{"gene":"PSME3","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2008,"finding":"PA28gamma (PSME3) polymer form interacts directly with both MDM2 and p53, facilitating their physical interaction and promoting ubiquitination- and MDM2-dependent proteasomal degradation of p53. Elimination of endogenous PA28gamma in human cancer cells abrogates MDM2-mediated p53 degradation, increases p53 activity, and enhances apoptosis after DNA damage.","method":"Co-immunoprecipitation, siRNA knockdown, ubiquitination assays, apoptosis assays in human cancer cells","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, siRNA loss-of-function with defined molecular phenotype, multiple orthogonal methods in a single rigorous study","pmids":["18309296"],"is_preprint":false},{"year":2016,"finding":"PSME3 (11S proteasome subunit) is upregulated by NF-κB in macrophages downstream of TLR ligands during bacterial infections. PSME3 then directly binds to and destabilizes KLF2, a negative regulator of NF-κB transcriptional activity, creating a positive feedforward loop. This mechanism is proteolysis-dependent but ubiquitin-independent. Hematopoietic-specific loss of PSME3 renders hosts more susceptible to bacterial infections with increased bacterial burdens.","method":"Co-immunoprecipitation, siRNA knockdown, NF-κB reporter assays, in vivo mouse infection models, bone marrow transplantation experiments","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct binding demonstrated, loss-of-function in vivo and in vitro with defined molecular and phenotypic readouts, multiple orthogonal methods","pmids":["26776519"],"is_preprint":false},{"year":2011,"finding":"REG-gamma (PSME3) interacts in high stoichiometry with nuclear activation-induced deaminase (AID) in B cells. A stable stoichiometric AID-REG-gamma complex can be reconstituted in co-transformed bacteria. REG-gamma accelerates proteasomal degradation of AID in in vitro assays. REG-gamma deficiency results in increased AID accumulation and increased immunoglobulin class switching.","method":"Co-immunoprecipitation, bacterial reconstitution, in vitro proteasomal degradation assay, REG-gamma knockout mouse analysis, immunoglobulin class switch assay","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution of complex, in vitro degradation assay, genetic KO with defined cellular phenotype, multiple orthogonal methods","pmids":["22042974"],"is_preprint":false},{"year":2003,"finding":"PA28gamma (PSME3) directly binds MEKK3 (a MAP kinase kinase kinase) but not B-Raf. The PA28gamma-binding domain of MEKK3 maps to its N-terminal regulatory domain (amino acids 1-178). Expression of MEKK3 in Cos-7 cells increases endogenous and co-expressed PA28gamma protein levels, while kinase-deficient MEKK3 has no effect. In vitro assays indicate PA28gamma is a substrate for MEKK3-mediated phosphorylation.","method":"Co-immunoprecipitation, deletion mapping, in vitro kinase assay, overexpression in Cos-7 cells","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding demonstrated by Co-IP with domain mapping, in vitro kinase assay confirming phosphorylation, single lab","pmids":["12650640"],"is_preprint":false},{"year":2004,"finding":"The proteasome activation properties of recombinant REG-gamma (PSME3) depend on purification conditions. Prior to ammonium sulfate precipitation, REG-gamma activates only the trypsin-like catalytic subunit of the proteasome; afterwards it activates all three catalytic subunits. The expanded activation specificity is accompanied by reduced stability of the REG-gamma heptamer. Endogenous REG-gamma in mammalian cells is found to be largely monomeric. FLAG-REG-gamma expressed in COS7 cells forms oligomers with untagged REG-gamma, and mixed oligomers preferentially activate the trypsin-like subunit.","method":"In vitro proteasome activity assays, ammonium sulfate precipitation, co-immunoprecipitation from COS7 cells, biochemical fractionation of mammalian tissue extracts","journal":"Archives of biochemistry and biophysics","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic reconstitution with biochemical manipulation, single lab with multiple methods","pmids":["15111123"],"is_preprint":false},{"year":1997,"finding":"Mouse Ki (PSME3/PA28gamma) cDNA was cloned and sequenced. Northern blot analysis demonstrated broad tissue distribution with two differently sized transcripts (suggesting alternative splicing or alternate polyadenylation). Ki mRNA levels increase transiently in response to IFN-gamma in mouse H6 hepatoma cells, though to a lesser extent and more transiently than PA28alpha and PA28beta. Southern blot analysis indicates Ki is a single-copy gene.","method":"RT-PCR cloning, Northern blot, Southern blot, IFN-gamma stimulation experiments","journal":"Immunogenetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct molecular characterization of the gene/transcript, multiple methods, single lab","pmids":["9162094"],"is_preprint":false},{"year":2014,"finding":"siRNA-mediated knockdown of Psme3 in RAW264.7 macrophages and bone marrow-derived macrophages induced significant increases of cytokine production in S. aureus-challenged cells through enhancing NF-κB signaling activity. Psme3 is differentially expressed between S. aureus-susceptible (A/J) and resistant (C57BL/6J) mice, contributing to infection susceptibility.","method":"siRNA knockdown, NF-κB reporter assays, cytokine measurements, QTL analysis, qPCR in mouse models","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA loss-of-function with defined signaling phenotype, confirmed in multiple cell types, single lab","pmids":["24901344"],"is_preprint":false},{"year":2013,"finding":"miR-7 targets Psme3 (along with Skp2) to promote increased p27(KIP) levels and G1/S phase growth arrest in CHO cells. Down-regulation of Psme3 by miR-7 contributes to cell cycle arrest at the G1 to S transition.","method":"miRNA overexpression, flow cytometry cell cycle analysis, western blot for p27, target validation","journal":"PloS one","confidence":"Low","confidence_rationale":"Tier 3 / Weak — miRNA overexpression with downstream readout, Psme3 identified as a target but direct mechanistic validation of PSME3's role in p27 regulation limited","pmids":["23762407"],"is_preprint":false},{"year":2017,"finding":"Overexpression of PSME3 in MDA-MB-231 breast cancer cells induces epithelial-mesenchymal transition, increases expression of cancer stem cell markers, and promotes cell migration and invasion. PSME3 overexpression reduces chemotaxis of CD8+ T cells and induces T cell apoptosis in vitro. PSME3 knockdown increases CD8+ T cell infiltration and reduces subcutaneous tumor growth in vivo.","method":"Overexpression and knockdown experiments, migration/invasion assays, T cell chemotaxis assay, in vivo xenograft mouse model","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function in vitro and in vivo, multiple cellular phenotype readouts, single lab","pmids":["28529105"],"is_preprint":false},{"year":2023,"finding":"CP2c transcription factor is SUMOylated in a SUMO1-dependent manner, and SUMOylated CP2c is degraded through the ubiquitin-independent PSME3/20S proteasome system. SUMOylated PSME3 can also interact with CP2c to mediate its degradation via the 20S proteasomal pathway through mutual SUMO-SIM interactions. Precisely timed degradation of CP2c via the SUMO1/PSME3/20S proteasome axis is required for accurate cell cycle progression.","method":"Co-immunoprecipitation, SUMOylation assays, proteasome degradation assays, mutagenesis of SUMO sites, cell cycle analysis by flow cytometry","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1 / Strong — biochemical reconstitution of SUMO-mediated degradation, mutagenesis, multiple orthogonal methods establishing mechanism and functional consequence","pmids":["36706181"],"is_preprint":false},{"year":2021,"finding":"O-GlcNAc modification at serine 111 (S111) of Psme3 promotes proteasomal degradation of Ddx6, which is essential for processing body (P-body) assembly in mouse embryonic stem cells. Loss of S111 O-GlcNAcylation stabilizes Ddx6, increases P-body levels, and causes spontaneous exit from the pluripotent state. This establishes Psme3 O-GlcNAcylation as a regulatory switch for ESC pluripotency via P-body homeostasis.","method":"Site-specific mutagenesis (S111A), O-GlcNAc mass spectrometry, protein stability assays, P-body quantification, ESC pluripotency assays, Psme3 knockdown","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 / Strong — site-specific mutagenesis of PTM site, multiple orthogonal methods (MS, imaging, functional assays), clear mechanistic chain from modification to phenotype","pmids":["34260942"],"is_preprint":false},{"year":2020,"finding":"Up-regulation of PSME3 in cancer cells results in increased destruction of pioneer translation product (PTP)-derived peptides in the nucleus, enabling cancer cells to subvert immunosurveillance by reducing MHC-I peptide ligand availability from aberrantly spliced/transcribed mRNAs.","method":"PSME3 overexpression in cancer cells, MHC-I peptide presentation assays, immunosurveillance functional assays","journal":"Oncoimmunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function with functional antigen presentation readout, single lab, mechanistic link to nuclear proteasome activity","pmids":["32923122"],"is_preprint":false},{"year":2019,"finding":"PSME3 regulates TGFB1 secretion in pancreatic cancer cells by inhibiting activation protein-1 (AP-1) transcription factor activity. Conditioned medium from PSME3-knockdown pancreatic cancer cells suppresses pancreatic stellate cell proliferation by downregulating TGFB1 secretion. PSME3 is also involved in pancreatic cancer cell apoptosis.","method":"RNAi knockdown, PCR array, transcription factor activation assays, cell co-culture conditioned medium experiments, apoptosis assays","journal":"Journal of Cancer","confidence":"Low","confidence_rationale":"Tier 3 / Weak — knockdown with downstream readouts, AP-1 interaction inferred from TF reporter assay, single lab, no direct binding demonstrated","pmids":["31205573"],"is_preprint":false},{"year":2019,"finding":"Knockdown of PSME3 in colorectal cancer cells triggers cell cycle arrest at G2/M phase by downregulating cyclin B1 and CDK1 expression, thereby enhancing radiosensitivity of colorectal cancer cells.","method":"siRNA knockdown, flow cytometry cell cycle analysis, western blot for cyclin B1 and CDK1, clonogenic radiosensitivity assays","journal":"Experimental biology and medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, knockdown with downstream marker changes, no direct molecular mechanism linking PSME3 to cyclin B1/CDK1 established","pmids":["31630568"],"is_preprint":false},{"year":2010,"finding":"REG-gamma (PSME3) is broadly expressed across multiple mouse tissues, with highest expression in the testis. REG-gamma shows unique expression in a subset of neurons including retinal ganglion cells and Purkinje cells. REG-gamma deficiency in mice results in dose-dependent reduction in litter size, suggesting a role in reproductive function.","method":"Systematic tissue expression analysis by RT-PCR and immunohistochemistry, REG-gamma knockout mouse analysis","journal":"Journal of molecular cell biology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — tissue distribution and KO phenotype, no defined molecular mechanism for reproductive function","pmids":["20494959"],"is_preprint":false}],"current_model":"PSME3 (PA28gamma/REG-gamma) is the nuclear homo-heptameric activator cap of the 20S proteasome that mediates ubiquitin-independent, ATP-independent protein degradation; it binds and targets multiple substrates including p53 (facilitating MDM2-mediated degradation), AID (controlling immunoglobulin class switching), CP2c transcription factor (via a SUMO1/PSME3 axis required for cell cycle progression), and Ddx6 (regulated by O-GlcNAcylation at S111 to control P-body homeostasis and embryonic stem cell pluripotency); it also acts as a positive feedforward regulator of NF-κB by binding and destabilizing KLF2, and participates in antigen processing by degrading pioneer translation products in the nucleus to influence immunosurveillance."},"narrative":{"mechanistic_narrative":"PSME3 (PA28gamma/REG-gamma) is a nuclear activator of the 20S proteasome that drives ubiquitin- and ATP-independent degradation of a defined set of regulatory substrates, thereby coupling proteasome activity to cell cycle, immune, and developmental decisions [PMID:36706181, PMID:22042974]. As a heptameric proteasome activator, its catalytic output is tunable: recombinant REG-gamma activates only the trypsin-like proteasome subunit under conditions that favor the intact heptamer but gains broad activation of all three catalytic activities when heptamer stability is reduced, and endogenous REG-gamma exists largely as monomer that assembles into mixed oligomers [PMID:15111123]. PSME3 targets multiple substrates for destruction: it bridges MDM2 and p53 to promote ubiquitin- and MDM2-dependent p53 degradation, restraining p53 activity and apoptosis after DNA damage [PMID:18309296]; it forms a stoichiometric complex with activation-induced deaminase (AID) and accelerates its proteasomal turnover to limit immunoglobulin class switching [PMID:22042974]; and it mediates SUMO1-dependent degradation of the CP2c transcription factor through mutual SUMO–SIM interactions, a timed event required for accurate cell cycle progression [PMID:36706181]. PSME3 also acts as a positive feedforward regulator of NF-κB by binding and destabilizing the NF-κB repressor KLF2 in macrophages, a proteolysis-dependent but ubiquitin-independent mechanism important for antibacterial defense [PMID:26776519]. Its activity is itself controlled by post-translational modification: O-GlcNAcylation at serine 111 promotes PSME3-mediated degradation of Ddx6 to control P-body homeostasis and embryonic stem cell pluripotency [PMID:34260942], and PSME3 is a substrate of MEKK3 phosphorylation [PMID:12650640]. In cancer, elevated PSME3 enhances nuclear destruction of pioneer translation product–derived peptides, reducing MHC-I ligand availability and enabling immune evasion [PMID:32923122], and promotes EMT and tumor growth [PMID:28529105].","teleology":[{"year":1997,"claim":"Establishing the gene's molecular identity and expression behavior was the first step toward defining a distinct PA28 family member; cloning showed it is a broadly expressed single-copy gene whose transcription responds to IFN-gamma.","evidence":"RT-PCR cloning, Northern and Southern blot, IFN-gamma stimulation in mouse hepatoma cells","pmids":["9162094"],"confidence":"Medium","gaps":["No protein-level function or substrate defined","IFN-gamma response weaker than PA28alpha/beta, role unresolved"]},{"year":2003,"claim":"Identifying MEKK3 as a direct binding partner and kinase for PA28gamma raised the possibility that the activator is regulated by upstream signaling.","evidence":"Co-IP with deletion mapping and in vitro kinase assay in Cos-7 cells","pmids":["12650640"],"confidence":"Medium","gaps":["Functional consequence of phosphorylation not established","Phospho-site not mapped","Single lab"]},{"year":2004,"claim":"Biochemical reconstitution showed PA28gamma proteasome activation is conformation- and oligomerization-dependent, explaining how the activator can switch from trypsin-like-only to broad catalytic activation.","evidence":"In vitro proteasome activity assays with biochemical manipulation of heptamer stability and Co-IP of oligomers from COS7 cells","pmids":["15111123"],"confidence":"Medium","gaps":["Physiological trigger for heptamer-versus-monomer state unknown","In-cell relevance of the activation switch not tested"]},{"year":2008,"claim":"Demonstrating that PA28gamma bridges MDM2 and p53 to drive p53 degradation established a concrete substrate-targeting role linking the activator to the DNA-damage/apoptosis axis.","evidence":"Reciprocal Co-IP, siRNA knockdown, ubiquitination and apoptosis assays in human cancer cells","pmids":["18309296"],"confidence":"High","gaps":["Whether degradation requires direct 20S handoff vs MDM2-dependent ubiquitination not fully separated","Structural basis of the ternary complex unresolved"]},{"year":2010,"claim":"Systematic expression mapping and a knockout phenotype placed REG-gamma in specific tissues (notably testis and select neurons) and tied it to reproductive output.","evidence":"RT-PCR, immunohistochemistry, and litter-size analysis in REG-gamma knockout mice","pmids":["20494959"],"confidence":"Low","gaps":["No molecular mechanism for reproductive role","Substrate(s) in testis/neurons unidentified"]},{"year":2011,"claim":"Reconstituting a stable AID-REG-gamma complex and showing accelerated AID degradation defined a substrate controlling immunoglobulin class switching, broadening the activator's role into adaptive immunity.","evidence":"Co-IP, bacterial reconstitution of the complex, in vitro degradation assay, and class-switch assay in REG-gamma knockout mice","pmids":["22042974"],"confidence":"High","gaps":["Whether degradation is fully ubiquitin-independent in vivo not dissected","Regulation of complex formation unknown"]},{"year":2016,"claim":"Identifying KLF2 as a PSME3 target created a feedforward NF-κB amplification loop, showing the activator can promote rather than dampen inflammatory signaling during infection.","evidence":"Co-IP, siRNA, NF-κB reporters, and hematopoietic-specific loss in mouse bacterial infection models","pmids":["26776519"],"confidence":"High","gaps":["Whether KLF2 is degraded directly by the 20S-PSME3 complex vs indirectly not fully resolved","Structural determinants of KLF2 binding unknown"]},{"year":2021,"claim":"Mapping S111 O-GlcNAcylation as a switch controlling Ddx6 degradation showed PSME3 activity is itself gated by a PTM that links it to P-body homeostasis and stem cell pluripotency.","evidence":"S111A mutagenesis, O-GlcNAc mass spectrometry, stability and P-body assays, and pluripotency readouts in mouse ESCs","pmids":["34260942"],"confidence":"High","gaps":["Enzyme(s) writing/erasing S111 O-GlcNAc not defined in this context","How O-GlcNAc alters PSME3 substrate selectivity mechanistically unclear"]},{"year":2023,"claim":"Demonstrating SUMO1-dependent CP2c degradation via mutual SUMO-SIM interactions revealed a SUMO-coded routing mechanism by which PSME3 selects substrates for ubiquitin-independent 20S degradation during the cell cycle.","evidence":"Co-IP, SUMOylation and proteasome degradation assays, SUMO-site mutagenesis, and cell cycle analysis","pmids":["36706181"],"confidence":"High","gaps":["Generality of SUMO-SIM substrate selection beyond CP2c unknown","Timing control of CP2c degradation upstream of PSME3 not defined"]},{"year":null,"claim":"How PSME3 oligomerization state, phosphorylation, O-GlcNAcylation, and SUMOylation are coordinated to select among its diverse substrates (p53, AID, KLF2, CP2c, Ddx6) in different cell contexts remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No unified substrate-recognition code established","No structural model of substrate-loaded PSME3-20S complex","Interplay among the regulatory PTMs untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,2,9,10]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[4,9]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2,11]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,2,9]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[9,13]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,2,11]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,6]}],"complexes":["20S proteasome activator (PA28gamma/REG-gamma heptamer)"],"partners":["MDM2","TP53","AICDA","KLF2","CP2C","DDX6","MAP3K3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P61289","full_name":"Proteasome activator complex subunit 3","aliases":["11S regulator complex subunit gamma","REG-gamma","Activator of multicatalytic protease subunit 3","Ki nuclear autoantigen","Proteasome activator 28 subunit gamma","PA28g","PA28gamma"],"length_aa":254,"mass_kda":29.5,"function":"Subunit of the 11S REG-gamma (also called PA28-gamma) proteasome regulator, a doughnut-shaped homoheptamer which associates with the proteasome. 11S REG-gamma activates the trypsin-like catalytic subunit of the proteasome but inhibits the chymotrypsin-like and postglutamyl-preferring (PGPH) subunits. Facilitates the MDM2-p53/TP53 interaction which promotes ubiquitination- and MDM2-dependent proteasomal degradation of p53/TP53, limiting its accumulation and resulting in inhibited apoptosis after DNA damage. May also be involved in cell cycle regulation. Mediates CCAR2 and CHEK2-dependent SIRT1 inhibition (PubMed:25361978)","subcellular_location":"Nucleus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/P61289/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PSME3","classification":"Not Classified","n_dependent_lines":169,"n_total_lines":1208,"dependency_fraction":0.13990066225165562},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000131467","cell_line_id":"CID000101","localizations":[{"compartment":"nucleoplasm","grade":3}],"interactors":[{"gene":"MIF","stoichiometry":10.0},{"gene":"PSMA1","stoichiometry":10.0},{"gene":"PSMB1","stoichiometry":10.0},{"gene":"PSMB3","stoichiometry":10.0},{"gene":"PSMB7","stoichiometry":10.0},{"gene":"PSMA5","stoichiometry":4.0},{"gene":"PSMG3","stoichiometry":4.0},{"gene":"ANKRD54","stoichiometry":0.2},{"gene":"CAPZB","stoichiometry":0.2},{"gene":"CLK3","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000101","total_profiled":1310},"omim":[{"mim_id":"605129","title":"PROTEASOME ACTIVATOR SUBUNIT 3; PSME3","url":"https://www.omim.org/entry/605129"},{"mim_id":"601937","title":"NUCLEAR RECEPTOR COACTIVATOR 3; NCOA3","url":"https://www.omim.org/entry/601937"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Primary cilium","reliability":"Additional"},{"location":"Basal body","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PSME3"},"hgnc":{"alias_symbol":["Ki","PA28-gamma","REG-GAMMA","PA28G"],"prev_symbol":[]},"alphafold":{"accession":"P61289","domains":[{"cath_id":"1.20.120.180","chopping":"16-53_115-246","consensus_level":"medium","plddt":96.834,"start":16,"end":246}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P61289","model_url":"https://alphafold.ebi.ac.uk/files/AF-P61289-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P61289-F1-predicted_aligned_error_v6.png","plddt_mean":87.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PSME3","jax_strain_url":"https://www.jax.org/strain/search?query=PSME3"},"sequence":{"accession":"P61289","fasta_url":"https://rest.uniprot.org/uniprotkb/P61289.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P61289/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P61289"}},"corpus_meta":[{"pmid":"10653597","id":"PMC_10653597","title":"The Ki-67 protein: from the known and the unknown.","date":"2000","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/10653597","citation_count":3487,"is_preprint":false},{"pmid":"29322240","id":"PMC_29322240","title":"Ki-67: more than a proliferation marker.","date":"2018","source":"Chromosoma","url":"https://pubmed.ncbi.nlm.nih.gov/29322240","citation_count":685,"is_preprint":false},{"pmid":"11897369","id":"PMC_11897369","title":"The utility of Ki-67 and BrdU as proliferative markers of adult neurogenesis.","date":"2002","source":"Journal of neuroscience methods","url":"https://pubmed.ncbi.nlm.nih.gov/11897369","citation_count":654,"is_preprint":false},{"pmid":"16192605","id":"PMC_16192605","title":"Proliferation marker Ki-67 in early breast cancer.","date":"2005","source":"Journal of clinical oncology : official journal of the American Society of Clinical Oncology","url":"https://pubmed.ncbi.nlm.nih.gov/16192605","citation_count":650,"is_preprint":false},{"pmid":"27362226","id":"PMC_27362226","title":"Ki-67 acts as a biological surfactant to disperse mitotic chromosomes.","date":"2016","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/27362226","citation_count":418,"is_preprint":false},{"pmid":"30653951","id":"PMC_30653951","title":"Ki-67 protein as a tumour proliferation marker.","date":"2019","source":"Clinica chimica acta; 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\"discoveries\": [\n    {\n      \"year\": 2008,\n      \"finding\": \"PA28gamma (PSME3) polymer form interacts directly with both MDM2 and p53, facilitating their physical interaction and promoting ubiquitination- and MDM2-dependent proteasomal degradation of p53. Elimination of endogenous PA28gamma in human cancer cells abrogates MDM2-mediated p53 degradation, increases p53 activity, and enhances apoptosis after DNA damage.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, ubiquitination assays, apoptosis assays in human cancer cells\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, siRNA loss-of-function with defined molecular phenotype, multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"18309296\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PSME3 (11S proteasome subunit) is upregulated by NF-κB in macrophages downstream of TLR ligands during bacterial infections. PSME3 then directly binds to and destabilizes KLF2, a negative regulator of NF-κB transcriptional activity, creating a positive feedforward loop. This mechanism is proteolysis-dependent but ubiquitin-independent. Hematopoietic-specific loss of PSME3 renders hosts more susceptible to bacterial infections with increased bacterial burdens.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, NF-κB reporter assays, in vivo mouse infection models, bone marrow transplantation experiments\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct binding demonstrated, loss-of-function in vivo and in vitro with defined molecular and phenotypic readouts, multiple orthogonal methods\",\n      \"pmids\": [\"26776519\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"REG-gamma (PSME3) interacts in high stoichiometry with nuclear activation-induced deaminase (AID) in B cells. A stable stoichiometric AID-REG-gamma complex can be reconstituted in co-transformed bacteria. REG-gamma accelerates proteasomal degradation of AID in in vitro assays. REG-gamma deficiency results in increased AID accumulation and increased immunoglobulin class switching.\",\n      \"method\": \"Co-immunoprecipitation, bacterial reconstitution, in vitro proteasomal degradation assay, REG-gamma knockout mouse analysis, immunoglobulin class switch assay\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution of complex, in vitro degradation assay, genetic KO with defined cellular phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"22042974\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"PA28gamma (PSME3) directly binds MEKK3 (a MAP kinase kinase kinase) but not B-Raf. The PA28gamma-binding domain of MEKK3 maps to its N-terminal regulatory domain (amino acids 1-178). Expression of MEKK3 in Cos-7 cells increases endogenous and co-expressed PA28gamma protein levels, while kinase-deficient MEKK3 has no effect. In vitro assays indicate PA28gamma is a substrate for MEKK3-mediated phosphorylation.\",\n      \"method\": \"Co-immunoprecipitation, deletion mapping, in vitro kinase assay, overexpression in Cos-7 cells\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding demonstrated by Co-IP with domain mapping, in vitro kinase assay confirming phosphorylation, single lab\",\n      \"pmids\": [\"12650640\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"The proteasome activation properties of recombinant REG-gamma (PSME3) depend on purification conditions. Prior to ammonium sulfate precipitation, REG-gamma activates only the trypsin-like catalytic subunit of the proteasome; afterwards it activates all three catalytic subunits. The expanded activation specificity is accompanied by reduced stability of the REG-gamma heptamer. Endogenous REG-gamma in mammalian cells is found to be largely monomeric. FLAG-REG-gamma expressed in COS7 cells forms oligomers with untagged REG-gamma, and mixed oligomers preferentially activate the trypsin-like subunit.\",\n      \"method\": \"In vitro proteasome activity assays, ammonium sulfate precipitation, co-immunoprecipitation from COS7 cells, biochemical fractionation of mammalian tissue extracts\",\n      \"journal\": \"Archives of biochemistry and biophysics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic reconstitution with biochemical manipulation, single lab with multiple methods\",\n      \"pmids\": [\"15111123\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Mouse Ki (PSME3/PA28gamma) cDNA was cloned and sequenced. Northern blot analysis demonstrated broad tissue distribution with two differently sized transcripts (suggesting alternative splicing or alternate polyadenylation). Ki mRNA levels increase transiently in response to IFN-gamma in mouse H6 hepatoma cells, though to a lesser extent and more transiently than PA28alpha and PA28beta. Southern blot analysis indicates Ki is a single-copy gene.\",\n      \"method\": \"RT-PCR cloning, Northern blot, Southern blot, IFN-gamma stimulation experiments\",\n      \"journal\": \"Immunogenetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct molecular characterization of the gene/transcript, multiple methods, single lab\",\n      \"pmids\": [\"9162094\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"siRNA-mediated knockdown of Psme3 in RAW264.7 macrophages and bone marrow-derived macrophages induced significant increases of cytokine production in S. aureus-challenged cells through enhancing NF-κB signaling activity. Psme3 is differentially expressed between S. aureus-susceptible (A/J) and resistant (C57BL/6J) mice, contributing to infection susceptibility.\",\n      \"method\": \"siRNA knockdown, NF-κB reporter assays, cytokine measurements, QTL analysis, qPCR in mouse models\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA loss-of-function with defined signaling phenotype, confirmed in multiple cell types, single lab\",\n      \"pmids\": [\"24901344\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"miR-7 targets Psme3 (along with Skp2) to promote increased p27(KIP) levels and G1/S phase growth arrest in CHO cells. Down-regulation of Psme3 by miR-7 contributes to cell cycle arrest at the G1 to S transition.\",\n      \"method\": \"miRNA overexpression, flow cytometry cell cycle analysis, western blot for p27, target validation\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — miRNA overexpression with downstream readout, Psme3 identified as a target but direct mechanistic validation of PSME3's role in p27 regulation limited\",\n      \"pmids\": [\"23762407\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Overexpression of PSME3 in MDA-MB-231 breast cancer cells induces epithelial-mesenchymal transition, increases expression of cancer stem cell markers, and promotes cell migration and invasion. PSME3 overexpression reduces chemotaxis of CD8+ T cells and induces T cell apoptosis in vitro. PSME3 knockdown increases CD8+ T cell infiltration and reduces subcutaneous tumor growth in vivo.\",\n      \"method\": \"Overexpression and knockdown experiments, migration/invasion assays, T cell chemotaxis assay, in vivo xenograft mouse model\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function in vitro and in vivo, multiple cellular phenotype readouts, single lab\",\n      \"pmids\": [\"28529105\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CP2c transcription factor is SUMOylated in a SUMO1-dependent manner, and SUMOylated CP2c is degraded through the ubiquitin-independent PSME3/20S proteasome system. SUMOylated PSME3 can also interact with CP2c to mediate its degradation via the 20S proteasomal pathway through mutual SUMO-SIM interactions. Precisely timed degradation of CP2c via the SUMO1/PSME3/20S proteasome axis is required for accurate cell cycle progression.\",\n      \"method\": \"Co-immunoprecipitation, SUMOylation assays, proteasome degradation assays, mutagenesis of SUMO sites, cell cycle analysis by flow cytometry\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — biochemical reconstitution of SUMO-mediated degradation, mutagenesis, multiple orthogonal methods establishing mechanism and functional consequence\",\n      \"pmids\": [\"36706181\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"O-GlcNAc modification at serine 111 (S111) of Psme3 promotes proteasomal degradation of Ddx6, which is essential for processing body (P-body) assembly in mouse embryonic stem cells. Loss of S111 O-GlcNAcylation stabilizes Ddx6, increases P-body levels, and causes spontaneous exit from the pluripotent state. This establishes Psme3 O-GlcNAcylation as a regulatory switch for ESC pluripotency via P-body homeostasis.\",\n      \"method\": \"Site-specific mutagenesis (S111A), O-GlcNAc mass spectrometry, protein stability assays, P-body quantification, ESC pluripotency assays, Psme3 knockdown\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — site-specific mutagenesis of PTM site, multiple orthogonal methods (MS, imaging, functional assays), clear mechanistic chain from modification to phenotype\",\n      \"pmids\": [\"34260942\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Up-regulation of PSME3 in cancer cells results in increased destruction of pioneer translation product (PTP)-derived peptides in the nucleus, enabling cancer cells to subvert immunosurveillance by reducing MHC-I peptide ligand availability from aberrantly spliced/transcribed mRNAs.\",\n      \"method\": \"PSME3 overexpression in cancer cells, MHC-I peptide presentation assays, immunosurveillance functional assays\",\n      \"journal\": \"Oncoimmunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function with functional antigen presentation readout, single lab, mechanistic link to nuclear proteasome activity\",\n      \"pmids\": [\"32923122\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PSME3 regulates TGFB1 secretion in pancreatic cancer cells by inhibiting activation protein-1 (AP-1) transcription factor activity. Conditioned medium from PSME3-knockdown pancreatic cancer cells suppresses pancreatic stellate cell proliferation by downregulating TGFB1 secretion. PSME3 is also involved in pancreatic cancer cell apoptosis.\",\n      \"method\": \"RNAi knockdown, PCR array, transcription factor activation assays, cell co-culture conditioned medium experiments, apoptosis assays\",\n      \"journal\": \"Journal of Cancer\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — knockdown with downstream readouts, AP-1 interaction inferred from TF reporter assay, single lab, no direct binding demonstrated\",\n      \"pmids\": [\"31205573\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Knockdown of PSME3 in colorectal cancer cells triggers cell cycle arrest at G2/M phase by downregulating cyclin B1 and CDK1 expression, thereby enhancing radiosensitivity of colorectal cancer cells.\",\n      \"method\": \"siRNA knockdown, flow cytometry cell cycle analysis, western blot for cyclin B1 and CDK1, clonogenic radiosensitivity assays\",\n      \"journal\": \"Experimental biology and medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, knockdown with downstream marker changes, no direct molecular mechanism linking PSME3 to cyclin B1/CDK1 established\",\n      \"pmids\": [\"31630568\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"REG-gamma (PSME3) is broadly expressed across multiple mouse tissues, with highest expression in the testis. REG-gamma shows unique expression in a subset of neurons including retinal ganglion cells and Purkinje cells. REG-gamma deficiency in mice results in dose-dependent reduction in litter size, suggesting a role in reproductive function.\",\n      \"method\": \"Systematic tissue expression analysis by RT-PCR and immunohistochemistry, REG-gamma knockout mouse analysis\",\n      \"journal\": \"Journal of molecular cell biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — tissue distribution and KO phenotype, no defined molecular mechanism for reproductive function\",\n      \"pmids\": [\"20494959\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PSME3 (PA28gamma/REG-gamma) is the nuclear homo-heptameric activator cap of the 20S proteasome that mediates ubiquitin-independent, ATP-independent protein degradation; it binds and targets multiple substrates including p53 (facilitating MDM2-mediated degradation), AID (controlling immunoglobulin class switching), CP2c transcription factor (via a SUMO1/PSME3 axis required for cell cycle progression), and Ddx6 (regulated by O-GlcNAcylation at S111 to control P-body homeostasis and embryonic stem cell pluripotency); it also acts as a positive feedforward regulator of NF-κB by binding and destabilizing KLF2, and participates in antigen processing by degrading pioneer translation products in the nucleus to influence immunosurveillance.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PSME3 (PA28gamma/REG-gamma) is a nuclear activator of the 20S proteasome that drives ubiquitin- and ATP-independent degradation of a defined set of regulatory substrates, thereby coupling proteasome activity to cell cycle, immune, and developmental decisions [#9, #2]. As a heptameric proteasome activator, its catalytic output is tunable: recombinant REG-gamma activates only the trypsin-like proteasome subunit under conditions that favor the intact heptamer but gains broad activation of all three catalytic activities when heptamer stability is reduced, and endogenous REG-gamma exists largely as monomer that assembles into mixed oligomers [#4]. PSME3 targets multiple substrates for destruction: it bridges MDM2 and p53 to promote ubiquitin- and MDM2-dependent p53 degradation, restraining p53 activity and apoptosis after DNA damage [#0]; it forms a stoichiometric complex with activation-induced deaminase (AID) and accelerates its proteasomal turnover to limit immunoglobulin class switching [#2]; and it mediates SUMO1-dependent degradation of the CP2c transcription factor through mutual SUMO–SIM interactions, a timed event required for accurate cell cycle progression [#9]. PSME3 also acts as a positive feedforward regulator of NF-\\u03baB by binding and destabilizing the NF-\\u03baB repressor KLF2 in macrophages, a proteolysis-dependent but ubiquitin-independent mechanism important for antibacterial defense [#1]. Its activity is itself controlled by post-translational modification: O-GlcNAcylation at serine 111 promotes PSME3-mediated degradation of Ddx6 to control P-body homeostasis and embryonic stem cell pluripotency [#10], and PSME3 is a substrate of MEKK3 phosphorylation [#3]. In cancer, elevated PSME3 enhances nuclear destruction of pioneer translation product–derived peptides, reducing MHC-I ligand availability and enabling immune evasion [#11], and promotes EMT and tumor growth [#8].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Establishing the gene's molecular identity and expression behavior was the first step toward defining a distinct PA28 family member; cloning showed it is a broadly expressed single-copy gene whose transcription responds to IFN-gamma.\",\n      \"evidence\": \"RT-PCR cloning, Northern and Southern blot, IFN-gamma stimulation in mouse hepatoma cells\",\n      \"pmids\": [\"9162094\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No protein-level function or substrate defined\", \"IFN-gamma response weaker than PA28alpha/beta, role unresolved\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identifying MEKK3 as a direct binding partner and kinase for PA28gamma raised the possibility that the activator is regulated by upstream signaling.\",\n      \"evidence\": \"Co-IP with deletion mapping and in vitro kinase assay in Cos-7 cells\",\n      \"pmids\": [\"12650640\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of phosphorylation not established\", \"Phospho-site not mapped\", \"Single lab\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Biochemical reconstitution showed PA28gamma proteasome activation is conformation- and oligomerization-dependent, explaining how the activator can switch from trypsin-like-only to broad catalytic activation.\",\n      \"evidence\": \"In vitro proteasome activity assays with biochemical manipulation of heptamer stability and Co-IP of oligomers from COS7 cells\",\n      \"pmids\": [\"15111123\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological trigger for heptamer-versus-monomer state unknown\", \"In-cell relevance of the activation switch not tested\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstrating that PA28gamma bridges MDM2 and p53 to drive p53 degradation established a concrete substrate-targeting role linking the activator to the DNA-damage/apoptosis axis.\",\n      \"evidence\": \"Reciprocal Co-IP, siRNA knockdown, ubiquitination and apoptosis assays in human cancer cells\",\n      \"pmids\": [\"18309296\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether degradation requires direct 20S handoff vs MDM2-dependent ubiquitination not fully separated\", \"Structural basis of the ternary complex unresolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Systematic expression mapping and a knockout phenotype placed REG-gamma in specific tissues (notably testis and select neurons) and tied it to reproductive output.\",\n      \"evidence\": \"RT-PCR, immunohistochemistry, and litter-size analysis in REG-gamma knockout mice\",\n      \"pmids\": [\"20494959\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No molecular mechanism for reproductive role\", \"Substrate(s) in testis/neurons unidentified\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Reconstituting a stable AID-REG-gamma complex and showing accelerated AID degradation defined a substrate controlling immunoglobulin class switching, broadening the activator's role into adaptive immunity.\",\n      \"evidence\": \"Co-IP, bacterial reconstitution of the complex, in vitro degradation assay, and class-switch assay in REG-gamma knockout mice\",\n      \"pmids\": [\"22042974\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether degradation is fully ubiquitin-independent in vivo not dissected\", \"Regulation of complex formation unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identifying KLF2 as a PSME3 target created a feedforward NF-\\u03baB amplification loop, showing the activator can promote rather than dampen inflammatory signaling during infection.\",\n      \"evidence\": \"Co-IP, siRNA, NF-\\u03baB reporters, and hematopoietic-specific loss in mouse bacterial infection models\",\n      \"pmids\": [\"26776519\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether KLF2 is degraded directly by the 20S-PSME3 complex vs indirectly not fully resolved\", \"Structural determinants of KLF2 binding unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Mapping S111 O-GlcNAcylation as a switch controlling Ddx6 degradation showed PSME3 activity is itself gated by a PTM that links it to P-body homeostasis and stem cell pluripotency.\",\n      \"evidence\": \"S111A mutagenesis, O-GlcNAc mass spectrometry, stability and P-body assays, and pluripotency readouts in mouse ESCs\",\n      \"pmids\": [\"34260942\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Enzyme(s) writing/erasing S111 O-GlcNAc not defined in this context\", \"How O-GlcNAc alters PSME3 substrate selectivity mechanistically unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrating SUMO1-dependent CP2c degradation via mutual SUMO-SIM interactions revealed a SUMO-coded routing mechanism by which PSME3 selects substrates for ubiquitin-independent 20S degradation during the cell cycle.\",\n      \"evidence\": \"Co-IP, SUMOylation and proteasome degradation assays, SUMO-site mutagenesis, and cell cycle analysis\",\n      \"pmids\": [\"36706181\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality of SUMO-SIM substrate selection beyond CP2c unknown\", \"Timing control of CP2c degradation upstream of PSME3 not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PSME3 oligomerization state, phosphorylation, O-GlcNAcylation, and SUMOylation are coordinated to select among its diverse substrates (p53, AID, KLF2, CP2c, Ddx6) in different cell contexts remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unified substrate-recognition code established\", \"No structural model of substrate-loaded PSME3-20S complex\", \"Interplay among the regulatory PTMs untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 2, 9, 10]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2, 11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 2, 9]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [9, 13]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 2, 11]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 6]}\n    ],\n    \"complexes\": [\"20S proteasome activator (PA28gamma/REG-gamma heptamer)\"],\n    \"partners\": [\"MDM2\", \"TP53\", \"AICDA\", \"KLF2\", \"CP2c\", \"DDX6\", \"MAP3K3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}