{"gene":"PFDN5","run_date":"2026-06-10T05:19:53","timeline":{"discoveries":[{"year":1998,"finding":"PFDN5/MM-1 binds directly to the N-terminal domain of c-Myc (covering myc box 2, a transcription-activating domain) and represses E-box-dependent transcriptional activation by c-Myc. GST-MM-1 bound in vitro to c-Myc translated in reticulocyte lysate; mammalian two-hybrid assays confirmed in vivo interaction in CHO cells.","method":"GST pulldown, yeast two-hybrid, mammalian two-hybrid, reporter gene assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro binding reconstitution plus in vivo two-hybrid plus functional reporter assay, replicated across subsequent studies","pmids":["9792694"],"is_preprint":false},{"year":2001,"finding":"PFDN5/MM-1 recruits a transcriptional corepressor complex to c-Myc via direct binding to TIF1β/KAP1. The MM-1–TIF1β complex in HeLa cells also contains c-Myc, mSin3, and HDAC1. Dominant-negative TIF1β abrogated MM-1's inhibitory activity toward c-Myc, and the HDAC inhibitor trichostatin A canceled MM-1-mediated repression, establishing HDAC1-dependent repression as the mechanism.","method":"Yeast two-hybrid, in vitro and in vivo binding assays, co-immunoprecipitation, dominant-negative overexpression, reporter gene assay, TSA treatment","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (Co-IP, dominant-negative, pharmacological inhibition, reporter assay) in a single study, replicated by subsequent work","pmids":["11585818"],"is_preprint":false},{"year":2001,"finding":"A point mutation A157R in PFDN5/MM-1, frequently found in leukemia/lymphoma and tongue cancer patients, abolishes MM-1's ability to repress E-box-dependent c-Myc transcription and to suppress myc/ras cooperative transformation, while retaining c-Myc binding, indicating that repressor activity is separable from binding and that this region is critical for tumor suppressor function.","method":"Site-directed mutagenesis, reporter gene assay, transformation assay in rat 3Y1 cells, cell growth arrest assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — mutagenesis with multiple functional readouts (reporter, transformation, growth arrest) in single rigorous study","pmids":["11567024"],"is_preprint":false},{"year":2004,"finding":"The c-Myc–MM-1–TIF1β complex represses the c-fms oncogene promoter in fibroblast cells via an E-box-dependent mechanism. Dominant-negative TIF1β in rat-1 cells activated c-fms expression and conferred tumorigenic behavior, identified by DNA microarray and confirmed by reporter assay with c-fms promoter deletion constructs.","method":"Dominant-negative TIF1β expression, DNA microarray, reporter gene assay with c-fms promoter deletions","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two orthogonal methods (microarray + reporter assay), single lab","pmids":["15304350"],"is_preprint":false},{"year":2006,"finding":"Four splicing isoforms of PFDN5/MM-1 (MM-1α, MM-1β, MM-1γ, MM-1δ) differ in subcellular localization and repressive activity toward c-Myc. MM-1β and MM-1δ localize mainly to the cytoplasm while MM-1α and MM-1γ localize to the nucleus with c-Myc and TIF1β. Only the nuclear isoforms (MM-1α, MM-1γ) robustly repress c-Myc transcription in reporter assays, linking nuclear localization to repressor function.","method":"Isoform cloning, subcellular localization by fluorescence microscopy, reporter gene assay","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — direct localization experiments linked to functional reporter assays, single lab","pmids":["16173081"],"is_preprint":false},{"year":2007,"finding":"PFDN5/MM-1 promotes proteasomal degradation of c-Myc by: (1) directly binding Rpt3, a subunit of the 26S proteasome; (2) facilitating assembly of a novel ubiquitin E3 ligase (Skp2–ElonginC–ElonginB–Cullin2) that ubiquitinates c-Myc. siRNA knockdown of MM-1 or Cullin2 in HeLa cells stabilized endogenous c-Myc.","method":"siRNA knockdown, in vivo and in vitro binding assays, co-immunoprecipitation, protein stability assay","journal":"International journal of oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal binding assays plus siRNA functional validation, single lab","pmids":["17786314"],"is_preprint":false},{"year":2008,"finding":"HCV ARFP/F protein physically interacts with PFDN5/MM-1 (confirmed by GST pulldown, co-immunoprecipitation, and confocal co-localization) and enhances c-Myc transcriptional activity, apparently by antagonizing MM-1's inhibitory effect on c-Myc.","method":"Yeast two-hybrid, GST pulldown, co-immunoprecipitation, confocal microscopy, reporter gene assay","journal":"Journal of biomedical science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple binding assays plus functional reporter, single lab","pmids":["18398700"],"is_preprint":false},{"year":2008,"finding":"PFDN5/MM-1 represses transcription of the wnt4 gene by binding to the wnt4 promoter region (−286 to −229 from the transcription start site) together with Egr-1, as demonstrated by chromatin immunoprecipitation and gel mobility shift assays. MM-1 knockdown increased Wnt4 expression, accumulated β-catenin, and upregulated TCF/Lef-1, establishing MM-1 as a negative regulator of the Wnt–β-catenin pathway upstream of c-Myc.","method":"siRNA knockdown, DNA microarray, reporter gene assay with promoter deletions, chromatin immunoprecipitation (ChIP), gel mobility shift assay (EMSA), Western blot","journal":"Experimental cell research","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — multiple orthogonal methods (ChIP, EMSA, reporter assay, siRNA with pathway readout) in a single study","pmids":["18281035"],"is_preprint":false},{"year":2012,"finding":"Rabring7 (a Rab7-binding RING finger E3 ligase) binds PFDN5/MM-1 in the cytoplasm and mono-ubiquitinates MM-1 without degrading it. Rabring7 also binds c-Myc and ubiquitinates it in a Thr58-dependent manner. Co-transfection of MM-1 and Rabring7 led to c-Myc degradation; MM-1 knockdown stabilized c-Myc even when Rabring7 was present. MM-1 and Rabring7 co-translocate from cytoplasm to nucleus with c-Myc, suggesting MM-1 acts as a nuclear targeting factor for Rabring7-mediated c-Myc degradation.","method":"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, co-transfection, subcellular localization (fluorescence microscopy), protein stability assay","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, ubiquitination assay, siRNA validation, localization experiments, single lab","pmids":["22844532"],"is_preprint":false},{"year":2001,"finding":"Human PFDN5/MM-1 can functionally substitute for its S. pombe homolog Bob1 (Gim5/Pfd5), providing evolutionary conservation evidence. Bob1 interacts with MAPKK Byr1, co-precipitates from cell lysates, and bob1Δ mutants show cytoskeletal defects (hypersensitivity to cytoskeletal drugs), consistent with mammalian PFDN5's role in cytoskeletal regulation.","method":"Yeast two-hybrid, co-immunoprecipitation from S. pombe lysates, complementation assay with human MM-1, drug hypersensitivity assay","journal":"Differentiation; research in biological diversity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus genetic complementation by human protein, single lab","pmids":["11683500"],"is_preprint":false},{"year":2024,"finding":"Drosophila Pfdn5 associates with axonal microtubules in vivo and binds stabilized microtubules in biochemical assays. Loss of Pfdn5 reduces tubulin monomer levels, causes NMJ defects (supernumerary boutons, fewer microtubule loops), enhances hTauV337M-induced cytotoxicity and Tau-aggregate accumulation, while neuronal overexpression of Prefoldin ameliorates Tau-induced neurodegeneration and memory deficits, establishing Pfdn5 as a post-translational regulator of microtubule integrity and Tau toxicity.","method":"Drosophila genetic screen (RNAi modifier screen), in vivo imaging, biochemical microtubule co-sedimentation, NMJ morphology analysis, Tau-aggregate quantification, behavioral memory assay","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal in vivo and biochemical methods in single preprint study, not yet peer-reviewed","pmids":["bio_10.1101_2024.10.14.618171"],"is_preprint":true},{"year":2026,"finding":"PFDN5 overexpression in TNBC cells inhibits JAK2/STAT3/c-Myc signaling (reduced phospho-JAK2, phospho-STAT3, c-Myc protein levels in vivo), suppresses proliferation, colony formation, migration, and EMT, and promotes apoptosis. CRISPR/Cas9-mediated PFDN5 depletion enhanced tumorigenic traits. In vivo xenograft experiments confirmed growth inhibition upon PFDN5 overexpression.","method":"PFDN5 overexpression and CRISPR/Cas9 knockout, in vitro functional assays, xenograft in vivo model, protein array, bioinformatics, Western blot","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function and gain-of-function with defined in vivo phenotype and signaling readout, single lab","pmids":["42032729"],"is_preprint":false}],"current_model":"PFDN5/MM-1 is a c-Myc-binding co-chaperone/tumor suppressor that represses c-Myc transcriptional activity by recruiting a TIF1β/KAP1–mSin3–HDAC1 corepressor complex to E-box target gene promoters (including c-fms and wnt4), promotes c-Myc proteasomal degradation by bridging c-Myc to a Skp2–ElonginC/B–Cullin2 ubiquitin E3 ligase and the 26S proteasome subunit Rpt3, and facilitates Rabring7-mediated c-Myc ubiquitination via mono-ubiquitination-dependent nuclear translocation; additionally, PFDN5 functions as a microtubule-associated post-translational chaperone that maintains tubulin levels, suppresses Tau aggregation and neurotoxicity, and inhibits JAK2/STAT3 signaling in cancer cells."},"narrative":{"mechanistic_narrative":"PFDN5/MM-1 is a c-Myc-binding tumor suppressor that restrains c-Myc activity through two coupled mechanisms: transcriptional repression of E-box target genes and promotion of c-Myc proteasomal turnover [PMID:9792694, PMID:17786314]. It binds directly to the N-terminal transactivation domain of c-Myc and represses E-box-dependent transcription by recruiting a corepressor complex assembled on TIF1β/KAP1 together with mSin3 and HDAC1, an interaction that confers HDAC-dependent silencing of c-Myc target promoters such as c-fms [PMID:9792694, PMID:11585818, PMID:15304350]. PFDN5 also acts directly on Wnt signaling, repressing the wnt4 promoter in concert with Egr-1 and thereby limiting β-catenin/TCF accumulation upstream of c-Myc [PMID:18281035]. In parallel, PFDN5 drives c-Myc degradation by bridging it to a Skp2–ElonginC/B–Cullin2 E3 ligase and the 26S proteasome subunit Rpt3, and by serving as a nuclear-targeting factor for Rabring7-mediated, Thr58-dependent c-Myc ubiquitination [PMID:17786314, PMID:22844532]. Its repressor function is separable from c-Myc binding and is required for tumor suppression, as the cancer-associated A157R mutation abolishes repression and antagonism of myc/ras transformation while retaining binding [PMID:11567024]; nuclear-localizing isoforms are the active repressors [PMID:16173081]. Beyond the c-Myc axis, PFDN5 associates with stabilized microtubules and maintains tubulin levels, limiting Tau aggregation and neurotoxicity [PMID:bio_10.1101_2024.10.14.618171], and its overexpression suppresses JAK2/STAT3/c-Myc signaling and tumorigenic behavior in triple-negative breast cancer cells [PMID:42032729].","teleology":[{"year":1998,"claim":"Established PFDN5/MM-1 as a direct c-Myc-binding protein that antagonizes c-Myc transcriptional output, defining its founding role as a negative regulator of an oncogenic transcription factor.","evidence":"GST pulldown, yeast/mammalian two-hybrid, and E-box reporter assay in CHO cells","pmids":["9792694"],"confidence":"High","gaps":["Did not identify the corepressor machinery mediating repression","No demonstration of effect on endogenous c-Myc target genes"]},{"year":2001,"claim":"Resolved the mechanism of repression by showing PFDN5 recruits a TIF1β/KAP1–mSin3–HDAC1 corepressor complex to c-Myc, making repression HDAC-dependent.","evidence":"Co-IP, dominant-negative TIF1β, TSA inhibition, and reporter assays in HeLa cells","pmids":["11585818"],"confidence":"High","gaps":["Did not map which endogenous E-box genes are corepressed","Stoichiometry and assembly order of the complex not defined"]},{"year":2001,"claim":"Linked PFDN5 repressor activity to tumor suppression by showing the cancer-associated A157R mutation abolishes repression and transformation suppression while retaining c-Myc binding, separating binding from function.","evidence":"Site-directed mutagenesis with reporter, transformation, and growth-arrest assays in rat cells","pmids":["11567024"],"confidence":"High","gaps":["Structural basis of the repression-defective mutant unresolved","Prevalence/causality of A157R in patient tumors not established"]},{"year":2004,"claim":"Identified a specific endogenous target of the repressor complex, showing the c-Myc–MM-1–TIF1β complex silences the c-fms oncogene promoter.","evidence":"Dominant-negative TIF1β, microarray, and c-fms promoter-deletion reporter assays in rat-1 fibroblasts","pmids":["15304350"],"confidence":"Medium","gaps":["Single lab, fibroblast-specific","Direct PFDN5 promoter occupancy at c-fms not shown by ChIP"]},{"year":2006,"claim":"Explained functional heterogeneity by showing PFDN5 splice isoforms differ in localization, with nuclear isoforms being the active c-Myc repressors.","evidence":"Isoform cloning, fluorescence localization, and reporter assays","pmids":["16173081"],"confidence":"Medium","gaps":["Physiological abundance of each isoform not quantified","Determinants of differential localization unknown"]},{"year":2007,"claim":"Added a degradative arm to PFDN5 function by showing it bridges c-Myc to a Skp2–ElonginC/B–Cullin2 E3 ligase and the proteasome subunit Rpt3 to drive c-Myc turnover.","evidence":"Reciprocal binding assays, siRNA knockdown of MM-1/Cullin2, and protein stability assays in HeLa cells","pmids":["17786314"],"confidence":"Medium","gaps":["E3 ligase reconstitution in vitro not demonstrated","Relationship between repressive and degradative functions unresolved"]},{"year":2008,"claim":"Extended PFDN5's repressive reach upstream of c-Myc by showing it represses the wnt4 promoter with Egr-1, limiting β-catenin/TCF signaling.","evidence":"ChIP, EMSA, promoter-deletion reporters, and siRNA with pathway Western readouts","pmids":["18281035"],"confidence":"High","gaps":["Mechanism of cooperation with Egr-1 not defined","Whether TIF1β/HDAC1 corepressor is involved at wnt4 not tested"]},{"year":2008,"claim":"Showed viral subversion of PFDN5, with HCV ARFP/F protein binding MM-1 and relieving its inhibition of c-Myc.","evidence":"Yeast two-hybrid, GST pulldown, Co-IP, confocal co-localization, and reporter assay","pmids":["18398700"],"confidence":"Medium","gaps":["Physiological relevance in HCV-infected cells not established","Mechanism of antagonism (complex disruption vs sequestration) unclear"]},{"year":2012,"claim":"Defined PFDN5 as a nuclear-targeting factor for Rabring7-mediated, Thr58-dependent c-Myc ubiquitination, integrating cytoplasmic and nuclear control of c-Myc stability.","evidence":"Reciprocal Co-IP, ubiquitination assays, siRNA, co-transfection, and localization in cultured cells","pmids":["22844532"],"confidence":"Medium","gaps":["Relationship to the Skp2/Cullin2 ligase pathway not reconciled","Functional role of MM-1 mono-ubiquitination unknown"]},{"year":2001,"claim":"Provided evolutionary conservation, showing human MM-1 complements the S. pombe homolog Bob1, which interacts with MAPKK Byr1 and whose loss causes cytoskeletal defects.","evidence":"Yeast two-hybrid, Co-IP from S. pombe lysates, complementation by human MM-1, and drug-hypersensitivity assay","pmids":["11683500"],"confidence":"Medium","gaps":["Cytoskeletal role of mammalian PFDN5 not directly tested here","Connection between Byr1/MAPKK and c-Myc functions not bridged"]},{"year":2024,"claim":"Established a chaperone/cytoskeletal function in vivo, showing Drosophila Pfdn5 maintains tubulin levels, associates with microtubules, and suppresses Tau aggregation and neurotoxicity.","evidence":"RNAi modifier screen, in vivo imaging, microtubule co-sedimentation, NMJ analysis, Tau-aggregate quantification, and memory assay (preprint)","pmids":["bio_10.1101_2024.10.14.618171"],"confidence":"Medium","gaps":["Not peer-reviewed","Whether human PFDN5 functions identically in neurons not shown","Molecular link between tubulin maintenance and Tau suppression undefined"]},{"year":2026,"claim":"Demonstrated a tumor-suppressive role in a human cancer context, with PFDN5 inhibiting JAK2/STAT3/c-Myc signaling and tumorigenic behavior in TNBC.","evidence":"Overexpression and CRISPR/Cas9 knockout, in vitro functional assays, xenograft model, and protein-array/Western readouts","pmids":["42032729"],"confidence":"Medium","gaps":["Direct mechanism by which PFDN5 suppresses JAK2 phosphorylation not defined","Single lab; needs independent confirmation"]},{"year":null,"claim":"How PFDN5's two biochemical identities — a nuclear c-Myc corepressor/degradation adaptor and a cytoplasmic microtubule/tubulin chaperone — are coordinated within one protein, and which dominates in different cell types, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model integrating the two functional modes","Isoform/localization control of the two activities not mapped","No mammalian in vivo loss-of-function defining the dominant physiological role"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,1,3,7]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[5,8]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[10]},{"term_id":"GO:0044183","term_label":"protein folding chaperone","supporting_discovery_ids":[10]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,4,8]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[4,8]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[10]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,1,3,7]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[5,8]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[7,11]}],"complexes":["c-Myc-MM-1-TIF1β/KAP1-mSin3-HDAC1 corepressor complex","Skp2-ElonginC-ElonginB-Cullin2 E3 ligase","Prefoldin"],"partners":["MYC","TRIM28","SIN3A","HDAC1","CUL2","PSMC4","BIRC6","EGR1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q99471","full_name":"Prefoldin subunit 5","aliases":["Myc modulator 1","c-Myc-binding protein Mm-1"],"length_aa":154,"mass_kda":17.3,"function":"Binds specifically to cytosolic chaperonin (c-CPN) and transfers target proteins to it. Binds to nascent polypeptide chain and promotes folding in an environment in which there are many competing pathways for nonnative proteins. Represses the transcriptional activity of MYC","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q99471/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/PFDN5","classification":"Common Essential","n_dependent_lines":989,"n_total_lines":1208,"dependency_fraction":0.8187086092715232},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"PFDN6","stoichiometry":10.0},{"gene":"TUBB4B","stoichiometry":4.0},{"gene":"CCT2","stoichiometry":0.2},{"gene":"CCT4","stoichiometry":0.2},{"gene":"CCT6A","stoichiometry":0.2},{"gene":"CLINT1","stoichiometry":0.2},{"gene":"MAP4","stoichiometry":0.2},{"gene":"PDCL3","stoichiometry":0.2},{"gene":"TUBA1B","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/PFDN5","total_profiled":1310},"omim":[{"mim_id":"619535","title":"RING FINGER PROTEIN 115; RNF115","url":"https://www.omim.org/entry/619535"},{"mim_id":"604899","title":"PREFOLDIN 5; PFDN5","url":"https://www.omim.org/entry/604899"},{"mim_id":"604897","title":"PREFOLDIN 1; PFDN1","url":"https://www.omim.org/entry/604897"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Intermediate filaments","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PFDN5"},"hgnc":{"alias_symbol":["PFD5","MM-1"],"prev_symbol":[]},"alphafold":{"accession":"Q99471","domains":[{"cath_id":"1.10.287.370","chopping":"16-52_80-143","consensus_level":"high","plddt":95.967,"start":16,"end":143}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q99471","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q99471-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q99471-F1-predicted_aligned_error_v6.png","plddt_mean":91.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PFDN5","jax_strain_url":"https://www.jax.org/strain/search?query=PFDN5"},"sequence":{"accession":"Q99471","fasta_url":"https://rest.uniprot.org/uniprotkb/Q99471.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q99471/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q99471"}},"corpus_meta":[{"pmid":"12691914","id":"PMC_12691914","title":"Characterization of the MM.1 human multiple myeloma (MM) cell lines: a model system to elucidate the characteristics, behavior, and signaling of steroid-sensitive and -resistant MM cells.","date":"2003","source":"Experimental hematology","url":"https://pubmed.ncbi.nlm.nih.gov/12691914","citation_count":132,"is_preprint":false},{"pmid":"9792694","id":"PMC_9792694","title":"MM-1, a novel c-Myc-associating protein that represses transcriptional activity of c-Myc.","date":"1998","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9792694","citation_count":101,"is_preprint":false},{"pmid":"11585818","id":"PMC_11585818","title":"A novel transrepression pathway of c-Myc. Recruitment of a transcriptional corepressor complex to c-Myc by MM-1, a c-Myc-binding protein.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11585818","citation_count":87,"is_preprint":false},{"pmid":"11567024","id":"PMC_11567024","title":"MM-1, a c-Myc-binding protein, is a candidate for a tumor suppressor in leukemia/lymphoma and tongue cancer.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11567024","citation_count":63,"is_preprint":false},{"pmid":"2926241","id":"PMC_2926241","title":"Characterization of a novel myeloma cell line, MM.1.","date":"1989","source":"The Journal of laboratory and clinical medicine","url":"https://pubmed.ncbi.nlm.nih.gov/2926241","citation_count":55,"is_preprint":false},{"pmid":"17786314","id":"PMC_17786314","title":"MM-1 facilitates degradation of c-Myc by recruiting proteasome and a novel ubiquitin E3 ligase.","date":"2007","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/17786314","citation_count":34,"is_preprint":false},{"pmid":"18398700","id":"PMC_18398700","title":"Hepatitis C virus ARFP/F protein interacts with cellular MM-1 protein and enhances the gene trans-activation activity of c-Myc.","date":"2008","source":"Journal of biomedical science","url":"https://pubmed.ncbi.nlm.nih.gov/18398700","citation_count":33,"is_preprint":false},{"pmid":"23290483","id":"PMC_23290483","title":"Kinetics of arsenite oxidation by Variovorax sp. MM-1 isolated from a soil and identification of arsenite oxidase gene.","date":"2012","source":"Journal of hazardous materials","url":"https://pubmed.ncbi.nlm.nih.gov/23290483","citation_count":30,"is_preprint":false},{"pmid":"23682148","id":"PMC_23682148","title":"Complete Genome Sequence of the γ-Hexachlorocyclohexane-Degrading Bacterium Sphingomonas sp. Strain MM-1.","date":"2013","source":"Genome announcements","url":"https://pubmed.ncbi.nlm.nih.gov/23682148","citation_count":30,"is_preprint":false},{"pmid":"18281035","id":"PMC_18281035","title":"Negative regulation of the Wnt signal by MM-1 through inhibiting expression of the wnt4 gene.","date":"2008","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/18281035","citation_count":26,"is_preprint":false},{"pmid":"21389627","id":"PMC_21389627","title":"The lin genes for γ-hexachlorocyclohexane degradation in Sphingomonas sp. MM-1 proved to be dispersed across multiple plasmids.","date":"2011","source":"Bioscience, biotechnology, and biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21389627","citation_count":25,"is_preprint":false},{"pmid":"22844532","id":"PMC_22844532","title":"Rabring7 degrades c-Myc through complex formation with MM-1.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22844532","citation_count":24,"is_preprint":false},{"pmid":"15304350","id":"PMC_15304350","title":"Repression of the c-fms gene in fibroblast cells by c-Myc-MM-1-TIF1beta complex.","date":"2004","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/15304350","citation_count":20,"is_preprint":false},{"pmid":"16173081","id":"PMC_16173081","title":"Distinct localizations and repression activities of MM-1 isoforms toward c-Myc.","date":"2006","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16173081","citation_count":15,"is_preprint":false},{"pmid":"10979215","id":"PMC_10979215","title":"A novel human multiple myeloma-derived cell line, NCU-MM-1, carrying t(2;11)(q11;q23) and t(8;22)(q24;q11) chromosomal translocations with overexpression of c-Myc protein.","date":"2000","source":"International journal of hematology","url":"https://pubmed.ncbi.nlm.nih.gov/10979215","citation_count":7,"is_preprint":false},{"pmid":"9223622","id":"PMC_9223622","title":"Role of glucocorticoid on interleukin-6-induced cellular functions in the mouse macrophage cell line (Mm 1).","date":"1997","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/9223622","citation_count":6,"is_preprint":false},{"pmid":"3855662","id":"PMC_3855662","title":"Specific inhibition by prostaglandin D2 and its metabolites of lysozyme synthesis in mouse macrophage-like cell line, Mm-1.","date":"1985","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/3855662","citation_count":5,"is_preprint":false},{"pmid":"28826816","id":"PMC_28826816","title":"New nucleoside hydrolase with transribosylation activity from Agromyces sp. MM-1 and its application for enzymatic synthesis of 2'-O-methylribonucleosides.","date":"2017","source":"Journal of bioscience and bioengineering","url":"https://pubmed.ncbi.nlm.nih.gov/28826816","citation_count":5,"is_preprint":false},{"pmid":"11683500","id":"PMC_11683500","title":"Bob1, a Gim5/MM-1/Pfd5 homolog, interacts with the MAP kinase kinase Byr1 to regulate sexual differentiation in the fission yeast, Schizosaccharomyces pombe.","date":"2001","source":"Differentiation; research in biological diversity","url":"https://pubmed.ncbi.nlm.nih.gov/11683500","citation_count":4,"is_preprint":false},{"pmid":"39603569","id":"PMC_39603569","title":"Activating Esterase D by PFD5 exerts antiviral effect through inhibiting glutathionization of LAMP1 during Senecavirus A infection.","date":"2024","source":"Microbial pathogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/39603569","citation_count":2,"is_preprint":false},{"pmid":"39519211","id":"PMC_39519211","title":"Identification of Genes Associated with Familial Focal Segmental Glomerulosclerosis Through Transcriptomics and In Silico Analysis, Including RPL27, TUBB6, and PFDN5.","date":"2024","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/39519211","citation_count":1,"is_preprint":false},{"pmid":"26070481","id":"PMC_26070481","title":"Establishment and mutation analysis of a novel malignant peritoneal mesothelioma cell line, TU-MM-1, using whole genome sequencing.","date":"2015","source":"Human cell","url":"https://pubmed.ncbi.nlm.nih.gov/26070481","citation_count":1,"is_preprint":false},{"pmid":"42032729","id":"PMC_42032729","title":"PFDN5 synergizes with anti-PD1 therapy to promote triple-negative breast cancer cell death through JAK2/STAT3/c-Myc signaling axis.","date":"2026","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/42032729","citation_count":0,"is_preprint":false},{"pmid":"41990421","id":"PMC_41990421","title":"Virulent phages MM-1 and MM-2 attack enterohemorrhagic Escherichia coli and Salmonella enterica strains.","date":"2026","source":"International journal of medical microbiology : IJMM","url":"https://pubmed.ncbi.nlm.nih.gov/41990421","citation_count":0,"is_preprint":false},{"pmid":"16328889","id":"PMC_16328889","title":"Molecular cloning, expression and chromosomal localization of mouse MM-1.","date":"2005","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/16328889","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.10.14.618171","title":"Prefoldin 5 is a microtubule-associated protein that suppresses Tau-aggregation and neurotoxicity","date":"2024-10-16","source":"bioRxiv","url":"https://doi.org/10.1101/2024.10.14.618171","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14673,"output_tokens":3484,"usd":0.04814,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11102,"output_tokens":4217,"usd":0.080467,"stage2_stop_reason":"end_turn"},"total_usd":0.128607,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1998,\n      \"finding\": \"PFDN5/MM-1 binds directly to the N-terminal domain of c-Myc (covering myc box 2, a transcription-activating domain) and represses E-box-dependent transcriptional activation by c-Myc. GST-MM-1 bound in vitro to c-Myc translated in reticulocyte lysate; mammalian two-hybrid assays confirmed in vivo interaction in CHO cells.\",\n      \"method\": \"GST pulldown, yeast two-hybrid, mammalian two-hybrid, reporter gene assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro binding reconstitution plus in vivo two-hybrid plus functional reporter assay, replicated across subsequent studies\",\n      \"pmids\": [\"9792694\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"PFDN5/MM-1 recruits a transcriptional corepressor complex to c-Myc via direct binding to TIF1β/KAP1. The MM-1–TIF1β complex in HeLa cells also contains c-Myc, mSin3, and HDAC1. Dominant-negative TIF1β abrogated MM-1's inhibitory activity toward c-Myc, and the HDAC inhibitor trichostatin A canceled MM-1-mediated repression, establishing HDAC1-dependent repression as the mechanism.\",\n      \"method\": \"Yeast two-hybrid, in vitro and in vivo binding assays, co-immunoprecipitation, dominant-negative overexpression, reporter gene assay, TSA treatment\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (Co-IP, dominant-negative, pharmacological inhibition, reporter assay) in a single study, replicated by subsequent work\",\n      \"pmids\": [\"11585818\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"A point mutation A157R in PFDN5/MM-1, frequently found in leukemia/lymphoma and tongue cancer patients, abolishes MM-1's ability to repress E-box-dependent c-Myc transcription and to suppress myc/ras cooperative transformation, while retaining c-Myc binding, indicating that repressor activity is separable from binding and that this region is critical for tumor suppressor function.\",\n      \"method\": \"Site-directed mutagenesis, reporter gene assay, transformation assay in rat 3Y1 cells, cell growth arrest assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — mutagenesis with multiple functional readouts (reporter, transformation, growth arrest) in single rigorous study\",\n      \"pmids\": [\"11567024\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"The c-Myc–MM-1–TIF1β complex represses the c-fms oncogene promoter in fibroblast cells via an E-box-dependent mechanism. Dominant-negative TIF1β in rat-1 cells activated c-fms expression and conferred tumorigenic behavior, identified by DNA microarray and confirmed by reporter assay with c-fms promoter deletion constructs.\",\n      \"method\": \"Dominant-negative TIF1β expression, DNA microarray, reporter gene assay with c-fms promoter deletions\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal methods (microarray + reporter assay), single lab\",\n      \"pmids\": [\"15304350\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Four splicing isoforms of PFDN5/MM-1 (MM-1α, MM-1β, MM-1γ, MM-1δ) differ in subcellular localization and repressive activity toward c-Myc. MM-1β and MM-1δ localize mainly to the cytoplasm while MM-1α and MM-1γ localize to the nucleus with c-Myc and TIF1β. Only the nuclear isoforms (MM-1α, MM-1γ) robustly repress c-Myc transcription in reporter assays, linking nuclear localization to repressor function.\",\n      \"method\": \"Isoform cloning, subcellular localization by fluorescence microscopy, reporter gene assay\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — direct localization experiments linked to functional reporter assays, single lab\",\n      \"pmids\": [\"16173081\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"PFDN5/MM-1 promotes proteasomal degradation of c-Myc by: (1) directly binding Rpt3, a subunit of the 26S proteasome; (2) facilitating assembly of a novel ubiquitin E3 ligase (Skp2–ElonginC–ElonginB–Cullin2) that ubiquitinates c-Myc. siRNA knockdown of MM-1 or Cullin2 in HeLa cells stabilized endogenous c-Myc.\",\n      \"method\": \"siRNA knockdown, in vivo and in vitro binding assays, co-immunoprecipitation, protein stability assay\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal binding assays plus siRNA functional validation, single lab\",\n      \"pmids\": [\"17786314\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"HCV ARFP/F protein physically interacts with PFDN5/MM-1 (confirmed by GST pulldown, co-immunoprecipitation, and confocal co-localization) and enhances c-Myc transcriptional activity, apparently by antagonizing MM-1's inhibitory effect on c-Myc.\",\n      \"method\": \"Yeast two-hybrid, GST pulldown, co-immunoprecipitation, confocal microscopy, reporter gene assay\",\n      \"journal\": \"Journal of biomedical science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple binding assays plus functional reporter, single lab\",\n      \"pmids\": [\"18398700\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"PFDN5/MM-1 represses transcription of the wnt4 gene by binding to the wnt4 promoter region (−286 to −229 from the transcription start site) together with Egr-1, as demonstrated by chromatin immunoprecipitation and gel mobility shift assays. MM-1 knockdown increased Wnt4 expression, accumulated β-catenin, and upregulated TCF/Lef-1, establishing MM-1 as a negative regulator of the Wnt–β-catenin pathway upstream of c-Myc.\",\n      \"method\": \"siRNA knockdown, DNA microarray, reporter gene assay with promoter deletions, chromatin immunoprecipitation (ChIP), gel mobility shift assay (EMSA), Western blot\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — multiple orthogonal methods (ChIP, EMSA, reporter assay, siRNA with pathway readout) in a single study\",\n      \"pmids\": [\"18281035\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Rabring7 (a Rab7-binding RING finger E3 ligase) binds PFDN5/MM-1 in the cytoplasm and mono-ubiquitinates MM-1 without degrading it. Rabring7 also binds c-Myc and ubiquitinates it in a Thr58-dependent manner. Co-transfection of MM-1 and Rabring7 led to c-Myc degradation; MM-1 knockdown stabilized c-Myc even when Rabring7 was present. MM-1 and Rabring7 co-translocate from cytoplasm to nucleus with c-Myc, suggesting MM-1 acts as a nuclear targeting factor for Rabring7-mediated c-Myc degradation.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, co-transfection, subcellular localization (fluorescence microscopy), protein stability assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, ubiquitination assay, siRNA validation, localization experiments, single lab\",\n      \"pmids\": [\"22844532\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Human PFDN5/MM-1 can functionally substitute for its S. pombe homolog Bob1 (Gim5/Pfd5), providing evolutionary conservation evidence. Bob1 interacts with MAPKK Byr1, co-precipitates from cell lysates, and bob1Δ mutants show cytoskeletal defects (hypersensitivity to cytoskeletal drugs), consistent with mammalian PFDN5's role in cytoskeletal regulation.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation from S. pombe lysates, complementation assay with human MM-1, drug hypersensitivity assay\",\n      \"journal\": \"Differentiation; research in biological diversity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus genetic complementation by human protein, single lab\",\n      \"pmids\": [\"11683500\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Drosophila Pfdn5 associates with axonal microtubules in vivo and binds stabilized microtubules in biochemical assays. Loss of Pfdn5 reduces tubulin monomer levels, causes NMJ defects (supernumerary boutons, fewer microtubule loops), enhances hTauV337M-induced cytotoxicity and Tau-aggregate accumulation, while neuronal overexpression of Prefoldin ameliorates Tau-induced neurodegeneration and memory deficits, establishing Pfdn5 as a post-translational regulator of microtubule integrity and Tau toxicity.\",\n      \"method\": \"Drosophila genetic screen (RNAi modifier screen), in vivo imaging, biochemical microtubule co-sedimentation, NMJ morphology analysis, Tau-aggregate quantification, behavioral memory assay\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal in vivo and biochemical methods in single preprint study, not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2024.10.14.618171\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"PFDN5 overexpression in TNBC cells inhibits JAK2/STAT3/c-Myc signaling (reduced phospho-JAK2, phospho-STAT3, c-Myc protein levels in vivo), suppresses proliferation, colony formation, migration, and EMT, and promotes apoptosis. CRISPR/Cas9-mediated PFDN5 depletion enhanced tumorigenic traits. In vivo xenograft experiments confirmed growth inhibition upon PFDN5 overexpression.\",\n      \"method\": \"PFDN5 overexpression and CRISPR/Cas9 knockout, in vitro functional assays, xenograft in vivo model, protein array, bioinformatics, Western blot\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function and gain-of-function with defined in vivo phenotype and signaling readout, single lab\",\n      \"pmids\": [\"42032729\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PFDN5/MM-1 is a c-Myc-binding co-chaperone/tumor suppressor that represses c-Myc transcriptional activity by recruiting a TIF1β/KAP1–mSin3–HDAC1 corepressor complex to E-box target gene promoters (including c-fms and wnt4), promotes c-Myc proteasomal degradation by bridging c-Myc to a Skp2–ElonginC/B–Cullin2 ubiquitin E3 ligase and the 26S proteasome subunit Rpt3, and facilitates Rabring7-mediated c-Myc ubiquitination via mono-ubiquitination-dependent nuclear translocation; additionally, PFDN5 functions as a microtubule-associated post-translational chaperone that maintains tubulin levels, suppresses Tau aggregation and neurotoxicity, and inhibits JAK2/STAT3 signaling in cancer cells.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PFDN5/MM-1 is a c-Myc-binding tumor suppressor that restrains c-Myc activity through two coupled mechanisms: transcriptional repression of E-box target genes and promotion of c-Myc proteasomal turnover [#0, #5]. It binds directly to the N-terminal transactivation domain of c-Myc and represses E-box-dependent transcription by recruiting a corepressor complex assembled on TIF1\\u03b2/KAP1 together with mSin3 and HDAC1, an interaction that confers HDAC-dependent silencing of c-Myc target promoters such as c-fms [#0, #1, #3]. PFDN5 also acts directly on Wnt signaling, repressing the wnt4 promoter in concert with Egr-1 and thereby limiting \\u03b2-catenin/TCF accumulation upstream of c-Myc [#7]. In parallel, PFDN5 drives c-Myc degradation by bridging it to a Skp2\\u2013ElonginC/B\\u2013Cullin2 E3 ligase and the 26S proteasome subunit Rpt3, and by serving as a nuclear-targeting factor for Rabring7-mediated, Thr58-dependent c-Myc ubiquitination [#5, #8]. Its repressor function is separable from c-Myc binding and is required for tumor suppression, as the cancer-associated A157R mutation abolishes repression and antagonism of myc/ras transformation while retaining binding [#2]; nuclear-localizing isoforms are the active repressors [#4]. Beyond the c-Myc axis, PFDN5 associates with stabilized microtubules and maintains tubulin levels, limiting Tau aggregation and neurotoxicity [#10], and its overexpression suppresses JAK2/STAT3/c-Myc signaling and tumorigenic behavior in triple-negative breast cancer cells [#11].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established PFDN5/MM-1 as a direct c-Myc-binding protein that antagonizes c-Myc transcriptional output, defining its founding role as a negative regulator of an oncogenic transcription factor.\",\n      \"evidence\": \"GST pulldown, yeast/mammalian two-hybrid, and E-box reporter assay in CHO cells\",\n      \"pmids\": [\"9792694\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the corepressor machinery mediating repression\", \"No demonstration of effect on endogenous c-Myc target genes\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Resolved the mechanism of repression by showing PFDN5 recruits a TIF1\\u03b2/KAP1\\u2013mSin3\\u2013HDAC1 corepressor complex to c-Myc, making repression HDAC-dependent.\",\n      \"evidence\": \"Co-IP, dominant-negative TIF1\\u03b2, TSA inhibition, and reporter assays in HeLa cells\",\n      \"pmids\": [\"11585818\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not map which endogenous E-box genes are corepressed\", \"Stoichiometry and assembly order of the complex not defined\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Linked PFDN5 repressor activity to tumor suppression by showing the cancer-associated A157R mutation abolishes repression and transformation suppression while retaining c-Myc binding, separating binding from function.\",\n      \"evidence\": \"Site-directed mutagenesis with reporter, transformation, and growth-arrest assays in rat cells\",\n      \"pmids\": [\"11567024\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the repression-defective mutant unresolved\", \"Prevalence/causality of A157R in patient tumors not established\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identified a specific endogenous target of the repressor complex, showing the c-Myc\\u2013MM-1\\u2013TIF1\\u03b2 complex silences the c-fms oncogene promoter.\",\n      \"evidence\": \"Dominant-negative TIF1\\u03b2, microarray, and c-fms promoter-deletion reporter assays in rat-1 fibroblasts\",\n      \"pmids\": [\"15304350\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab, fibroblast-specific\", \"Direct PFDN5 promoter occupancy at c-fms not shown by ChIP\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Explained functional heterogeneity by showing PFDN5 splice isoforms differ in localization, with nuclear isoforms being the active c-Myc repressors.\",\n      \"evidence\": \"Isoform cloning, fluorescence localization, and reporter assays\",\n      \"pmids\": [\"16173081\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological abundance of each isoform not quantified\", \"Determinants of differential localization unknown\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Added a degradative arm to PFDN5 function by showing it bridges c-Myc to a Skp2\\u2013ElonginC/B\\u2013Cullin2 E3 ligase and the proteasome subunit Rpt3 to drive c-Myc turnover.\",\n      \"evidence\": \"Reciprocal binding assays, siRNA knockdown of MM-1/Cullin2, and protein stability assays in HeLa cells\",\n      \"pmids\": [\"17786314\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligase reconstitution in vitro not demonstrated\", \"Relationship between repressive and degradative functions unresolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Extended PFDN5's repressive reach upstream of c-Myc by showing it represses the wnt4 promoter with Egr-1, limiting \\u03b2-catenin/TCF signaling.\",\n      \"evidence\": \"ChIP, EMSA, promoter-deletion reporters, and siRNA with pathway Western readouts\",\n      \"pmids\": [\"18281035\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of cooperation with Egr-1 not defined\", \"Whether TIF1\\u03b2/HDAC1 corepressor is involved at wnt4 not tested\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Showed viral subversion of PFDN5, with HCV ARFP/F protein binding MM-1 and relieving its inhibition of c-Myc.\",\n      \"evidence\": \"Yeast two-hybrid, GST pulldown, Co-IP, confocal co-localization, and reporter assay\",\n      \"pmids\": [\"18398700\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological relevance in HCV-infected cells not established\", \"Mechanism of antagonism (complex disruption vs sequestration) unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined PFDN5 as a nuclear-targeting factor for Rabring7-mediated, Thr58-dependent c-Myc ubiquitination, integrating cytoplasmic and nuclear control of c-Myc stability.\",\n      \"evidence\": \"Reciprocal Co-IP, ubiquitination assays, siRNA, co-transfection, and localization in cultured cells\",\n      \"pmids\": [\"22844532\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relationship to the Skp2/Cullin2 ligase pathway not reconciled\", \"Functional role of MM-1 mono-ubiquitination unknown\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Provided evolutionary conservation, showing human MM-1 complements the S. pombe homolog Bob1, which interacts with MAPKK Byr1 and whose loss causes cytoskeletal defects.\",\n      \"evidence\": \"Yeast two-hybrid, Co-IP from S. pombe lysates, complementation by human MM-1, and drug-hypersensitivity assay\",\n      \"pmids\": [\"11683500\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cytoskeletal role of mammalian PFDN5 not directly tested here\", \"Connection between Byr1/MAPKK and c-Myc functions not bridged\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established a chaperone/cytoskeletal function in vivo, showing Drosophila Pfdn5 maintains tubulin levels, associates with microtubules, and suppresses Tau aggregation and neurotoxicity.\",\n      \"evidence\": \"RNAi modifier screen, in vivo imaging, microtubule co-sedimentation, NMJ analysis, Tau-aggregate quantification, and memory assay (preprint)\",\n      \"pmids\": [\"bio_10.1101_2024.10.14.618171\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Not peer-reviewed\", \"Whether human PFDN5 functions identically in neurons not shown\", \"Molecular link between tubulin maintenance and Tau suppression undefined\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Demonstrated a tumor-suppressive role in a human cancer context, with PFDN5 inhibiting JAK2/STAT3/c-Myc signaling and tumorigenic behavior in TNBC.\",\n      \"evidence\": \"Overexpression and CRISPR/Cas9 knockout, in vitro functional assays, xenograft model, and protein-array/Western readouts\",\n      \"pmids\": [\"42032729\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct mechanism by which PFDN5 suppresses JAK2 phosphorylation not defined\", \"Single lab; needs independent confirmation\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PFDN5's two biochemical identities \\u2014 a nuclear c-Myc corepressor/degradation adaptor and a cytoplasmic microtubule/tubulin chaperone \\u2014 are coordinated within one protein, and which dominates in different cell types, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model integrating the two functional modes\", \"Isoform/localization control of the two activities not mapped\", \"No mammalian in vivo loss-of-function defining the dominant physiological role\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1, 3, 7]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [5, 8]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"GO:0044183\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 4, 8]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [4, 8]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 1, 3, 7]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [5, 8]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [7, 11]}\n    ],\n    \"complexes\": [\n      \"c-Myc-MM-1-TIF1\\u03b2/KAP1-mSin3-HDAC1 corepressor complex\",\n      \"Skp2-ElonginC-ElonginB-Cullin2 E3 ligase\",\n      \"Prefoldin\"\n    ],\n    \"partners\": [\n      \"MYC\",\n      \"TRIM28\",\n      \"SIN3A\",\n      \"HDAC1\",\n      \"CUL2\",\n      \"PSMC4\",\n      \"BIRC6\",\n      \"EGR1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":6,"faith_pct":83.33333333333333}}