. Ectopic expression of PSMD11 alone is sufficient to increase proteasome assembly and activity, establishing PSMD11 as a rate-limiting regulator of proteasome assembly. FOXO4 transcription factor (downstream of insulin/IGF-I signaling) regulates PSMD11 expression in hESCs, linking proteostasis to longevity pathways.","method":"Ectopic overexpression of PSMD11 with proteasome activity assays; immunoprecipitation of 26S/30S complexes; FOXO4 knockdown; proteasome inhibition with pluripotency marker readout","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (overexpression, proteasome assembly assays, transcription factor knockdown) in a high-impact study, independently supported by C. elegans RPN-6 ortholog data","pmids":["22972301"],"is_preprint":false},{"year":2015,"finding":"PKA (cAMP-dependent protein kinase) directly phosphorylates the 19S regulatory subunit Rpn6/PSMD11 at Ser14. This phosphorylation enhances 26S proteasome activity and the selective degradation of ubiquitinated proteins, short-lived proteins, and aggregation-prone neurodegenerative disease proteins (mutant FUS, SOD1, TDP43, tau). A phosphomimetic Rpn6 S14D mutant activates proteasomes, whereas a non-phosphorylatable S14A mutant decreases activity. cAMP-raising agents also increase formation of doubly-capped 26S proteasomes.","method":"In vitro PKA phosphorylation of purified 26S proteasomes; site-directed mutagenesis (S14D and S14A); proteasome activity assays with ubiquitinated substrates and peptides; protein phosphatase treatment; degradation assays in multiple mammalian cell lines","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution with mutagenesis, replicated across multiple cell lines and substrate types","pmids":["26669444"],"is_preprint":false},{"year":2019,"finding":"In vivo, diverse hormones and physiological states that raise cAMP (glucagon, epinephrine, vasopressin, fasting, exercise) activate 26S proteasomes through PKA-mediated phosphorylation of Rpn6/PSMD11 in a tissue-specific manner. Rpn6 phosphorylation and proteasome activation were demonstrated in hepatocytes, working hearts, skeletal muscles of exercising humans, electrically stimulated rat muscles, and kidney cells. PKA-knockout cells failed to respond to vasopressin, confirming the PKA→Rpn6 axis.","method":"In vivo and ex vivo proteasome activity assays; Rpn6 phosphorylation measurements by immunoblot; PKA knockout cells; hormone treatment of primary hepatocytes and intact tissues; exercise physiology samples","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — replicated across multiple tissues and physiological conditions with genetic (PKA KO) validation","pmids":["30782827"],"is_preprint":false},{"year":2004,"finding":"Yeast Rpn6p (PSMD11 ortholog) is essential for the structural integrity and assembly of the 19S lid complex. Temperature-sensitive rpn6 mutants accumulate a sub-lid complex containing only Rpn5p, Rpn8p, Rpn9p, and Rpn11p, demonstrating that Rpn6p is specifically required for the incorporation of Rpn3p, Rpn7p, Rpn12p, and Sem1p/Rpn15p into the lid. The defect is at the assembly level rather than in proteolytic function of pre-assembled proteasomes.","method":"Temperature-sensitive yeast mutants; affinity-purified 26S proteasome activity assays; polyubiquitinated substrate (Sic1p) degradation; native gel analysis of lid sub-complexes; in vivo protein degradation assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis with temperature-sensitive alleles, proteasome reconstitution, and sub-complex identification in a bona fide ortholog system","pmids":["15611133"],"is_preprint":false},{"year":2002,"finding":"Drosophila Rpn6 (PSMD11 ortholog) physically interacts with the COP9 signalosome subunit Alien/CSN2 via its PCI domain. Rpn6 is essential for Drosophila development, as P-element insertion and newly generated alleles are lethal. The temporal and spatial expression patterns of Rpn6 and alien/CSN2 overlap during development, consistent with an in vivo interaction between the 19S lid and COP9 signalosome.","method":"Yeast two-hybrid screen; PCI domain interaction mapping; P-element insertion mutant analysis; developmental expression pattern analysis","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 3 — yeast two-hybrid plus genetic loss-of-function, single study without reciprocal Co-IP in Drosophila cells","pmids":["12426099"],"is_preprint":false},{"year":2009,"finding":"PSMD11 was identified as a novel physical interaction partner of AMP-activated protein kinase (AMPK) by yeast two-hybrid screening of a human skeletal muscle cDNA library using constitutively active AMPKα2 as bait. Co-IP confirmed the physical interaction, and AMPK was shown to modify the phosphorylation status of PSMD11, suggesting AMPK regulates proteasome function through PSMD11.","method":"Yeast two-hybrid screening; co-immunoprecipitation; in vitro phosphorylation assays","journal":"The international journal of biochemistry & cell biology","confidence":"Medium","confidence_rationale":"Tier 3 — yeast two-hybrid confirmed by Co-IP, single lab study with phosphorylation modification shown","pmids":["19616115"],"is_preprint":false},{"year":2022,"finding":"The 1,2,4-oxadiazole derivative DDO-7263 (an Nrf2-ARE activator) directly binds Rpn6/PSMD11, as identified by affinity chromatography and mass spectrometry using biotin-labeled and fluorescein-based probes. DDO-7263 binding to Rpn6 blocks 26S proteasome assembly, preventing degradation of ubiquitinated Nrf2 and thereby activating the Nrf2 signaling pathway for cytoprotection.","method":"Affinity chromatography with biotin-labeled probe; mass spectrometry target identification; in vitro 26S proteasome assembly assays; Nrf2 ubiquitination and degradation assays","journal":"Journal of medicinal chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — chemical probe-based target identification with functional validation of assembly blockade, single study","pmids":["35253427"],"is_preprint":false},{"year":2018,"finding":"Homoharringtonine (HHT), a protein synthesis inhibitor, paradoxically induces rapid PSMD11 protein synthesis in pancreatic cancer cells (MiaPaCa-2, PANC-1) through activation of the MEK1/ERK1/2 signaling pathway. This acute PSMD11 upregulation protects cancer cells from HHT-induced apoptosis. Co-inhibition of MEK1/ERK1/2 with sorafenib improves HHT cytotoxicity in vitro and in a genetically engineered mouse model of pancreatic cancer.","method":"Western blot analysis of PSMD11 protein levels; MEK1/ERK1/2 pathway inhibition with sorafenib; in vitro proliferation/apoptosis assays; genetically engineered mouse model experiments","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 — mechanistic pathway placement (MEK1/ERK1/2 → PSMD11) validated with pharmacological inhibition in vitro and in vivo, single lab","pmids":["29665121"],"is_preprint":false},{"year":2020,"finding":"In a mouse epilepsy model, Psmd11 expression is downregulated in hippocampal tissues. Overexpression of Psmd11 improved spatial learning and memory, protected hippocampal neurons from injury, inhibited apoptosis, suppressed microglial/astrocyte activation, and reduced inflammatory responses. Mechanistically, Psmd11 inactivates the Wnt/β-catenin pathway. The lncRNA Peg13 upregulates Psmd11 by sponging miR-490-3p (which targets Psmd11 mRNA), establishing a Peg13/miR-490-3p/Psmd11/Wnt-β-catenin axis in epilepsy.","method":"Epileptic mouse model; stereotaxic overexpression; HE and Nissl staining; ELISA for cytokines; luciferase reporter assays for miR-490-3p/Psmd11 interaction; Western blot for Wnt/β-catenin pathway components","journal":"American journal of translational research","confidence":"Medium","confidence_rationale":"Tier 3 — loss/gain-of-function with phenotypic readouts and pathway placement, single lab study","pmids":["33437373"],"is_preprint":false},{"year":2019,"finding":"MicroRNA-451 directly targets PSMD11 (validated by dual-luciferase reporter assay). In high-glucose-treated glomerular mesangial cells, PSMD11 promotes inflammation and proliferation through NF-κB p65 signaling (as evidenced by increased p-IκBα, NF-κB p65, COX-2, and cyclinD1). miR-451 mimics suppress these effects, which are reversed by PSMD11 overexpression, establishing a miR-451/PSMD11/NF-κB axis.","method":"Dual-luciferase reporter assay; miR-451 mimic transfection; PSMD11 overexpression; ELISA for inflammatory cytokines; Western blot for NF-κB pathway; flow cytometry for cell cycle","journal":"Bioscience reports","confidence":"Medium","confidence_rationale":"Tier 3 — validated miRNA-target interaction with pathway placement, but single lab and single cell type study","pmids":["31652441"],"is_preprint":false}],"current_model":"PSMD11 (Rpn6) is a non-ATPase subunit of the 19S regulatory particle lid that acts as a rate-limiting determinant of 26S proteasome assembly and activity; its activity is acutely upregulated by PKA-mediated phosphorylation at Ser14 downstream of cAMP-raising hormonal signals (glucagon, epinephrine, vasopressin) and by the FOXO4 transcription factor in stem cells, while AMPK and MEK1/ERK1/2 pathways also modify its phosphorylation status and expression; PSMD11 additionally interfaces with COP9 signalosome subunits via its PCI domain and modulates downstream NF-κB and Wnt/β-catenin signaling in disease contexts."},"narrative":{"teleology":[{"year":2002,"claim":"Establishing that Rpn6 physically interfaces with the COP9 signalosome via its PCI domain addressed whether the 19S lid shares functional crosstalk with structurally related PCI-containing complexes.","evidence":"Yeast two-hybrid and PCI domain mapping in Drosophila; P-element insertion alleles showing developmental lethality","pmids":["12426099"],"confidence":"Medium","gaps":["Interaction detected by yeast two-hybrid without reciprocal Co-IP in Drosophila cells","Functional consequence of Rpn6–CSN2 interaction on proteasome or signalosome activity unknown","Not tested in mammalian systems"]},{"year":2004,"claim":"Defining Rpn6 as essential for lid assembly resolved how the 19S regulatory particle is built and identified the specific subunit recruitment step that depends on Rpn6.","evidence":"Temperature-sensitive yeast rpn6 mutants accumulating sub-lid complexes; native gel and affinity-purified proteasome analysis","pmids":["15611133"],"confidence":"High","gaps":["Structural basis for how Rpn6 bridges the sub-lid to late-incorporating subunits not resolved","Whether the assembly role is conserved quantitatively in mammalian cells was untested"]},{"year":2009,"claim":"Identifying AMPK as a PSMD11-binding kinase raised the possibility that metabolic energy sensing directly modulates proteasome function.","evidence":"Yeast two-hybrid screen with constitutively active AMPKα2 bait from human skeletal muscle library; Co-IP and in vitro phosphorylation","pmids":["19616115"],"confidence":"Medium","gaps":["Specific AMPK phosphorylation site(s) on PSMD11 not mapped","Functional consequence on proteasome activity not determined","Single-lab study without independent replication"]},{"year":2012,"claim":"Demonstrating that PSMD11 abundance is rate-limiting for 26S proteasome assembly in human stem cells established a direct link between proteostasis capacity and stem cell identity, with FOXO4 as the upstream transcriptional regulator.","evidence":"Ectopic PSMD11 overexpression increasing 26S/30S assembly and activity; FOXO4 knockdown reducing PSMD11; proteasome inhibition compromising pluripotency markers in hESCs","pmids":["22972301"],"confidence":"High","gaps":["Whether FOXO4-driven PSMD11 expression is the dominant mechanism in somatic tissues unknown","Contribution of other lid subunit levels to the rate-limiting step not fully dissected"]},{"year":2015,"claim":"Identifying Ser14 as the PKA phosphorylation site on Rpn6 that directly stimulates 26S proteasome activity provided the first acute, post-translational mechanism for hormonal regulation of proteasome function.","evidence":"In vitro PKA phosphorylation of purified 26S proteasomes; S14D phosphomimetic and S14A mutants; degradation of neurodegenerative-disease-associated substrates in multiple cell lines","pmids":["26669444"],"confidence":"High","gaps":["Structural mechanism by which Ser14 phosphorylation enhances gate opening or substrate engagement unresolved","Relative contribution of Rpn6-Ser14 versus other PKA proteasome targets not fully delineated"]},{"year":2018,"claim":"Finding that MEK1/ERK1/2 signaling acutely induces PSMD11 protein synthesis in cancer cells revealed an additional kinase pathway converging on PSMD11 expression, with therapeutic implications for drug resistance.","evidence":"Homoharringtonine treatment of pancreatic cancer cells; MEK1/ERK1/2 inhibition by sorafenib; in vivo validation in genetically engineered mouse model","pmids":["29665121"],"confidence":"Medium","gaps":["Mechanism of selective PSMD11 translational upregulation under global translation inhibition unexplained","Single-lab study in pancreatic cancer context"]},{"year":2019,"claim":"Demonstrating that diverse cAMP-raising hormones and physiological states activate proteasomes through Rpn6-Ser14 phosphorylation in vivo extended the PKA–Rpn6 axis from biochemistry to whole-organism physiology, encompassing liver, heart, skeletal muscle, and kidney.","evidence":"In vivo proteasome activity and Rpn6 phosphorylation in multiple tissues; PKA-knockout cells; fasting and exercise models; human muscle biopsies","pmids":["30782827"],"confidence":"High","gaps":["Tissue-specific quantitative contribution of Rpn6 phosphorylation versus transcriptional upregulation not resolved","Long-term physiological consequences of chronic Rpn6-Ser14 phosphorylation unexplored"]},{"year":2019,"claim":"Establishing that PSMD11 is a direct miR-451 target linked to NF-κB signaling in glomerular mesangial cells connected proteasome subunit expression to inflammatory pathway activation in diabetic nephropathy.","evidence":"Dual-luciferase reporter assay for miR-451/PSMD11; PSMD11 overexpression rescue; NF-κB pathway Western blots in high-glucose-treated mesangial cells","pmids":["31652441"],"confidence":"Medium","gaps":["Whether PSMD11 activates NF-κB via proteasome-mediated IκBα degradation or a proteasome-independent mechanism not distinguished","Single cell type and single lab"]},{"year":2022,"claim":"Identification of Rpn6/PSMD11 as the direct molecular target of the small molecule DDO-7263 that blocks 26S proteasome assembly validated PSMD11 as a druggable node for modulating Nrf2 stability.","evidence":"Affinity chromatography with biotin/fluorescein probes; mass spectrometry target identification; proteasome assembly and Nrf2 degradation assays","pmids":["35253427"],"confidence":"Medium","gaps":["Binding site and selectivity of DDO-7263 on Rpn6 not structurally resolved","In vivo pharmacokinetics and off-target effects not fully characterized"]},{"year":null,"claim":"The structural basis for how Ser14 phosphorylation and small-molecule binding to Rpn6 alter 26S proteasome conformation, gate opening, or substrate translocation remains unresolved, as does the functional significance of the AMPK–PSMD11 interaction.","evidence":"","pmids":[],"confidence":"High","gaps":["No cryo-EM or crystal structure of phospho-Ser14 Rpn6 within the 26S proteasome","AMPK phosphorylation site(s) and functional outcome on proteasome activity not mapped","Whether PSMD11 has proteasome-independent scaffolding roles in NF-κB or Wnt/β-catenin signaling is unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,3]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,3]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1,2]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,1,2,3]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,2,7]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[1,2,6]}],"complexes":["26S proteasome","19S regulatory particle lid"],"partners":["FOXO4","PRKACA","PRKAA2","CSN2","PSMD3","PSMD6","PSMD12"],"other_free_text":[]},"mechanistic_narrative":"PSMD11 (Rpn6) is a non-ATPase subunit of the 19S regulatory particle lid that serves as a rate-limiting determinant of 26S proteasome assembly and activity. Rpn6 is essential for incorporating a subset of lid subunits (Rpn3, Rpn7, Rpn12, Sem1/Rpn15) into the 19S complex, and its abundance directly controls the proportion of assembled, doubly-capped 26S proteasomes capable of degrading ubiquitinated substrates [PMID:15611133, PMID:22972301]. PKA-mediated phosphorylation at Ser14, triggered by cAMP-raising hormones (glucagon, epinephrine, vasopressin) and physiological states such as fasting and exercise, acutely stimulates 26S proteasome activity and enhances clearance of aggregation-prone proteins in a tissue-specific manner [PMID:26669444, PMID:30782827]. PSMD11 expression is transcriptionally regulated by FOXO4 in human embryonic stem cells and is additionally modulated by AMPK and MEK1/ERK1/2 signaling, positioning PSMD11 as a convergence point through which multiple signaling pathways tune cellular proteostasis [PMID:22972301, PMID:19616115, PMID:29665121]."},"prefetch_data":{"uniprot":{"accession":"O00231","full_name":"26S proteasome non-ATPase regulatory subunit 11","aliases":["26S proteasome regulatory subunit RPN6","26S proteasome regulatory subunit S9","26S proteasome regulatory subunit p44.5"],"length_aa":422,"mass_kda":47.5,"function":"Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair. In the complex, PSMD11 is required for proteasome assembly. Plays a key role in increased proteasome activity in embryonic stem cells (ESCs): its high expression in ESCs promotes enhanced assembly of the 26S proteasome, followed by higher proteasome activity","subcellular_location":"Nucleus; Cytoplasm, cytosol","url":"https://www.uniprot.org/uniprotkb/O00231/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/PSMD11","classification":"Common Essential","n_dependent_lines":1199,"n_total_lines":1208,"dependency_fraction":0.9925496688741722},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000108671","cell_line_id":"CID000123","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"nucleoplasm","grade":3}],"interactors":[{"gene":"PSMA1","stoichiometry":10.0},{"gene":"PSMA5","stoichiometry":10.0},{"gene":"PSMA6","stoichiometry":10.0},{"gene":"PSMB1","stoichiometry":10.0},{"gene":"PSMB2","stoichiometry":10.0},{"gene":"PSMB3","stoichiometry":10.0},{"gene":"PSMB4","stoichiometry":10.0},{"gene":"PSMB5","stoichiometry":10.0},{"gene":"PSMB7","stoichiometry":10.0},{"gene":"PSMC2","stoichiometry":10.0}],"url":"https://opencell.sf.czbiohub.org/target/CID000123","total_profiled":1310},"omim":[{"mim_id":"609618","title":"NONCODING REPRESSOR OF NFAT; NRON","url":"https://www.omim.org/entry/609618"},{"mim_id":"604449","title":"PROTEASOME 26S SUBUNIT, NON-ATPase, 11; PSMD11","url":"https://www.omim.org/entry/604449"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Golgi apparatus","reliability":"Approved"},{"location":"Perinuclear theca","reliability":"Additional"},{"location":"Principal piece","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PSMD11"},"hgnc":{"alias_symbol":["S9","p44.5","MGC3844","Rpn6"],"prev_symbol":[]},"alphafold":{"accession":"O00231","domains":[{"cath_id":"1.25.40","chopping":"1-96_108-121","consensus_level":"medium","plddt":73.1961,"start":1,"end":121},{"cath_id":"1.10.10.10","chopping":"343-391","consensus_level":"medium","plddt":86.7322,"start":343,"end":391},{"cath_id":"1.20.5","chopping":"393-422","consensus_level":"medium","plddt":90.1917,"start":393,"end":422}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O00231","model_url":"https://alphafold.ebi.ac.uk/files/AF-O00231-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O00231-F1-predicted_aligned_error_v6.png","plddt_mean":82.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PSMD11","jax_strain_url":"https://www.jax.org/strain/search?query=PSMD11"},"sequence":{"accession":"O00231","fasta_url":"https://rest.uniprot.org/uniprotkb/O00231.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O00231/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O00231"}},"corpus_meta":[{"pmid":"22972301","id":"PMC_22972301","title":"Increased proteasome activity in human embryonic stem cells is regulated by PSMD11.","date":"2012","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/22972301","citation_count":331,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9391153","id":"PMC_9391153","title":"Large conductance voltage- and calcium-dependent K+ channel, a distinct member of voltage-dependent ion channels with seven N-terminal transmembrane segments (S0-S6), an extracellular N terminus, and an intracellular (S9-S10) C terminus.","date":"1997","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/9391153","citation_count":248,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26669444","id":"PMC_26669444","title":"cAMP-induced phosphorylation of 26S proteasomes on Rpn6/PSMD11 enhances their activity and the degradation of misfolded proteins.","date":"2015","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/26669444","citation_count":202,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31053798","id":"PMC_31053798","title":"High-resolution, strand-specific R-loop mapping via S9.6-based DNA-RNA immunoprecipitation and high-throughput sequencing.","date":"2019","source":"Nature protocols","url":"https://pubmed.ncbi.nlm.nih.gov/31053798","citation_count":195,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"10471721","id":"PMC_10471721","title":"Genomic organization of the S locus: Identification and characterization of genes in SLG/SRK region of S(9) haplotype of Brassica campestris (syn. rapa).","date":"1999","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/10471721","citation_count":195,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"14691209","id":"PMC_14691209","title":"Potent estrogenic metabolites of bisphenol A and bisphenol B formed by rat liver S9 fraction: their structures and estrogenic potency.","date":"2003","source":"Toxicological sciences : an official journal of the Society of Toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/14691209","citation_count":133,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23784994","id":"PMC_23784994","title":"The sub-nanomolar binding of DNA-RNA hybrids by the single-chain Fv fragment of antibody S9.6.","date":"2013","source":"Journal of molecular recognition : JMR","url":"https://pubmed.ncbi.nlm.nih.gov/23784994","citation_count":126,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29289567","id":"PMC_29289567","title":"The Affinity of the S9.6 Antibody for Double-Stranded RNAs Impacts the Accurate Mapping of R-Loops in Fission Yeast.","date":"2017","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/29289567","citation_count":111,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"11452134","id":"PMC_11452134","title":"Metabolic activation of bisphenol A by rat liver S9 fraction.","date":"2001","source":"Toxicological sciences : an official journal of the Society of Toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/11452134","citation_count":109,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33830170","id":"PMC_33830170","title":"Recognition of RNA by the S9.6 antibody creates pervasive artifacts when imaging RNA:DNA hybrids.","date":"2021","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/33830170","citation_count":108,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"11925449","id":"PMC_11925449","title":"The conformationally flexible S9-S10 linker region in the core domain of p53 contains a novel MDM2 binding site whose mutation increases ubiquitination of p53 in vivo.","date":"2002","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11925449","citation_count":103,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9634092","id":"PMC_9634092","title":"Detection and assignment of proteins encoded by rice black streaked dwarf fijivirus S7, S8, S9 and S10.","date":"1998","source":"The Journal of general virology","url":"https://pubmed.ncbi.nlm.nih.gov/9634092","citation_count":102,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30782827","id":"PMC_30782827","title":"26S Proteasomes are rapidly activated by diverse hormones and physiological states that raise cAMP and cause Rpn6 phosphorylation.","date":"2019","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/30782827","citation_count":98,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16401077","id":"PMC_16401077","title":"Dermaseptin S9, an alpha-helical antimicrobial peptide with a hydrophobic core and cationic termini.","date":"2006","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16401077","citation_count":88,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35347133","id":"PMC_35347133","title":"Structural basis of R-loop recognition by the S9.6 monoclonal antibody.","date":"2022","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/35347133","citation_count":74,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"947902","id":"PMC_947902","title":"The isolation of eukaryotic ribosomal proteins. The purification and characterization of the 40 S ribosomal subunit proteins S2, S3, S4, S5, S6, S7, S8, S9, S13, S23/S24, S27, and S28.","date":"1976","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/947902","citation_count":72,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"20221446","id":"PMC_20221446","title":"Silencing of ribosomal protein S9 elicits a multitude of cellular responses inhibiting the growth of cancer cells subsequent to p53 activation.","date":"2010","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/20221446","citation_count":71,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"18056278","id":"PMC_18056278","title":"Cidofovir and (S)-9-[3-hydroxy-(2-phosphonomethoxy)propyl]adenine are highly effective inhibitors of vaccinia virus DNA polymerase when incorporated into the template strand.","date":"2007","source":"Antimicrobial agents and chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/18056278","citation_count":68,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"3373531","id":"PMC_3373531","title":"Probing the assembly of the 3' major domain of 16 S ribosomal RNA. Quaternary interactions involving ribosomal proteins S7, S9 and S19.","date":"1988","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/3373531","citation_count":67,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"2579333","id":"PMC_2579333","title":"The action of anticlastogens in human lymphocyte cultures and their modification by rat-liver S9 mix. II. Studies with vitamins C and E.","date":"1985","source":"Mutation research","url":"https://pubmed.ncbi.nlm.nih.gov/2579333","citation_count":67,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"1100389","id":"PMC_1100389","title":"Nucleotide sequences of Escherichia coli 16-S RNA associated with ribosomal proteins S7, S9, S10, S14 and S19.","date":"1975","source":"European journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/1100389","citation_count":64,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"15611133","id":"PMC_15611133","title":"Functional analysis of Rpn6p, a lid component of the 26 S proteasome, using temperature-sensitive rpn6 mutants of the yeast Saccharomyces cerevisiae.","date":"2004","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15611133","citation_count":61,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"14675435","id":"PMC_14675435","title":"A mutation in the nuclear-encoded plastid ribosomal protein S9 leads to early embryo lethality in maize.","date":"2004","source":"The Plant journal : for cell and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/14675435","citation_count":60,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"925037","id":"PMC_925037","title":"Isolation of eukaryotic ribosomal proteins. Purification and characterization of the 40 S ribosomal subunit proteins Sa, Sc, S3a, S3b, S5', S9, S10, S11, S12, S14, S15, S15', S16, S17, S18, S19, S20, S21, S26, S27', and S29.","date":"1977","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/925037","citation_count":60,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"4346030","id":"PMC_4346030","title":"Requirement of proteins S5 and S9 from 30S subunits for the ribosome-dependent GTPase activity of elongation factor G.","date":"1973","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/4346030","citation_count":57,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31699809","id":"PMC_31699809","title":"Comparative Proteomics Analysis of Human Liver Microsomes and S9 Fractions.","date":"2019","source":"Drug metabolism and disposition: the biological fate of chemicals","url":"https://pubmed.ncbi.nlm.nih.gov/31699809","citation_count":55,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"6946249","id":"PMC_6946249","title":"Greater effectiveness of hepatocyte and liver S9 preparations from hamsters than rat preparations in activating N-nitroso compounds to metabolites mutagenic to Salmonella.","date":"1981","source":"Journal of the National Cancer Institute","url":"https://pubmed.ncbi.nlm.nih.gov/6946249","citation_count":55,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23872582","id":"PMC_23872582","title":"Utility of rat liver S9 fractions to study skin-sensitizing prohaptens in a modified KeratinoSens assay.","date":"2013","source":"Toxicological sciences : an official journal of the Society of Toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/23872582","citation_count":52,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22896006","id":"PMC_22896006","title":"Assessment of metabolic stability using the rainbow trout (Oncorhynchus mykiss) liver S9 fraction.","date":"2012","source":"Current protocols in toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/22896006","citation_count":52,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17907785","id":"PMC_17907785","title":"NADPH-dependent covalent binding of [3H]paroxetine to human liver microsomes and S-9 fractions: identification of an electrophilic quinone metabolite of paroxetine.","date":"2007","source":"Chemical research in toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/17907785","citation_count":50,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"6392870","id":"PMC_6392870","title":"Mutagenicity of derivatives and metabolites of 1-nitropyrene: activation by rat liver S9 and bacterial enzymes.","date":"1984","source":"Mutation research","url":"https://pubmed.ncbi.nlm.nih.gov/6392870","citation_count":50,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"19293927","id":"PMC_19293927","title":"S9, a novel anticancer agent, exerts its anti-proliferative activity by interfering with both PI3K-Akt-mTOR signaling and microtubule cytoskeleton.","date":"2009","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/19293927","citation_count":49,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28594954","id":"PMC_28594954","title":"The monoclonal S9.6 antibody exhibits highly variable binding affinities towards different R-loop sequences.","date":"2017","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/28594954","citation_count":47,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"18521591","id":"PMC_18521591","title":"Cloning, expression, and characterization of a new xylanase with broad temperature adaptability from Streptomyces sp. S9.","date":"2008","source":"Applied microbiology and biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/18521591","citation_count":45,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26712374","id":"PMC_26712374","title":"The utility of metabolic activation mixtures containing human hepatic post-mitochondrial supernatant (S9) for in vitro genetic toxicity assessment.","date":"2015","source":"Mutagenesis","url":"https://pubmed.ncbi.nlm.nih.gov/26712374","citation_count":44,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9858674","id":"PMC_9858674","title":"Advantage of the use of human liver S9 in the Ames test.","date":"1999","source":"Mutation research","url":"https://pubmed.ncbi.nlm.nih.gov/9858674","citation_count":42,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30682400","id":"PMC_30682400","title":"Tools for studying the metabolism of new psychoactive substances for toxicological screening purposes - A comparative study using pooled human liver S9, HepaRG cells, and zebrafish larvae.","date":"2019","source":"Toxicology letters","url":"https://pubmed.ncbi.nlm.nih.gov/30682400","citation_count":41,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35459186","id":"PMC_35459186","title":"Circular RNA circ-MTHFD1L induces HR repair to promote gemcitabine resistance via the miR-615-3p/RPN6 axis in pancreatic ductal adenocarcinoma.","date":"2022","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/35459186","citation_count":39,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"1901992","id":"PMC_1901992","title":"Effects of capsaicin on rat liver S9-mediated metabolism and DNA binding of aflatoxin.","date":"1991","source":"Nutrition and cancer","url":"https://pubmed.ncbi.nlm.nih.gov/1901992","citation_count":38,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32766204","id":"PMC_32766204","title":"How to Study the Metabolism of New Psychoactive Substances for the Purpose of Toxicological Screenings-A Follow-Up Study Comparing Pooled Human Liver S9, HepaRG Cells, and Zebrafish Larvae.","date":"2020","source":"Frontiers in chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/32766204","citation_count":38,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26946220","id":"PMC_26946220","title":"Application of the TGx-28.65 transcriptomic biomarker to classify genotoxic and non-genotoxic chemicals in human TK6 cells in the presence of rat liver S9.","date":"2016","source":"Environmental and molecular mutagenesis","url":"https://pubmed.ncbi.nlm.nih.gov/26946220","citation_count":34,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"36109620","id":"PMC_36109620","title":"Lactobacillus plantarum S9 alleviates lipid profile, insulin resistance, and inflammation in high-fat diet-induced metabolic syndrome rats.","date":"2022","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/36109620","citation_count":33,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24009741","id":"PMC_24009741","title":"The flavonoid apigenin downregulates CDK1 by directly targeting ribosomal protein S9.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24009741","citation_count":33,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"118381","id":"PMC_118381","title":"Effects of the hepatic S9 fraction from aroclor-1254-treated rats on the mutagenicity of benzo[alpha]pyrene and 2-aminoanthracene in the Salmonella/microsome assay.","date":"1979","source":"Mutation research","url":"https://pubmed.ncbi.nlm.nih.gov/118381","citation_count":33,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"12426099","id":"PMC_12426099","title":"The proteasome regulatory particle subunit Rpn6 is required for Drosophila development and interacts physically with signalosome subunit Alien/CSN2.","date":"2002","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/12426099","citation_count":30,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"6402697","id":"PMC_6402697","title":"Spindle disturbances in mammalian cells. II. Induction of viable aneuploid/polyploid cells and multiple chromatid exchanges after treatment of V79 Chinese hamster cells with carbaryl. Modifying effects of glutathione and S9.","date":"1983","source":"Mutation research","url":"https://pubmed.ncbi.nlm.nih.gov/6402697","citation_count":30,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33437373","id":"PMC_33437373","title":"Long-noncoding RNA Peg13 alleviates epilepsy progression in mice via the miR-490-3p/Psmd11 axis to inactivate the Wnt/β-catenin pathway.","date":"2020","source":"American journal of translational research","url":"https://pubmed.ncbi.nlm.nih.gov/33437373","citation_count":28,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"12662906","id":"PMC_12662906","title":"Use of human liver S9 in the Ames test: assay of three procarcinogens using human S9 derived from multiple donors.","date":"2003","source":"Regulatory toxicology and pharmacology : RTP","url":"https://pubmed.ncbi.nlm.nih.gov/12662906","citation_count":28,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22829543","id":"PMC_22829543","title":"In vitro studies on the oxidative metabolism of 20(s)-ginsenoside Rh2 in human, monkey, dog, rat, and mouse liver microsomes, and human liver s9.","date":"2012","source":"Drug metabolism and disposition: the biological fate of chemicals","url":"https://pubmed.ncbi.nlm.nih.gov/22829543","citation_count":27,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8208127","id":"PMC_8208127","title":"Evaluation of pyrazole and ethanol induced S9 fraction in bacterial mutagenicity testing.","date":"1994","source":"Mutagenesis","url":"https://pubmed.ncbi.nlm.nih.gov/8208127","citation_count":26,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22519982","id":"PMC_22519982","title":"Comparison of metabolism-mediated effects of pyrrolizidine alkaloids in a HepG2/C3A cell-S9 co-incubation system and quantification of their glutathione conjugates.","date":"2012","source":"Xenobiotica; the fate of foreign compounds in biological systems","url":"https://pubmed.ncbi.nlm.nih.gov/22519982","citation_count":26,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"27364561","id":"PMC_27364561","title":"γH2AX and p53 responses in TK6 cells discriminate promutagens and nongenotoxicants in the presence of rat liver S9.","date":"2016","source":"Environmental and molecular mutagenesis","url":"https://pubmed.ncbi.nlm.nih.gov/27364561","citation_count":25,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23530111","id":"PMC_23530111","title":"Distinctive contributions of the ribosomal P-site elements m2G966, m5C967 and the C-terminal tail of the S9 protein in the fidelity of initiation of translation in Escherichia coli.","date":"2013","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/23530111","citation_count":25,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"3884974","id":"PMC_3884974","title":"Cloning and nucleotide sequencing of the genes for ribosomal proteins S9 (rpsI) and L13 (rplM) of Escherichia coli.","date":"1985","source":"Molecular & general genetics : MGG","url":"https://pubmed.ncbi.nlm.nih.gov/3884974","citation_count":24,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"2391501","id":"PMC_2391501","title":"Nucleotide sequence of segment S9 of the genome of rice gall dwarf virus.","date":"1990","source":"The Journal of general virology","url":"https://pubmed.ncbi.nlm.nih.gov/2391501","citation_count":24,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29665121","id":"PMC_29665121","title":"Homoharringtonine could induce quick protein synthesis of PSMD11 through activating MEK1/ERK1/2 signaling pathway in pancreatic cancer cells.","date":"2018","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/29665121","citation_count":23,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"19616115","id":"PMC_19616115","title":"Two-hybrid analysis identifies PSMD11, a non-ATPase subunit of the proteasome, as a novel interaction partner of AMP-activated protein kinase.","date":"2009","source":"The international journal of biochemistry & cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/19616115","citation_count":23,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32663515","id":"PMC_32663515","title":"PSMD11, PTPRM and PTPRB as novel biomarkers of pancreatic cancer progression.","date":"2020","source":"Biochimica et biophysica acta. General subjects","url":"https://pubmed.ncbi.nlm.nih.gov/32663515","citation_count":23,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"3821768","id":"PMC_3821768","title":"The effectiveness of S9 and microsomal mix on activation of cyclophosphamide to induce genotoxicity in human lymphocytes.","date":"1987","source":"Mutation research","url":"https://pubmed.ncbi.nlm.nih.gov/3821768","citation_count":22,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"7678915","id":"PMC_7678915","title":"Influence of S9 mix composition on the SOS response in Escherichia coli PQ37 by polycyclic aromatic hydrocarbons.","date":"1993","source":"Mutation research","url":"https://pubmed.ncbi.nlm.nih.gov/7678915","citation_count":22,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"7251593","id":"PMC_7251593","title":"Characterization of the binding of rat liver ribosomal proteins L6, L8, L19, S9, and S13 to 5.8 S ribosomal ribonucleic acid.","date":"1981","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/7251593","citation_count":22,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26188517","id":"PMC_26188517","title":"PUB22 and PUB23 U-BOX E3 ligases directly ubiquitinate RPN6, a 26S proteasome lid subunit, for subsequent degradation in Arabidopsis thaliana.","date":"2015","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/26188517","citation_count":21,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"7027031","id":"PMC_7027031","title":"Mutagenicity and rat-liver S9 demethylation kinetics of N-nitrosomethylaniline and its ring-substituted derivatives.","date":"1981","source":"Mutation research","url":"https://pubmed.ncbi.nlm.nih.gov/7027031","citation_count":21,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23719930","id":"PMC_23719930","title":"Inhibition of pathogenic bacterial biofilm by biosurfactant produced by Lysinibacillus fusiformis S9.","date":"2013","source":"Bioprocess and biosystems engineering","url":"https://pubmed.ncbi.nlm.nih.gov/23719930","citation_count":21,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23285058","id":"PMC_23285058","title":"Elucidation of motifs in ribosomal protein S9 that mediate its nucleolar localization and binding to NPM1/nucleophosmin.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23285058","citation_count":20,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"6865998","id":"PMC_6865998","title":"Activation of nitrosamines and other carcinogens by mouse-liver S9, mouse hepatocytes and in the host-mediated assay produces different mutagenic responses in Salmonella TA1535.","date":"1983","source":"Mutation research","url":"https://pubmed.ncbi.nlm.nih.gov/6865998","citation_count":20,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"27321842","id":"PMC_27321842","title":"Identification of allocryptopine and protopine metabolites in rat liver S9 by high-performance liquid chromatography/quadrupole-time-of-flight mass spectrometry.","date":"2016","source":"Rapid communications in mass spectrometry : RCM","url":"https://pubmed.ncbi.nlm.nih.gov/27321842","citation_count":20,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31652441","id":"PMC_31652441","title":"MicroRNA-451 inhibits inflammation and proliferation of glomerular mesangial cells through down-regulating PSMD11 and NF-κB p65.","date":"2019","source":"Bioscience reports","url":"https://pubmed.ncbi.nlm.nih.gov/31652441","citation_count":19,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"3070287","id":"PMC_3070287","title":"Studies of an S9-based metabolic activation system used in the mouse lymphoma L5178Y cell mutation assay.","date":"1988","source":"Mutagenesis","url":"https://pubmed.ncbi.nlm.nih.gov/3070287","citation_count":19,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"3540655","id":"PMC_3540655","title":"Mutagenicity of nitracrine analogues in Salmonella typhimurium: mutational specificity and activation by bacterial enzymes and rat-liver S9.","date":"1987","source":"Mutation research","url":"https://pubmed.ncbi.nlm.nih.gov/3540655","citation_count":19,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"10786150","id":"PMC_10786150","title":"Cytotoxicity of dental resin monomers in the presence of S9 mix enzymes.","date":"1999","source":"Dental materials journal","url":"https://pubmed.ncbi.nlm.nih.gov/10786150","citation_count":19,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"34515688","id":"PMC_34515688","title":"Mapping R-Loops and RNA:DNA Hybrids with S9.6-Based Immunoprecipitation Methods.","date":"2021","source":"Journal of visualized experiments : JoVE","url":"https://pubmed.ncbi.nlm.nih.gov/34515688","citation_count":18,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"2423965","id":"PMC_2423965","title":"Multiple crosslinks of proteins S7, S9, S13 to domains 3 and 4 of 16S RNA in the 30S particle.","date":"1986","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/2423965","citation_count":18,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26263063","id":"PMC_26263063","title":"Formation of GSH-trapped reactive metabolites in human liver microsomes, S9 fraction, HepaRG-cells, and human hepatocytes.","date":"2015","source":"Journal of pharmaceutical and biomedical analysis","url":"https://pubmed.ncbi.nlm.nih.gov/26263063","citation_count":18,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33910564","id":"PMC_33910564","title":"Nitric oxide donor sodium nitroprusside-induced transcriptional changes and hypocrellin biosynthesis of Shiraia sp. S9.","date":"2021","source":"Microbial cell factories","url":"https://pubmed.ncbi.nlm.nih.gov/33910564","citation_count":18,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17711575","id":"PMC_17711575","title":"Genome-wide polysomal analysis of a yeast strain with mutated ribosomal protein S9.","date":"2007","source":"BMC genomics","url":"https://pubmed.ncbi.nlm.nih.gov/17711575","citation_count":17,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"336507","id":"PMC_336507","title":"Sequence determination of protein S9 from the Escherichia coli ribosome.","date":"1977","source":"Hoppe-Seyler's Zeitschrift fur physiologische Chemie","url":"https://pubmed.ncbi.nlm.nih.gov/336507","citation_count":17,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"6209573","id":"PMC_6209573","title":"The action of anticlastogens in human lymphocyte cultures and its modification by rat liver S9 mix. I. Studies with AET and sodium fluoride.","date":"1984","source":"Mutation research","url":"https://pubmed.ncbi.nlm.nih.gov/6209573","citation_count":17,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33741472","id":"PMC_33741472","title":"Effect of chain length and branching on the in vitro metabolism of a series of parabens in human liver S9, human skin S9, and human plasma.","date":"2021","source":"Regulatory toxicology and pharmacology : RTP","url":"https://pubmed.ncbi.nlm.nih.gov/33741472","citation_count":16,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31421535","id":"PMC_31421535","title":"In vitro biotransformation of pharmaceuticals and pesticides by trout liver S9 in the presence and absence of carbamazepine.","date":"2019","source":"Ecotoxicology and environmental safety","url":"https://pubmed.ncbi.nlm.nih.gov/31421535","citation_count":15,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"3309638","id":"PMC_3309638","title":"Comparative activation of 3,3'-dichlorobenzidine and related benzidines to mutagens in the Salmonella typhimurium assay by hepatic S9 and microsomes from rats pretreated with different inducers of cytochrome P-450.","date":"1987","source":"Mutation research","url":"https://pubmed.ncbi.nlm.nih.gov/3309638","citation_count":15,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32891393","id":"PMC_32891393","title":"New incorporation of the S9 metabolizing system into methods for detecting acetylcholinesterase inhibition.","date":"2020","source":"Analytica chimica acta","url":"https://pubmed.ncbi.nlm.nih.gov/32891393","citation_count":15,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23729652","id":"PMC_23729652","title":"Role of the ribosomal P-site elements of m²G966, m⁵C967, and the S9 C-terminal tail in maintenance of the reading frame during translational elongation in Escherichia coli.","date":"2013","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/23729652","citation_count":15,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"1287147","id":"PMC_1287147","title":"Mutagenicity of analgesics, their derivatives, and anti-inflammatory drugs with S-9 mix of several animal species.","date":"1992","source":"The Journal of Nihon University School of Dentistry","url":"https://pubmed.ncbi.nlm.nih.gov/1287147","citation_count":15,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29684454","id":"PMC_29684454","title":"Process desired functional attributes of an endoxylanase of GH10 family from a new strain of Aspergillus terreus S9.","date":"2018","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/29684454","citation_count":14,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"3568192","id":"PMC_3568192","title":"An investigation of the metabolism of N-nitroso-N-methylaniline by phenobarbital- and pyrazole-induced Sprague-Dawley rat liver and esophagus derived S-9.","date":"1987","source":"Chemico-biological interactions","url":"https://pubmed.ncbi.nlm.nih.gov/3568192","citation_count":14,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33548873","id":"PMC_33548873","title":"Hepatic in vitro metabolism of peptides; Comparison of human liver S9, hepatocytes and Upcyte hepatocytes with cyclosporine A, leuprorelin, desmopressin and cetrorelix as model compounds.","date":"2021","source":"Journal of pharmaceutical and biomedical analysis","url":"https://pubmed.ncbi.nlm.nih.gov/33548873","citation_count":14,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"36183361","id":"PMC_36183361","title":"The SLC26A9 inhibitor S9-A13 provides no evidence for a role of SLC26A9 in airway chloride secretion but suggests a contribution to regulation of ASL pH and gastric proton secretion.","date":"2022","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/36183361","citation_count":14,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33182016","id":"PMC_33182016","title":"Using a high-throughput method in the micronucleus assay to compare animal-free with rat-derived S9.","date":"2020","source":"The Science of the total environment","url":"https://pubmed.ncbi.nlm.nih.gov/33182016","citation_count":14,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"1747934","id":"PMC_1747934","title":"S9-mediated metabolism of 1-nitropyrene to a mutagen in Chinese hamster ovary cells by ring-oxidation under aerobic conditions and by nitroreduction under anaerobic conditions.","date":"1991","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/1747934","citation_count":14,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35253427","id":"PMC_35253427","title":"Target Fishing Reveals a Novel Mechanism of 1,2,4-Oxadiazole Derivatives Targeting Rpn6, a Subunit of 26S Proteasome.","date":"2022","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/35253427","citation_count":13,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"2882940","id":"PMC_2882940","title":"DNA repair synthesis in cultured fish and human cells exposed to fish S9-activated aromatic hydrocarbons.","date":"1987","source":"Comparative biochemistry and physiology. C, Comparative pharmacology and toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/2882940","citation_count":13,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"2002800","id":"PMC_2002800","title":"Arylamine activation following chronic ethanol ingestion by rats: studies on the liver S9, microsomal and cytosolic fractions and comparison with Aroclor 1254 pretreatment.","date":"1991","source":"Mutation research","url":"https://pubmed.ncbi.nlm.nih.gov/2002800","citation_count":13,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"331074","id":"PMC_331074","title":"Further evidence that the ribosomal 30S proteins S3, S5, S9, S11, S12, and S18 possess specific 16S RNA binding sites.","date":"1977","source":"Molecular & general genetics : MGG","url":"https://pubmed.ncbi.nlm.nih.gov/331074","citation_count":13,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"2517593","id":"PMC_2517593","title":"Effect of tannic acid on rat liver S9 mediated mutagenesis, metabolism and DNA binding of benzo[a]pyrene.","date":"1989","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/2517593","citation_count":13,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31701564","id":"PMC_31701564","title":"Comparison of the metabolism of 10 cosmetics-relevant chemicals in EpiSkin™ S9 subcellular fractions and in vitro human skin explants.","date":"2019","source":"Journal of applied toxicology : JAT","url":"https://pubmed.ncbi.nlm.nih.gov/31701564","citation_count":13,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23686223","id":"PMC_23686223","title":"Isolation and characterization of multiple F-box genes linked to the S9- and S10-RNase in apple (Malus × domestica Borkh.).","date":"2013","source":"Plant reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/23686223","citation_count":12,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38322170","id":"PMC_38322170","title":"Metabolic activation of short-chain alkyl N-nitrosamines using Aroclor 1254 or phenobarbital/beta-naphthoflavone-induced rat or hamster S9 - A comparative analysis.","date":"2024","source":"Toxicology reports","url":"https://pubmed.ncbi.nlm.nih.gov/38322170","citation_count":12,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26824293","id":"PMC_26824293","title":"Cloning, expression, and biochemical characterization of a cold-active GDSL-esterase of a Pseudomonas sp. S9 isolated from Spitsbergen island soil.","date":"2016","source":"Acta biochimica Polonica","url":"https://pubmed.ncbi.nlm.nih.gov/26824293","citation_count":12,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"11287298","id":"PMC_11287298","title":"Chromosome analysis of human spermatozoa following in vitro exposure to cyclophosphamide, benzo(a)pyrene and N-nitrosodimethylamine in the presence of rat liver S9.","date":"2001","source":"Mutation research","url":"https://pubmed.ncbi.nlm.nih.gov/11287298","citation_count":12,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17081983","id":"PMC_17081983","title":"Global, in vivo, and site-specific phosphorylation dynamics in signaling networks.","date":"2006","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/17081983","citation_count":2861,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"8811196","id":"PMC_8811196","title":"Structure and functions of the 20S and 26S proteasomes.","date":"1996","source":"Annual review of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8811196","citation_count":2108,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12167863","id":"PMC_12167863","title":"Isolation of a human gene that inhibits HIV-1 infection and is suppressed by the viral Vif protein.","date":"2002","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/12167863","citation_count":1924,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"16169070","id":"PMC_16169070","title":"A human protein-protein interaction network: a resource for annotating the proteome.","date":"2005","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/16169070","citation_count":1704,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12477932","id":"PMC_12477932","title":"Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.","date":"2002","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/12477932","citation_count":1479,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"19489727","id":"PMC_19489727","title":"Recognition and processing of ubiquitin-protein conjugates by the proteasome.","date":"2009","source":"Annual review of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19489727","citation_count":1398,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"19615732","id":"PMC_19615732","title":"Defining the human deubiquitinating enzyme interaction landscape.","date":"2009","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/19615732","citation_count":1282,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12808466","id":"PMC_12808466","title":"Broad antiretroviral defence by human APOBEC3G through lethal editing of nascent reverse transcripts.","date":"2003","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/12808466","citation_count":1236,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12809610","id":"PMC_12809610","title":"DNA deamination mediates innate immunity to retroviral infection.","date":"2003","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/12809610","citation_count":1150,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26186194","id":"PMC_26186194","title":"The BioPlex Network: A Systematic Exploration of the Human Interactome.","date":"2015","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/26186194","citation_count":1118,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"28514442","id":"PMC_28514442","title":"Architecture of the human interactome defines protein communities and disease networks.","date":"2017","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/28514442","citation_count":1085,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26496610","id":"PMC_26496610","title":"A human interactome in three quantitative dimensions organized by stoichiometries and abundances.","date":"2015","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/26496610","citation_count":1015,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"14564014","id":"PMC_14564014","title":"Induction of APOBEC3G ubiquitination and degradation by an HIV-1 Vif-Cul5-SCF complex.","date":"2003","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/14564014","citation_count":1006,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12808465","id":"PMC_12808465","title":"The cytidine deaminase CEM15 induces hypermutation in newly synthesized HIV-1 DNA.","date":"2003","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/12808465","citation_count":912,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"23503661","id":"PMC_23503661","title":"Landscape of the PARKIN-dependent ubiquitylome in response to mitochondrial depolarization.","date":"2013","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/23503661","citation_count":870,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"32296183","id":"PMC_32296183","title":"A reference map of the human binary protein interactome.","date":"2020","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/32296183","citation_count":849,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"29507755","id":"PMC_29507755","title":"VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation.","date":"2018","source":"Cell discovery","url":"https://pubmed.ncbi.nlm.nih.gov/29507755","citation_count":829,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"14528300","id":"PMC_14528300","title":"The antiretroviral enzyme APOBEC3G is degraded by the proteasome in response to HIV-1 Vif.","date":"2003","source":"Nature medicine","url":"https://pubmed.ncbi.nlm.nih.gov/14528300","citation_count":798,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12859895","id":"PMC_12859895","title":"Species-specific exclusion of APOBEC3G from HIV-1 virions by Vif.","date":"2003","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/12859895","citation_count":763,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"14702039","id":"PMC_14702039","title":"Complete sequencing and characterization of 21,243 full-length human cDNAs.","date":"2003","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/14702039","citation_count":754,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"17353931","id":"PMC_17353931","title":"Large-scale mapping of human protein-protein interactions by mass spectrometry.","date":"2007","source":"Molecular systems biology","url":"https://pubmed.ncbi.nlm.nih.gov/17353931","citation_count":733,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"33961781","id":"PMC_33961781","title":"Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.","date":"2021","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/33961781","citation_count":705,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"22939629","id":"PMC_22939629","title":"A census of human soluble protein complexes.","date":"2012","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/22939629","citation_count":689,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"14528301","id":"PMC_14528301","title":"HIV-1 Vif protein binds the editing enzyme APOBEC3G and induces its degradation.","date":"2003","source":"Nature medicine","url":"https://pubmed.ncbi.nlm.nih.gov/14528301","citation_count":679,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21873635","id":"PMC_21873635","title":"Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium.","date":"2011","source":"Briefings in bioinformatics","url":"https://pubmed.ncbi.nlm.nih.gov/21873635","citation_count":656,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"14527406","id":"PMC_14527406","title":"HIV-1 Vif blocks the antiviral activity of APOBEC3G by impairing both its translation and intracellular stability.","date":"2003","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/14527406","citation_count":607,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"22190034","id":"PMC_22190034","title":"Global landscape of HIV-human protein complexes.","date":"2011","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/22190034","citation_count":593,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12750511","id":"PMC_12750511","title":"Hypermutation of HIV-1 DNA in the absence of the Vif protein.","date":"2003","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/12750511","citation_count":570,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"33845483","id":"PMC_33845483","title":"Multilevel proteomics reveals host perturbations by SARS-CoV-2 and SARS-CoV.","date":"2021","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/33845483","citation_count":532,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"17110338","id":"PMC_17110338","title":"Hsp90 cochaperone Aha1 downregulation rescues misfolding of CFTR in cystic fibrosis.","date":"2006","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/17110338","citation_count":517,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":50735,"output_tokens":2744,"usd":0.096683},"stage2":{"model":"claude-opus-4-6","input_tokens":6080,"output_tokens":2211,"usd":0.128513},"total_usd":0.500879,"stage1_batch_id":"msgbatch_01SUR8NDzVrNmyszWyJeCct7","stage2_batch_id":"msgbatch_01G7Yfutko3cDWzejrwH5AMx","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":62074,"output_tokens":3890,"usd":0.122286},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":6808,"output_tokens":2729,"usd":0.153397}},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2012,\n      \"finding\": \"PSMD11 (RPN-6 in C. elegans) is expressed at elevated levels in human embryonic stem cells and is sufficient to increase 26S/30S proteasome assembly and activity when ectopically expressed. FOXO4 transcription factor regulates proteasome activity by modulating PSMD11 expression in hESCs.\",\n      \"method\": \"Ectopic overexpression, proteasome activity assays, proteasome assembly measurements, knockdown experiments with pluripotency marker readouts\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (overexpression, assembly assays, activity assays, transcription factor regulation), replicated in hESCs and C. elegans\",\n      \"pmids\": [\"22972301\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PKA phosphorylates PSMD11/Rpn6 at Ser14 in response to elevated cAMP, enhancing 26S proteasome activity and the degradation of ubiquitinated proteins, misfolded proteins, and aggregation-prone proteins associated with neurodegeneration. A phosphomimetic Rpn6 mutant activates proteasomes, while a nonphosphorylatable mutant decreases activity.\",\n      \"method\": \"In vitro PKA phosphorylation assays, purified 26S proteasome activity assays, phosphomimetic and nonphosphorylatable mutant overexpression, peptide and ubiquitinated substrate degradation assays, pharmacological cAMP manipulation in multiple cell lines\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro reconstitution with purified proteasomes, site-specific mutagenesis (Ser14), multiple orthogonal methods, replicated across cell lines\",\n      \"pmids\": [\"26669444\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Physiological hormones (glucagon, epinephrine) and exercise raise cAMP levels, leading to PKA-mediated phosphorylation of Rpn6/PSMD11 and increased 26S proteasome activity and selective degradation of short-lived proteins in hepatocytes, heart, and skeletal muscle in vivo. This was absent in cells lacking PKA.\",\n      \"method\": \"In vivo and ex vivo proteasome activity assays, Rpn6 phosphorylation measurements, genetic PKA knockout comparison, exercise model in humans and electrically stimulated rats, hormone treatment of mouse tissues\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — strong replicated evidence across multiple physiological conditions and tissues, PKA genetic knockout control\",\n      \"pmids\": [\"30782827\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Rpn6p (yeast ortholog of PSMD11) is an essential component of the 19S regulatory particle lid complex required for incorporation of Rpn3p, Rpn7p, Rpn12p, and Sem1p into the lid. Temperature-sensitive rpn6 mutants are defective in 26S proteasome assembly at restrictive temperature, resulting in accumulation of a partial lid complex (Rpn5p, Rpn8p, Rpn9p, Rpn11p).\",\n      \"method\": \"Temperature-sensitive yeast mutant analysis, affinity-purified proteasome activity assays, gel filtration/sedimentation analysis of proteasome assembly, in vivo protein degradation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean genetic mutants with defined assembly phenotypes, multiple orthogonal methods, functional rescue, yeast ortholog\",\n      \"pmids\": [\"15611133\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Drosophila Rpn6 (ortholog of PSMD11) physically interacts with Alien/CSN2 (a COP9 signalosome subunit) via its PCI domain, as demonstrated by yeast two-hybrid screening. Rpn6 is essential for Drosophila development.\",\n      \"method\": \"Yeast two-hybrid screening, PCI domain interaction analysis, P-element insertion mutant and allele generation with lethality phenotype\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — yeast two-hybrid single method, Drosophila ortholog with developmental phenotype but no direct biochemical reconstitution\",\n      \"pmids\": [\"12426099\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"PSMD11 (non-ATPase subunit of the 26S proteasome) physically interacts with the beta2 subunit of AMPK as identified by yeast two-hybrid screening of a human skeletal muscle cDNA library, and AMPK modifies the phosphorylation status of PSMD11.\",\n      \"method\": \"Yeast two-hybrid screening, co-immunoprecipitation, phosphorylation assay\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — yeast two-hybrid plus co-IP confirmation, single lab, no functional reconstitution\",\n      \"pmids\": [\"19616115\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"1,2,4-Oxadiazole derivative DDO-7263 binds directly to Rpn6/PSMD11, blocking assembly of the 26S proteasome and preventing degradation of ubiquitinated Nrf2, thereby activating the Nrf2 signaling pathway.\",\n      \"method\": \"Affinity chromatography with biotin-labeled probes, mass spectrometry target identification, in vitro affinity binding assays, proteasome assembly analysis\",\n      \"journal\": \"Journal of medicinal chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — affinity chromatography plus MS target ID plus in vitro binding confirmation, single lab\",\n      \"pmids\": [\"35253427\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Circ-MTHFD1L acts as a sponge for miR-615-3p, thereby upregulating PSMD11/RPN6 expression, which promotes homologous recombination DNA repair and gemcitabine resistance in pancreatic ductal adenocarcinoma cells.\",\n      \"method\": \"Dual-luciferase reporter assay, FISH, RNA immunoprecipitation, siRNA knockdown with functional rescue, drug sensitivity assays\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — multiple methods confirming ceRNA axis, functional rescue experiments, single lab\",\n      \"pmids\": [\"35459186\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PSMD11 (Psmd11) is a downstream target of miR-490-3p, and lncRNA Peg13 acts as a sponge for miR-490-3p to upregulate Psmd11. Overexpression of Psmd11 in epileptic mice inhibits neuronal apoptosis, suppresses microglial/astrocyte activation, reduces inflammation, and inactivates the Wnt/β-catenin pathway in hippocampal tissue.\",\n      \"method\": \"Epileptic mouse model, luciferase reporter assay, overexpression/knockdown with HE staining, Nissl staining, ELISA, western blot\",\n      \"journal\": \"American journal of translational research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, mechanistic pathway placement is indirect (Wnt/β-catenin), limited orthogonal validation of direct PSMD11 mechanism\",\n      \"pmids\": [\"33437373\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"miR-451 directly targets PSMD11 (identified by dual luciferase reporter assay), and downregulation of PSMD11 by miR-451 suppresses NF-κB p65 signaling, reducing inflammation and proliferation in glomerular mesangial cells under high-glucose conditions.\",\n      \"method\": \"Dual luciferase reporter assay, qRT-PCR, western blot, MTT assay, flow cytometry, ELISA\",\n      \"journal\": \"Bioscience reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, miRNA-target validation by luciferase assay, downstream pathway placement indirect\",\n      \"pmids\": [\"31652441\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Homoharringtonine (HHT) paradoxically induces rapid protein synthesis of PSMD11 through activation of the MEK1/ERK1/2 signaling pathway in pancreatic cancer cells, providing a survival mechanism that limits HHT-induced apoptosis.\",\n      \"method\": \"Western blot, MEK1/ERK1/2 pathway inhibition with sorafenib, in vitro and in vivo (genetically engineered mouse) combination treatment\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, mechanism linking ERK to PSMD11 protein synthesis is not directly demonstrated at molecular level\",\n      \"pmids\": [\"29665121\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PSMD11 (Rpn6) is a critical non-ATPase subunit of the 19S regulatory particle lid that is required for full 26S proteasome assembly; its expression level determines proteasome assembly efficiency and activity, and it is acutely activated by PKA-mediated phosphorylation at Ser14 downstream of cAMP-raising hormones and physiological stimuli, thereby enhancing degradation of ubiquitinated, short-lived, and misfolded proteins; PSMD11 expression is transcriptionally controlled by FOXO4 in stem cells, and the protein also interacts with AMPK and with the COP9 signalosome subunit CSN2 via its PCI domain.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll systematically classify each paper before extracting discoveries.\n\n**Classification of key papers:**\n\n- PMID:22972301 — KEEP (PSMD11/Rpn6 in hESC proteasome activity)\n- PMID:26669444 — KEEP (PKA phosphorylates Rpn6/PSMD11 at Ser14)\n- PMID:30782827 — KEEP (Rpn6/PSMD11 phosphorylation by PKA in physiological contexts)\n- PMID:15611133 — KEEP (yeast Rpn6p/PSMD11 ortholog, assembly function)\n- PMID:12426099 — KEEP (Drosophila Rpn6/PSMD11 ortholog, PCI domain interaction)\n- PMID:35253427 — KEEP (DDO-7263 binds Rpn6/PSMD11 to block 26S assembly)\n- PMID:19616115 — KEEP (AMPK interacts with PSMD11, modifies phosphorylation)\n- PMID:29665121 — KEEP (HHT induces PSMD11 via MEK1/ERK1/2)\n- PMID:35459186 — KEEP (circ-MTHFD1L/miR-615-3p/RPN6 axis — but this is about a circRNA regulating PSMD11 expression; the mechanistic finding about PSMD11 itself is that it promotes HR repair/gemcitabine resistance)\n- PMID:33437373 — KEEP (Psmd11 overexpression in epilepsy, inactivates Wnt/β-catenin)\n- PMID:31652441 — KEEP (miR-451 targets PSMD11, NF-κB signaling)\n- PMID:26188517 — EXCLUDE (Arabidopsis RPN6, plant-specific E3 ligase context — symbol collision in plants)\n- PMID:17081983 — KEEP (phosphoproteomics identifying PSMD11 phosphorylation sites)\n\nPapers about S9 antibody, liver S9 fractions, ribosomal protein S9 (bacterial/eukaryotic ribosomal), bisphenol S9, dermaseptin S9, Brassica S locus, etc. — all EXCLUDE (alias/symbol collisions).\n\nPMID:9391153 (MaxiK channels), PMID:31053798 (R-loop mapping), PMID:10471721 (Brassica S locus) — EXCLUDE.\n\nThe gene2pubmed papers about APOBEC3G/CEM15/HIV — EXCLUDE (these are about CEM15/APOBEC3G, not PSMD11).\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2012,\n      \"finding\": \"Human embryonic stem cells (hESCs) exhibit elevated proteasome activity correlated with increased PSMD11 (Rpn6) protein levels and enhanced 26S/30S proteasome assembly. Ectopic expression of PSMD11 alone is sufficient to increase proteasome assembly and activity, establishing PSMD11 as a rate-limiting regulator of proteasome assembly. FOXO4 transcription factor (downstream of insulin/IGF-I signaling) regulates PSMD11 expression in hESCs, linking proteostasis to longevity pathways.\",\n      \"method\": \"Ectopic overexpression of PSMD11 with proteasome activity assays; immunoprecipitation of 26S/30S complexes; FOXO4 knockdown; proteasome inhibition with pluripotency marker readout\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (overexpression, proteasome assembly assays, transcription factor knockdown) in a high-impact study, independently supported by C. elegans RPN-6 ortholog data\",\n      \"pmids\": [\"22972301\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PKA (cAMP-dependent protein kinase) directly phosphorylates the 19S regulatory subunit Rpn6/PSMD11 at Ser14. This phosphorylation enhances 26S proteasome activity and the selective degradation of ubiquitinated proteins, short-lived proteins, and aggregation-prone neurodegenerative disease proteins (mutant FUS, SOD1, TDP43, tau). A phosphomimetic Rpn6 S14D mutant activates proteasomes, whereas a non-phosphorylatable S14A mutant decreases activity. cAMP-raising agents also increase formation of doubly-capped 26S proteasomes.\",\n      \"method\": \"In vitro PKA phosphorylation of purified 26S proteasomes; site-directed mutagenesis (S14D and S14A); proteasome activity assays with ubiquitinated substrates and peptides; protein phosphatase treatment; degradation assays in multiple mammalian cell lines\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with mutagenesis, replicated across multiple cell lines and substrate types\",\n      \"pmids\": [\"26669444\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In vivo, diverse hormones and physiological states that raise cAMP (glucagon, epinephrine, vasopressin, fasting, exercise) activate 26S proteasomes through PKA-mediated phosphorylation of Rpn6/PSMD11 in a tissue-specific manner. Rpn6 phosphorylation and proteasome activation were demonstrated in hepatocytes, working hearts, skeletal muscles of exercising humans, electrically stimulated rat muscles, and kidney cells. PKA-knockout cells failed to respond to vasopressin, confirming the PKA→Rpn6 axis.\",\n      \"method\": \"In vivo and ex vivo proteasome activity assays; Rpn6 phosphorylation measurements by immunoblot; PKA knockout cells; hormone treatment of primary hepatocytes and intact tissues; exercise physiology samples\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — replicated across multiple tissues and physiological conditions with genetic (PKA KO) validation\",\n      \"pmids\": [\"30782827\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Yeast Rpn6p (PSMD11 ortholog) is essential for the structural integrity and assembly of the 19S lid complex. Temperature-sensitive rpn6 mutants accumulate a sub-lid complex containing only Rpn5p, Rpn8p, Rpn9p, and Rpn11p, demonstrating that Rpn6p is specifically required for the incorporation of Rpn3p, Rpn7p, Rpn12p, and Sem1p/Rpn15p into the lid. The defect is at the assembly level rather than in proteolytic function of pre-assembled proteasomes.\",\n      \"method\": \"Temperature-sensitive yeast mutants; affinity-purified 26S proteasome activity assays; polyubiquitinated substrate (Sic1p) degradation; native gel analysis of lid sub-complexes; in vivo protein degradation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with temperature-sensitive alleles, proteasome reconstitution, and sub-complex identification in a bona fide ortholog system\",\n      \"pmids\": [\"15611133\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Drosophila Rpn6 (PSMD11 ortholog) physically interacts with the COP9 signalosome subunit Alien/CSN2 via its PCI domain. Rpn6 is essential for Drosophila development, as P-element insertion and newly generated alleles are lethal. The temporal and spatial expression patterns of Rpn6 and alien/CSN2 overlap during development, consistent with an in vivo interaction between the 19S lid and COP9 signalosome.\",\n      \"method\": \"Yeast two-hybrid screen; PCI domain interaction mapping; P-element insertion mutant analysis; developmental expression pattern analysis\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — yeast two-hybrid plus genetic loss-of-function, single study without reciprocal Co-IP in Drosophila cells\",\n      \"pmids\": [\"12426099\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"PSMD11 was identified as a novel physical interaction partner of AMP-activated protein kinase (AMPK) by yeast two-hybrid screening of a human skeletal muscle cDNA library using constitutively active AMPKα2 as bait. Co-IP confirmed the physical interaction, and AMPK was shown to modify the phosphorylation status of PSMD11, suggesting AMPK regulates proteasome function through PSMD11.\",\n      \"method\": \"Yeast two-hybrid screening; co-immunoprecipitation; in vitro phosphorylation assays\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — yeast two-hybrid confirmed by Co-IP, single lab study with phosphorylation modification shown\",\n      \"pmids\": [\"19616115\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The 1,2,4-oxadiazole derivative DDO-7263 (an Nrf2-ARE activator) directly binds Rpn6/PSMD11, as identified by affinity chromatography and mass spectrometry using biotin-labeled and fluorescein-based probes. DDO-7263 binding to Rpn6 blocks 26S proteasome assembly, preventing degradation of ubiquitinated Nrf2 and thereby activating the Nrf2 signaling pathway for cytoprotection.\",\n      \"method\": \"Affinity chromatography with biotin-labeled probe; mass spectrometry target identification; in vitro 26S proteasome assembly assays; Nrf2 ubiquitination and degradation assays\",\n      \"journal\": \"Journal of medicinal chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — chemical probe-based target identification with functional validation of assembly blockade, single study\",\n      \"pmids\": [\"35253427\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Homoharringtonine (HHT), a protein synthesis inhibitor, paradoxically induces rapid PSMD11 protein synthesis in pancreatic cancer cells (MiaPaCa-2, PANC-1) through activation of the MEK1/ERK1/2 signaling pathway. This acute PSMD11 upregulation protects cancer cells from HHT-induced apoptosis. Co-inhibition of MEK1/ERK1/2 with sorafenib improves HHT cytotoxicity in vitro and in a genetically engineered mouse model of pancreatic cancer.\",\n      \"method\": \"Western blot analysis of PSMD11 protein levels; MEK1/ERK1/2 pathway inhibition with sorafenib; in vitro proliferation/apoptosis assays; genetically engineered mouse model experiments\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic pathway placement (MEK1/ERK1/2 → PSMD11) validated with pharmacological inhibition in vitro and in vivo, single lab\",\n      \"pmids\": [\"29665121\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In a mouse epilepsy model, Psmd11 expression is downregulated in hippocampal tissues. Overexpression of Psmd11 improved spatial learning and memory, protected hippocampal neurons from injury, inhibited apoptosis, suppressed microglial/astrocyte activation, and reduced inflammatory responses. Mechanistically, Psmd11 inactivates the Wnt/β-catenin pathway. The lncRNA Peg13 upregulates Psmd11 by sponging miR-490-3p (which targets Psmd11 mRNA), establishing a Peg13/miR-490-3p/Psmd11/Wnt-β-catenin axis in epilepsy.\",\n      \"method\": \"Epileptic mouse model; stereotaxic overexpression; HE and Nissl staining; ELISA for cytokines; luciferase reporter assays for miR-490-3p/Psmd11 interaction; Western blot for Wnt/β-catenin pathway components\",\n      \"journal\": \"American journal of translational research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — loss/gain-of-function with phenotypic readouts and pathway placement, single lab study\",\n      \"pmids\": [\"33437373\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MicroRNA-451 directly targets PSMD11 (validated by dual-luciferase reporter assay). In high-glucose-treated glomerular mesangial cells, PSMD11 promotes inflammation and proliferation through NF-κB p65 signaling (as evidenced by increased p-IκBα, NF-κB p65, COX-2, and cyclinD1). miR-451 mimics suppress these effects, which are reversed by PSMD11 overexpression, establishing a miR-451/PSMD11/NF-κB axis.\",\n      \"method\": \"Dual-luciferase reporter assay; miR-451 mimic transfection; PSMD11 overexpression; ELISA for inflammatory cytokines; Western blot for NF-κB pathway; flow cytometry for cell cycle\",\n      \"journal\": \"Bioscience reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — validated miRNA-target interaction with pathway placement, but single lab and single cell type study\",\n      \"pmids\": [\"31652441\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PSMD11 (Rpn6) is a non-ATPase subunit of the 19S regulatory particle lid that acts as a rate-limiting determinant of 26S proteasome assembly and activity; its activity is acutely upregulated by PKA-mediated phosphorylation at Ser14 downstream of cAMP-raising hormonal signals (glucagon, epinephrine, vasopressin) and by the FOXO4 transcription factor in stem cells, while AMPK and MEK1/ERK1/2 pathways also modify its phosphorylation status and expression; PSMD11 additionally interfaces with COP9 signalosome subunits via its PCI domain and modulates downstream NF-κB and Wnt/β-catenin signaling in disease contexts.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"PSMD11 (Rpn6) is an essential non-ATPase subunit of the 19S regulatory particle lid that serves as a key determinant of 26S proteasome assembly, activity, and regulated protein degradation. In yeast, Rpn6 is required for incorporation of multiple lid subunits (Rpn3, Rpn7, Rpn12, Sem1) into the intact lid complex, and temperature-sensitive rpn6 mutants accumulate partial lid intermediates with defective 26S proteasome assembly [PMID:15611133]. PSMD11 expression levels directly control proteasome capacity: elevated PSMD11 in human embryonic stem cells is sufficient to increase 26S/30S assembly and activity, under transcriptional control by FOXO4 [PMID:22972301]. PKA-mediated phosphorylation of PSMD11 at Ser14 in response to cAMP-raising stimuli—including glucagon, epinephrine, and exercise—acutely enhances 26S proteasome activity and selective degradation of ubiquitinated, short-lived, and misfolded proteins across multiple tissues in vivo [PMID:26669444, PMID:30782827].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Establishing that Rpn6 is an essential developmental gene and identifying its PCI-domain-mediated physical interaction with the COP9 signalosome subunit CSN2 raised the question of whether Rpn6 bridges the proteasome lid and COP9 signalosome regulatory systems.\",\n      \"evidence\": \"Yeast two-hybrid screen and P-element insertion lethality in Drosophila\",\n      \"pmids\": [\"12426099\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Interaction with CSN2 demonstrated only by yeast two-hybrid without reciprocal biochemical reconstitution\",\n        \"Functional consequence of Rpn6–CSN2 interaction on proteasome or signalosome activity not determined\",\n        \"No mammalian validation of the Rpn6–CSN2 interaction\"\n      ]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Temperature-sensitive yeast mutants established that Rpn6 is required for a late step in 19S lid assembly, specifically the incorporation of Rpn3, Rpn7, Rpn12, and Sem1, resolving its structural role as a scaffold within the lid.\",\n      \"evidence\": \"Temperature-sensitive rpn6 mutants with gel filtration and sedimentation analysis of proteasome subcomplexes in S. cerevisiae\",\n      \"pmids\": [\"15611133\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Precise molecular contacts between Rpn6 and the subunits it recruits were not mapped\",\n        \"Whether Rpn6 catalyzes lid–base joining or only lid completion was not resolved\"\n      ]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Discovery that AMPK physically interacts with PSMD11 and modifies its phosphorylation introduced kinase-mediated regulation of the proteasome lid as a potential mechanism linking metabolic sensing to proteolysis.\",\n      \"evidence\": \"Yeast two-hybrid screen of human skeletal muscle library with co-immunoprecipitation and phosphorylation assay\",\n      \"pmids\": [\"19616115\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"AMPK phosphorylation site(s) on PSMD11 not mapped\",\n        \"Functional consequence of AMPK-mediated phosphorylation on proteasome activity not tested\",\n        \"Not independently replicated\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstrating that PSMD11 expression level is rate-limiting for 26S proteasome assembly and activity in human embryonic stem cells, and is controlled by FOXO4, linked proteasome capacity to stem cell identity and transcriptional regulation.\",\n      \"evidence\": \"Ectopic overexpression and knockdown in hESCs with proteasome assembly and activity assays; conservation in C. elegans\",\n      \"pmids\": [\"22972301\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether FOXO4 directly binds the PSMD11 promoter was not shown by ChIP\",\n        \"Mechanism by which elevated proteasome activity supports pluripotency versus differentiation not resolved\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identification of Ser14 as the PKA phosphorylation site on Rpn6/PSMD11 and demonstration that phosphomimetic versus nonphosphorylatable mutants bidirectionally control 26S proteasome activity provided a direct post-translational mechanism for acute proteasome activation.\",\n      \"evidence\": \"In vitro PKA phosphorylation of purified 26S proteasomes, site-directed mutagenesis, substrate degradation assays across multiple cell lines\",\n      \"pmids\": [\"26669444\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis for how Ser14 phosphorylation enhances proteasome activity not determined\",\n        \"Whether PKA phosphorylation alters gate opening, substrate engagement, or ATPase coupling was not distinguished\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Extending the PKA–Rpn6 axis to physiological hormones and exercise in vivo established that PSMD11 phosphorylation is a bona fide hormonal mechanism for enhancing selective protein degradation in liver, heart, and muscle.\",\n      \"evidence\": \"In vivo mouse tissue analysis after glucagon/epinephrine, human and rat exercise models, PKA-knockout genetic control\",\n      \"pmids\": [\"30782827\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Tissue-specific quantitative contribution of Rpn6 phosphorylation relative to other proteasome regulatory mechanisms not determined\",\n        \"Long-term consequences of sustained Rpn6 Ser14 phosphorylation not assessed\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identification of a small molecule (DDO-7263) that directly binds PSMD11 and blocks 26S proteasome assembly demonstrated that PSMD11 is a druggable node and confirmed its critical role in assembly from a pharmacological perspective; downstream Nrf2 stabilization provided a functional readout.\",\n      \"evidence\": \"Biotin-labeled affinity chromatography, mass spectrometry target ID, in vitro binding and proteasome assembly assays\",\n      \"pmids\": [\"35253427\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Binding site on PSMD11 not structurally resolved\",\n        \"Selectivity and off-target effects of DDO-7263 not fully profiled\",\n        \"Whether compound disrupts lid assembly or lid–base association not distinguished\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural mechanism by which Ser14 phosphorylation enhances proteasome activity and whether AMPK phosphorylation of PSMD11 has a distinct functional role from PKA phosphorylation remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No high-resolution structural data on phosphorylated PSMD11 in the context of the 26S holoenzyme\",\n        \"AMPK versus PKA phosphorylation site specificity and functional distinction not determined\",\n        \"Whether PSMD11 expression or phosphorylation is rate-limiting for proteasome activity in non-stem differentiated tissues in vivo is unclear\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\n        \"term_id\": \"GO:0005198\",\n        \"supporting_discovery_ids\": [0, 3]\n      }\n    ],\n    \"localization\": [\n      {\n        \"term_id\": \"GO:0005829\",\n        \"supporting_discovery_ids\": [1, 2, 3]\n      }\n    ],\n    \"pathway\": [\n      {\n        \"term_id\": \"R-HSA-392499\",\n        \"supporting_discovery_ids\": [0, 1, 2, 3, 6]\n      },\n      {\n        \"term_id\": \"R-HSA-162582\",\n        \"supporting_discovery_ids\": [1, 2]\n      }\n    ],\n    \"complexes\": [\n      \"26S proteasome\",\n      \"19S regulatory particle lid\"\n    ],\n    \"partners\": [\n      \"PRKACA\",\n      \"FOXO4\",\n      \"PRKAB2\",\n      \"GPS1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"PSMD11 (Rpn6) is a non-ATPase subunit of the 19S regulatory particle lid that serves as a rate-limiting determinant of 26S proteasome assembly and activity. Rpn6 is essential for incorporating a subset of lid subunits (Rpn3, Rpn7, Rpn12, Sem1/Rpn15) into the 19S complex, and its abundance directly controls the proportion of assembled, doubly-capped 26S proteasomes capable of degrading ubiquitinated substrates [PMID:15611133, PMID:22972301]. PKA-mediated phosphorylation at Ser14, triggered by cAMP-raising hormones (glucagon, epinephrine, vasopressin) and physiological states such as fasting and exercise, acutely stimulates 26S proteasome activity and enhances clearance of aggregation-prone proteins in a tissue-specific manner [PMID:26669444, PMID:30782827]. PSMD11 expression is transcriptionally regulated by FOXO4 in human embryonic stem cells and is additionally modulated by AMPK and MEK1/ERK1/2 signaling, positioning PSMD11 as a convergence point through which multiple signaling pathways tune cellular proteostasis [PMID:22972301, PMID:19616115, PMID:29665121].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Establishing that Rpn6 physically interfaces with the COP9 signalosome via its PCI domain addressed whether the 19S lid shares functional crosstalk with structurally related PCI-containing complexes.\",\n      \"evidence\": \"Yeast two-hybrid and PCI domain mapping in Drosophila; P-element insertion alleles showing developmental lethality\",\n      \"pmids\": [\"12426099\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Interaction detected by yeast two-hybrid without reciprocal Co-IP in Drosophila cells\",\n        \"Functional consequence of Rpn6–CSN2 interaction on proteasome or signalosome activity unknown\",\n        \"Not tested in mammalian systems\"\n      ]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Defining Rpn6 as essential for lid assembly resolved how the 19S regulatory particle is built and identified the specific subunit recruitment step that depends on Rpn6.\",\n      \"evidence\": \"Temperature-sensitive yeast rpn6 mutants accumulating sub-lid complexes; native gel and affinity-purified proteasome analysis\",\n      \"pmids\": [\"15611133\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis for how Rpn6 bridges the sub-lid to late-incorporating subunits not resolved\",\n        \"Whether the assembly role is conserved quantitatively in mammalian cells was untested\"\n      ]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identifying AMPK as a PSMD11-binding kinase raised the possibility that metabolic energy sensing directly modulates proteasome function.\",\n      \"evidence\": \"Yeast two-hybrid screen with constitutively active AMPKα2 bait from human skeletal muscle library; Co-IP and in vitro phosphorylation\",\n      \"pmids\": [\"19616115\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Specific AMPK phosphorylation site(s) on PSMD11 not mapped\",\n        \"Functional consequence on proteasome activity not determined\",\n        \"Single-lab study without independent replication\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstrating that PSMD11 abundance is rate-limiting for 26S proteasome assembly in human stem cells established a direct link between proteostasis capacity and stem cell identity, with FOXO4 as the upstream transcriptional regulator.\",\n      \"evidence\": \"Ectopic PSMD11 overexpression increasing 26S/30S assembly and activity; FOXO4 knockdown reducing PSMD11; proteasome inhibition compromising pluripotency markers in hESCs\",\n      \"pmids\": [\"22972301\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether FOXO4-driven PSMD11 expression is the dominant mechanism in somatic tissues unknown\",\n        \"Contribution of other lid subunit levels to the rate-limiting step not fully dissected\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identifying Ser14 as the PKA phosphorylation site on Rpn6 that directly stimulates 26S proteasome activity provided the first acute, post-translational mechanism for hormonal regulation of proteasome function.\",\n      \"evidence\": \"In vitro PKA phosphorylation of purified 26S proteasomes; S14D phosphomimetic and S14A mutants; degradation of neurodegenerative-disease-associated substrates in multiple cell lines\",\n      \"pmids\": [\"26669444\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural mechanism by which Ser14 phosphorylation enhances gate opening or substrate engagement unresolved\",\n        \"Relative contribution of Rpn6-Ser14 versus other PKA proteasome targets not fully delineated\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Finding that MEK1/ERK1/2 signaling acutely induces PSMD11 protein synthesis in cancer cells revealed an additional kinase pathway converging on PSMD11 expression, with therapeutic implications for drug resistance.\",\n      \"evidence\": \"Homoharringtonine treatment of pancreatic cancer cells; MEK1/ERK1/2 inhibition by sorafenib; in vivo validation in genetically engineered mouse model\",\n      \"pmids\": [\"29665121\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism of selective PSMD11 translational upregulation under global translation inhibition unexplained\",\n        \"Single-lab study in pancreatic cancer context\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrating that diverse cAMP-raising hormones and physiological states activate proteasomes through Rpn6-Ser14 phosphorylation in vivo extended the PKA–Rpn6 axis from biochemistry to whole-organism physiology, encompassing liver, heart, skeletal muscle, and kidney.\",\n      \"evidence\": \"In vivo proteasome activity and Rpn6 phosphorylation in multiple tissues; PKA-knockout cells; fasting and exercise models; human muscle biopsies\",\n      \"pmids\": [\"30782827\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Tissue-specific quantitative contribution of Rpn6 phosphorylation versus transcriptional upregulation not resolved\",\n        \"Long-term physiological consequences of chronic Rpn6-Ser14 phosphorylation unexplored\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Establishing that PSMD11 is a direct miR-451 target linked to NF-κB signaling in glomerular mesangial cells connected proteasome subunit expression to inflammatory pathway activation in diabetic nephropathy.\",\n      \"evidence\": \"Dual-luciferase reporter assay for miR-451/PSMD11; PSMD11 overexpression rescue; NF-κB pathway Western blots in high-glucose-treated mesangial cells\",\n      \"pmids\": [\"31652441\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether PSMD11 activates NF-κB via proteasome-mediated IκBα degradation or a proteasome-independent mechanism not distinguished\",\n        \"Single cell type and single lab\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identification of Rpn6/PSMD11 as the direct molecular target of the small molecule DDO-7263 that blocks 26S proteasome assembly validated PSMD11 as a druggable node for modulating Nrf2 stability.\",\n      \"evidence\": \"Affinity chromatography with biotin/fluorescein probes; mass spectrometry target identification; proteasome assembly and Nrf2 degradation assays\",\n      \"pmids\": [\"35253427\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Binding site and selectivity of DDO-7263 on Rpn6 not structurally resolved\",\n        \"In vivo pharmacokinetics and off-target effects not fully characterized\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis for how Ser14 phosphorylation and small-molecule binding to Rpn6 alter 26S proteasome conformation, gate opening, or substrate translocation remains unresolved, as does the functional significance of the AMPK–PSMD11 interaction.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No cryo-EM or crystal structure of phospho-Ser14 Rpn6 within the 26S proteasome\",\n        \"AMPK phosphorylation site(s) and functional outcome on proteasome activity not mapped\",\n        \"Whether PSMD11 has proteasome-independent scaffolding roles in NF-κB or Wnt/β-catenin signaling is unresolved\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1, 2, 3]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 2, 7]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [1, 2, 6]}\n    ],\n    \"complexes\": [\n      \"26S proteasome\",\n      \"19S regulatory particle lid\"\n    ],\n    \"partners\": [\n      \"FOXO4\",\n      \"PRKACA\",\n      \"PRKAA2\",\n      \"CSN2\",\n      \"PSMD3\",\n      \"PSMD6\",\n      \"PSMD12\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}