{"gene":"PSMA1","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2012,"finding":"TRAF6 knockdown in MDS/AML cells leads to downregulation of PSMA1 (proteasomal subunit α-1), and reduced PSMA1 expression resensitizes bortezomib-resistant cells to bortezomib-induced cytotoxicity, placing PSMA1 downstream of TRAF6 in controlling proteasome activity and bortezomib sensitivity.","method":"RNAi-mediated knockdown of TRAF6 in MDS/AML cell lines followed by gene-expression profiling and functional cytotoxicity assays","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KD with defined cellular phenotype and gene-expression profiling in multiple cell lines, single lab, two orthogonal methods (RNAi + gene expression profiling)","pmids":["22685174"],"is_preprint":false},{"year":2022,"finding":"The lncRNA MDHDH acts as a molecular scaffold that directly binds both MDH2 and PSMA1 (20S proteasomal core subunit alpha-type 1), promoting the binding of ubiquitinated MDH2 to the proteasome and accelerating its degradation, thereby reducing mitochondrial membrane potential and altering the NAD+/NADH ratio to impede glycolysis in glioma cells.","method":"RNA pulldown, mass spectrometry, RNA immunoprecipitation, co-immunoprecipitation, JC-1 mitochondrial membrane potential assay, cell energy-production assays, in vivo xenograft experiments","journal":"Journal of experimental & clinical cancer research : CR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP and pulldown with functional assays, single lab, multiple orthogonal methods","pmids":["36527092"],"is_preprint":false}],"current_model":"PSMA1 (proteasome subunit alpha type 1) functions as a core structural component of the 20S proteasome that can be regulated downstream of TRAF6 to control proteasome activity and bortezomib sensitivity in myeloid malignancies, and can be recruited as a scaffold-binding partner by the lncRNA MDHDH to facilitate ubiquitinated substrate delivery and degradation."},"narrative":{"mechanistic_narrative":"PSMA1 encodes an alpha-type core subunit of the 20S proteasome that participates in targeted degradation of ubiquitinated substrates [PMID:36527092]. In myeloid malignancies, PSMA1 expression is regulated downstream of TRAF6, and its level sets proteasome activity and sensitivity to the proteasome inhibitor bortezomib: reducing PSMA1 resensitizes bortezomib-resistant MDS/AML cells to bortezomib-induced cytotoxicity [PMID:22685174]. PSMA1 can also be recruited as a scaffold-binding partner by the lncRNA MDHDH, which directly bridges PSMA1 to MDH2 and promotes binding of ubiquitinated MDH2 to the proteasome to accelerate its degradation, thereby lowering mitochondrial membrane potential and shifting the NAD+/NADH ratio to impede glycolysis in glioma cells [PMID:36527092]. Beyond these two contexts, no further mechanistic detail of PSMA1 has been characterized in the available corpus.","teleology":[{"year":2012,"claim":"Established that PSMA1 is not merely a static proteasome subunit but a regulated node whose expression, controlled downstream of TRAF6, determines proteasome activity and drug sensitivity in myeloid cancer.","evidence":"RNAi knockdown of TRAF6 with gene-expression profiling and bortezomib cytotoxicity assays in MDS/AML cell lines","pmids":["22685174"],"confidence":"Medium","gaps":["Mechanism linking TRAF6 to PSMA1 transcription/expression not defined","Effect of PSMA1 on assembled 20S/26S proteasome structure or catalytic rate not measured directly","Not validated in primary patient samples or in vivo"]},{"year":2022,"claim":"Showed that PSMA1 can be recruited by a lncRNA scaffold to direct a specific substrate to the proteasome, linking proteasomal degradation to mitochondrial/metabolic control.","evidence":"RNA pulldown, mass spectrometry, RIP, reciprocal co-IP, JC-1 membrane potential and energy assays, and xenografts in glioma cells","pmids":["36527092"],"confidence":"Medium","gaps":["Direct RNA-binding interface on PSMA1 not mapped","Whether scaffold recruitment generalizes to other substrates is unknown","Structural basis of MDHDH–PSMA1 association not resolved"]},{"year":null,"claim":"How PSMA1 incorporation, abundance, or RNA-mediated recruitment is integrated into normal proteasome assembly and substrate selection remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of PSMA1 within the 20S core in the corpus","No catalytic or assembly mechanism characterized","Generality of PSMA1-mediated substrate targeting beyond MDH2 and bortezomib contexts untested"]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,1]}],"complexes":["20S proteasome"],"partners":["MDH2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P25786","full_name":"Proteasome subunit alpha type-1","aliases":["30 kDa prosomal protein","PROS-30","Macropain subunit C2","Multicatalytic endopeptidase complex subunit C2","Proteasome component C2","Proteasome nu chain","Proteasome subunit alpha-6","alpha-6"],"length_aa":263,"mass_kda":29.6,"function":"Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex)","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/P25786/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/PSMA1","classification":"Common Essential","n_dependent_lines":1208,"n_total_lines":1208,"dependency_fraction":1.0},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000129084","cell_line_id":"CID000115","localizations":[{"compartment":"nucleoplasm","grade":3},{"compartment":"cytoplasmic","grade":2}],"interactors":[{"gene":"NUCKS1","stoichiometry":10.0},{"gene":"PSMD4","stoichiometry":10.0},{"gene":"PSMC5","stoichiometry":10.0},{"gene":"PSMC1","stoichiometry":10.0},{"gene":"PSMD6","stoichiometry":10.0},{"gene":"PSMD2","stoichiometry":10.0},{"gene":"UCHL5","stoichiometry":10.0},{"gene":"PSMC3","stoichiometry":10.0},{"gene":"PSMA4","stoichiometry":10.0},{"gene":"PSMD1","stoichiometry":10.0}],"url":"https://opencell.sf.czbiohub.org/target/CID000115","total_profiled":1310},"omim":[{"mim_id":"613386","title":"PROTEASOME MATURATION PROTEIN; POMP","url":"https://www.omim.org/entry/613386"},{"mim_id":"602854","title":"PROTEASOME SUBUNIT, ALPHA-TYPE, 1; PSMA1","url":"https://www.omim.org/entry/602854"},{"mim_id":"176846","title":"PROTEASOME SUBUNIT, ALPHA-TYPE, 4; PSMA4","url":"https://www.omim.org/entry/176846"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Nuclear bodies","reliability":"Additional"},{"location":"Centrosome","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PSMA1"},"hgnc":{"alias_symbol":["HC2","NU","PROS30","MGC14542","MGC14575","MGC14751","MGC1667","MGC21459","MGC22853","MGC23915"],"prev_symbol":[]},"alphafold":{"accession":"P25786","domains":[{"cath_id":"3.60.20.10","chopping":"19-233","consensus_level":"medium","plddt":97.4605,"start":19,"end":233}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P25786","model_url":"https://alphafold.ebi.ac.uk/files/AF-P25786-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P25786-F1-predicted_aligned_error_v6.png","plddt_mean":91.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PSMA1","jax_strain_url":"https://www.jax.org/strain/search?query=PSMA1"},"sequence":{"accession":"P25786","fasta_url":"https://rest.uniprot.org/uniprotkb/P25786.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P25786/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P25786"}},"corpus_meta":[{"pmid":"32066625","id":"PMC_32066625","title":"Mediterranean diet intervention alters the gut microbiome in older people reducing frailty and improving health status: the NU-AGE 1-year dietary intervention across five European countries.","date":"2020","source":"Gut","url":"https://pubmed.ncbi.nlm.nih.gov/32066625","citation_count":709,"is_preprint":false},{"pmid":"1005117","id":"PMC_1005117","title":"Chromatin nu bodies: isolation, subfractionation and physical characterization.","date":"1976","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/1005117","citation_count":197,"is_preprint":false},{"pmid":"7604876","id":"PMC_7604876","title":"Keratinocyte growth factor is an important endogenous mediator of hair follicle growth, development, and differentiation. 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Cell physiology","url":"https://pubmed.ncbi.nlm.nih.gov/19726747","citation_count":26,"is_preprint":false},{"pmid":"6747601","id":"PMC_6747601","title":"Coxsackievirus B3 persistence and myocarditis in N:NIH(S) II nu/nu and +/nu mice.","date":"1984","source":"The Journal of general virology","url":"https://pubmed.ncbi.nlm.nih.gov/6747601","citation_count":26,"is_preprint":false},{"pmid":"19108687","id":"PMC_19108687","title":"Cranberry phytochemical extract inhibits SGC-7901 cell growth and human tumor xenografts in Balb/c nu/nu mice.","date":"2009","source":"Journal of agricultural and food chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19108687","citation_count":23,"is_preprint":false},{"pmid":"6982822","id":"PMC_6982822","title":"Development and continuous growth in culture of interleukin 2-producer lymphocytes from athymic nu/nu mice.","date":"1982","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/6982822","citation_count":23,"is_preprint":false},{"pmid":"37200937","id":"PMC_37200937","title":"The 'New (Nu)-clear' evidence for the tumor-driving role of PI3K.","date":"2022","source":"Acta materia medica","url":"https://pubmed.ncbi.nlm.nih.gov/37200937","citation_count":22,"is_preprint":false},{"pmid":"19083478","id":"PMC_19083478","title":"Grape and wine polyphenols down-regulate the expression of signal transduction genes and inhibit the growth of estrogen receptor-negative MDA-MB231 tumors in nu/nu mouse xenografts.","date":"2008","source":"Nutrition research (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/19083478","citation_count":22,"is_preprint":false},{"pmid":"2418248","id":"PMC_2418248","title":"Long-term serial transplantation of 30 different human renal cell carcinomas into NMRI (nu/nu) mice: flow cytometric, histologic, and growth studies.","date":"1986","source":"Journal of the National Cancer Institute","url":"https://pubmed.ncbi.nlm.nih.gov/2418248","citation_count":22,"is_preprint":false},{"pmid":"26056149","id":"PMC_26056149","title":"Peloruside A Inhibits Growth of Human Lung and Breast Tumor Xenografts in an Athymic nu/nu Mouse Model.","date":"2015","source":"Molecular cancer therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/26056149","citation_count":22,"is_preprint":false},{"pmid":"7673820","id":"PMC_7673820","title":"Effect of T-cell deficiency on the formation of periapical lesions in mice: histological comparison between periapical lesion formation in BALB/c and BALB/c nu/nu mice.","date":"1995","source":"Journal of endodontics","url":"https://pubmed.ncbi.nlm.nih.gov/7673820","citation_count":22,"is_preprint":false},{"pmid":"6968019","id":"PMC_6968019","title":"Polyclonal B cell activation by cell wall preparations of gram-positive bacteria. In vitro responses of spleen cells obtained from Balb/c, nu/nu, nu/+, C3H/He, C3H/HeJ and hybrid (DBA/N x Balb/c)F1 mice.","date":"1980","source":"Microbiology and immunology","url":"https://pubmed.ncbi.nlm.nih.gov/6968019","citation_count":21,"is_preprint":false},{"pmid":"6787601","id":"PMC_6787601","title":"Interleukin 2 is mitogenic for nu/nu and nu/+ murine spleen cells.","date":"1981","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/6787601","citation_count":20,"is_preprint":false},{"pmid":"10726045","id":"PMC_10726045","title":"The antithrombotic factor singlet oxygen/light (1O2/h nu).","date":"2000","source":"Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis","url":"https://pubmed.ncbi.nlm.nih.gov/10726045","citation_count":20,"is_preprint":false},{"pmid":"30093866","id":"PMC_30093866","title":"One-Year Consumption of a Mediterranean-Like Dietary Pattern With Vitamin D3 Supplements Induced Small Scale but Extensive Changes of Immune Cell Phenotype, Co-receptor Expression and Innate Immune Responses in Healthy Elderly Subjects: Results From the United Kingdom Arm of the NU-AGE Trial.","date":"2018","source":"Frontiers in physiology","url":"https://pubmed.ncbi.nlm.nih.gov/30093866","citation_count":20,"is_preprint":false},{"pmid":"3293775","id":"PMC_3293775","title":"Quantitative transplantation assays of spontaneous tumors of the C3H mouse as allografts in athymic NCr/Sed-nu/nu nude mice and isografts in C3Hf/Sed mice.","date":"1988","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/3293775","citation_count":20,"is_preprint":false},{"pmid":"21232163","id":"PMC_21232163","title":"Antimicrobial activity and mechanism of action of Nu-3, a protonated modified nucleotide.","date":"2011","source":"Annals of clinical microbiology and 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immunology","url":"https://pubmed.ncbi.nlm.nih.gov/10660259","citation_count":18,"is_preprint":false},{"pmid":"19320641","id":"PMC_19320641","title":"RET protein promotes non-adherent growth of NB-39-nu neuroblastoma cell line.","date":"2009","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/19320641","citation_count":17,"is_preprint":false},{"pmid":"28915665","id":"PMC_28915665","title":"The ketogenic diet is not feasible as a therapy in a CD-1 nu/nu mouse model of renal cell carcinoma with features of Stauffer's syndrome.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/28915665","citation_count":17,"is_preprint":false},{"pmid":"36280043","id":"PMC_36280043","title":"PSMA1-mediated ultrasmall gold nanoparticles facilitate tumor targeting and MR/CT/NIRF multimodal detection of early-stage prostate cancer.","date":"2022","source":"Nanomedicine : nanotechnology, biology, and 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biology","url":"https://pubmed.ncbi.nlm.nih.gov/36206753","citation_count":16,"is_preprint":false},{"pmid":"928067","id":"PMC_928067","title":"DNA chain flexibility and the structure of chromatin nu-bodies.","date":"1977","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/928067","citation_count":16,"is_preprint":false},{"pmid":"6280913","id":"PMC_6280913","title":"Immunoglobulin synthesis in nude (nu/nu), nu/+ and reconstituted nu/nu mice infected with a demyelinating strain of Semliki Forest virus.","date":"1982","source":"Clinical and experimental immunology","url":"https://pubmed.ncbi.nlm.nih.gov/6280913","citation_count":16,"is_preprint":false},{"pmid":"6088960","id":"PMC_6088960","title":"Coxsackievirus B3 persistence and myocarditis in NFR nu/nu and +/nu mice.","date":"1984","source":"Medical microbiology and immunology","url":"https://pubmed.ncbi.nlm.nih.gov/6088960","citation_count":15,"is_preprint":false},{"pmid":"4049479","id":"PMC_4049479","title":"The C57BL/6 nu/nu lpr/lpr mouse. II. Pedigree and preliminary characteristics.","date":"1985","source":"Thymus","url":"https://pubmed.ncbi.nlm.nih.gov/4049479","citation_count":14,"is_preprint":false},{"pmid":"32681389","id":"PMC_32681389","title":"Pleiotrophin selectively binds to vascular endothelial growth factor receptor 2 and inhibits or stimulates cell migration depending on ανβ3 integrin expression.","date":"2020","source":"Angiogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/32681389","citation_count":14,"is_preprint":false},{"pmid":"18058808","id":"PMC_18058808","title":"15-Hydroxyprostaglandin dehydrogenase suppresses K-RasV12-dependent tumor formation in Nu/Nu mice.","date":"2008","source":"Molecular carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/18058808","citation_count":14,"is_preprint":false},{"pmid":"20133969","id":"PMC_20133969","title":"Effectiveness of combined modality radiotherapy of orthotopic human squamous cell carcinomas in Nu/Nu mice using cetuximab, tirapazamine and MnSOD-plasmid liposome gene therapy.","date":"2010","source":"In vivo (Athens, Greece)","url":"https://pubmed.ncbi.nlm.nih.gov/20133969","citation_count":14,"is_preprint":false},{"pmid":"22176637","id":"PMC_22176637","title":"Treatment effects of the multikinase inhibitor sorafenib on hepatoblastoma cell lines and xenografts in NMRI-Foxn1 nu mice.","date":"2011","source":"Liver international : official journal of the International Association for the Study of the Liver","url":"https://pubmed.ncbi.nlm.nih.gov/22176637","citation_count":13,"is_preprint":false},{"pmid":"1999354","id":"PMC_1999354","title":"Rearrangement patterns of T-cell receptor genes in the spleen of athymic (nu/nu) young mice.","date":"1991","source":"Immunogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/1999354","citation_count":13,"is_preprint":false},{"pmid":"4057430","id":"PMC_4057430","title":"Characterization of a renal cell carcinoma cell line suitable as a target for immunological studies in vitro and in the nu/nu mouse.","date":"1985","source":"The Journal of urology","url":"https://pubmed.ncbi.nlm.nih.gov/4057430","citation_count":13,"is_preprint":false},{"pmid":"35839966","id":"PMC_35839966","title":"Sortase A-mediated cyclization of novel polycyclic RGD peptides for ανβ3 integrin targeting.","date":"2022","source":"Bioorganic & medicinal chemistry letters","url":"https://pubmed.ncbi.nlm.nih.gov/35839966","citation_count":13,"is_preprint":false},{"pmid":"6436173","id":"PMC_6436173","title":"Opposing effects of xid and nu mutations on proliferative and polyclonal antibody and autoantibody responses to peptidoglycan, LPS, protein A and PWM.","date":"1984","source":"Immunology","url":"https://pubmed.ncbi.nlm.nih.gov/6436173","citation_count":13,"is_preprint":false},{"pmid":"1707347","id":"PMC_1707347","title":"Characterization of a CD4-positive T-cell line derived from an athymic (nu/nu) mouse.","date":"1991","source":"Cellular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/1707347","citation_count":12,"is_preprint":false},{"pmid":"27279530","id":"PMC_27279530","title":"Downregulation of tetrahydrobiopterin inhibits tumor angiogenesis in BALB/c-nu mice with hepatocellular carcinoma.","date":"2016","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/27279530","citation_count":12,"is_preprint":false},{"pmid":"3876624","id":"PMC_3876624","title":"The C57BL/6 nu/nu lpr/lpr mouse. I. Expression of the 'lpr phenotype' in the C57BL/6 genetic background.","date":"1985","source":"Thymus","url":"https://pubmed.ncbi.nlm.nih.gov/3876624","citation_count":12,"is_preprint":false},{"pmid":"29481823","id":"PMC_29481823","title":"Targeted suicide gene transfections reveal promising results in nu/nu mice with aggressive neuroblastoma.","date":"2018","source":"Journal of controlled release : official journal of the Controlled Release Society","url":"https://pubmed.ncbi.nlm.nih.gov/29481823","citation_count":11,"is_preprint":false},{"pmid":"9241527","id":"PMC_9241527","title":"Analyses of extrathymic T cell differentiation in nu/nu mice by grafting embryonal organs.","date":"1997","source":"Immunobiology","url":"https://pubmed.ncbi.nlm.nih.gov/9241527","citation_count":11,"is_preprint":false},{"pmid":"2581902","id":"PMC_2581902","title":"Use of novel chemical supplements in the establishment of three human malignant lymphoma cell lines (NU-DHL-1, NU-DUL-1, and NU-AMB-1) with chromosome 14 translocations.","date":"1985","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/2581902","citation_count":11,"is_preprint":false},{"pmid":"26079185","id":"PMC_26079185","title":"Evaluation of self-emulsified DIM-14 in dogs for oral bioavailability and in Nu/nu mice bearing stem cell lung tumor models for anticancer activity.","date":"2015","source":"Journal of controlled release : official journal of the Controlled Release Society","url":"https://pubmed.ncbi.nlm.nih.gov/26079185","citation_count":11,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":51160,"output_tokens":881,"usd":0.083348,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7010,"output_tokens":1274,"usd":0.03345,"stage2_stop_reason":"end_turn"},"total_usd":0.116798,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking through the abstracts, I need to identify papers about PSMA1 (proteasome subunit alpha type 1, also known as PROS30). Most papers in this corpus are about \"nu\" (nude mouse mutation), \"ν\" (nu symbol in physics/chemistry), or other unrelated uses of \"nu.\" Let me identify the relevant papers:\n\n- Paper [15]: About bortezomib, TRAF6, and PSMA1 in MDS/AML - directly relevant\n- Paper [49]: About lncRNA MDHDH binding to MDH2 and PSMA1 as a scaffold - directly relevant\n- Paper [40]: Proteomic profiling identifying PSMA1 as a colon cancer immunogen - mentions PSMA1 but no mechanistic experiment on PSMA1 itself\n- Paper [78]: PSMA1 ligand for prostate cancer imaging - this is about PSMA (prostate-specific membrane antigen), not PSMA1 (proteasome subunit alpha 1) - different protein, exclude\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2012,\n      \"finding\": \"TRAF6 knockdown in MDS/AML cells leads to downregulation of PSMA1 (proteasomal subunit α-1), and reduced PSMA1 expression resensitizes bortezomib-resistant cells to bortezomib-induced cytotoxicity, placing PSMA1 downstream of TRAF6 in controlling proteasome activity and bortezomib sensitivity.\",\n      \"method\": \"RNAi-mediated knockdown of TRAF6 in MDS/AML cell lines followed by gene-expression profiling and functional cytotoxicity assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KD with defined cellular phenotype and gene-expression profiling in multiple cell lines, single lab, two orthogonal methods (RNAi + gene expression profiling)\",\n      \"pmids\": [\"22685174\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The lncRNA MDHDH acts as a molecular scaffold that directly binds both MDH2 and PSMA1 (20S proteasomal core subunit alpha-type 1), promoting the binding of ubiquitinated MDH2 to the proteasome and accelerating its degradation, thereby reducing mitochondrial membrane potential and altering the NAD+/NADH ratio to impede glycolysis in glioma cells.\",\n      \"method\": \"RNA pulldown, mass spectrometry, RNA immunoprecipitation, co-immunoprecipitation, JC-1 mitochondrial membrane potential assay, cell energy-production assays, in vivo xenograft experiments\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP and pulldown with functional assays, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"36527092\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PSMA1 (proteasome subunit alpha type 1) functions as a core structural component of the 20S proteasome that can be regulated downstream of TRAF6 to control proteasome activity and bortezomib sensitivity in myeloid malignancies, and can be recruited as a scaffold-binding partner by the lncRNA MDHDH to facilitate ubiquitinated substrate delivery and degradation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PSMA1 encodes an alpha-type core subunit of the 20S proteasome that participates in targeted degradation of ubiquitinated substrates [#1]. In myeloid malignancies, PSMA1 expression is regulated downstream of TRAF6, and its level sets proteasome activity and sensitivity to the proteasome inhibitor bortezomib: reducing PSMA1 resensitizes bortezomib-resistant MDS/AML cells to bortezomib-induced cytotoxicity [#0]. PSMA1 can also be recruited as a scaffold-binding partner by the lncRNA MDHDH, which directly bridges PSMA1 to MDH2 and promotes binding of ubiquitinated MDH2 to the proteasome to accelerate its degradation, thereby lowering mitochondrial membrane potential and shifting the NAD+/NADH ratio to impede glycolysis in glioma cells [#1]. Beyond these two contexts, no further mechanistic detail of PSMA1 has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"Established that PSMA1 is not merely a static proteasome subunit but a regulated node whose expression, controlled downstream of TRAF6, determines proteasome activity and drug sensitivity in myeloid cancer.\",\n      \"evidence\": \"RNAi knockdown of TRAF6 with gene-expression profiling and bortezomib cytotoxicity assays in MDS/AML cell lines\",\n      \"pmids\": [\"22685174\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism linking TRAF6 to PSMA1 transcription/expression not defined\",\n        \"Effect of PSMA1 on assembled 20S/26S proteasome structure or catalytic rate not measured directly\",\n        \"Not validated in primary patient samples or in vivo\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed that PSMA1 can be recruited by a lncRNA scaffold to direct a specific substrate to the proteasome, linking proteasomal degradation to mitochondrial/metabolic control.\",\n      \"evidence\": \"RNA pulldown, mass spectrometry, RIP, reciprocal co-IP, JC-1 membrane potential and energy assays, and xenografts in glioma cells\",\n      \"pmids\": [\"36527092\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct RNA-binding interface on PSMA1 not mapped\",\n        \"Whether scaffold recruitment generalizes to other substrates is unknown\",\n        \"Structural basis of MDHDH–PSMA1 association not resolved\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PSMA1 incorporation, abundance, or RNA-mediated recruitment is integrated into normal proteasome assembly and substrate selection remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No structural model of PSMA1 within the 20S core in the corpus\",\n        \"No catalytic or assembly mechanism characterized\",\n        \"Generality of PSMA1-mediated substrate targeting beyond MDH2 and bortezomib contexts untested\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [\"20S proteasome\"],\n    \"partners\": [\"MDH2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":3,"faith_total":3,"faith_pct":100.0}}