Affinage

PFDN5

Prefoldin subunit 5 · UniProt Q99471

Length
154 aa
Mass
17.3 kDa
Annotated
2026-06-10
25 papers in source corpus 12 papers cited in narrative 12 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/6 claims corpus-supported (83%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1998 High

    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

    PMID:9792694

    Open questions at the time
    • Did not identify the corepressor machinery mediating repression
    • No demonstration of effect on endogenous c-Myc target genes
  2. 2001 High

    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

    PMID:11585818

    Open questions at the time
    • Did not map which endogenous E-box genes are corepressed
    • Stoichiometry and assembly order of the complex not defined
  3. 2001 High

    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

    PMID:11567024

    Open questions at the time
    • Structural basis of the repression-defective mutant unresolved
    • Prevalence/causality of A157R in patient tumors not established
  4. 2004 Medium

    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

    PMID:15304350

    Open questions at the time
    • Single lab, fibroblast-specific
    • Direct PFDN5 promoter occupancy at c-fms not shown by ChIP
  5. 2006 Medium

    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

    PMID:16173081

    Open questions at the time
    • Physiological abundance of each isoform not quantified
    • Determinants of differential localization unknown
  6. 2007 Medium

    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

    PMID:17786314

    Open questions at the time
    • E3 ligase reconstitution in vitro not demonstrated
    • Relationship between repressive and degradative functions unresolved
  7. 2008 High

    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

    PMID:18281035

    Open questions at the time
    • Mechanism of cooperation with Egr-1 not defined
    • Whether TIF1β/HDAC1 corepressor is involved at wnt4 not tested
  8. 2008 Medium

    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

    PMID:18398700

    Open questions at the time
    • Physiological relevance in HCV-infected cells not established
    • Mechanism of antagonism (complex disruption vs sequestration) unclear
  9. 2012 Medium

    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

    PMID:22844532

    Open questions at the time
    • Relationship to the Skp2/Cullin2 ligase pathway not reconciled
    • Functional role of MM-1 mono-ubiquitination unknown
  10. 2001 Medium

    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

    PMID:11683500

    Open questions at the time
    • Cytoskeletal role of mammalian PFDN5 not directly tested here
    • Connection between Byr1/MAPKK and c-Myc functions not bridged
  11. 2024 Medium

    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)

    PMID:bio_10.1101_2024.10.14.618171

    Open questions at the time
    • Not peer-reviewed
    • Whether human PFDN5 functions identically in neurons not shown
    • Molecular link between tubulin maintenance and Tau suppression undefined
  12. 2026 Medium

    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

    PMID:42032729

    Open questions at the time
    • Direct mechanism by which PFDN5 suppresses JAK2 phosphorylation not defined
    • Single lab; needs independent confirmation

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 4 GO:0060090 molecular adaptor activity 2 GO:0008092 cytoskeletal protein binding 1 GO:0044183 protein folding chaperone 1
Localization
GO:0005634 nucleus 3 GO:0005829 cytosol 2 GO:0005856 cytoskeleton 1
Pathway
R-HSA-74160 Gene expression (Transcription) 4 R-HSA-162582 Signal Transduction 2 R-HSA-392499 Metabolism of proteins 2
Partners
BIRC6CUL2EGR1HDAC1MYCPSMC4SIN3ATRIM28
Complex memberships
PrefoldinSkp2-ElonginC-ElonginB-Cullin2 E3 ligasec-Myc-MM-1-TIF1β/KAP1-mSin3-HDAC1 corepressor complex

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 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. GST pulldown, yeast two-hybrid, mammalian two-hybrid, reporter gene assay The Journal of biological chemistry High 9792694
2001 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. Yeast two-hybrid, in vitro and in vivo binding assays, co-immunoprecipitation, dominant-negative overexpression, reporter gene assay, TSA treatment The Journal of biological chemistry High 11585818
2001 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. Site-directed mutagenesis, reporter gene assay, transformation assay in rat 3Y1 cells, cell growth arrest assay The Journal of biological chemistry High 11567024
2004 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. Dominant-negative TIF1β expression, DNA microarray, reporter gene assay with c-fms promoter deletions FEBS letters Medium 15304350
2006 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. Isoform cloning, subcellular localization by fluorescence microscopy, reporter gene assay Journal of cellular biochemistry Medium 16173081
2007 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. siRNA knockdown, in vivo and in vitro binding assays, co-immunoprecipitation, protein stability assay International journal of oncology Medium 17786314
2008 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. Yeast two-hybrid, GST pulldown, co-immunoprecipitation, confocal microscopy, reporter gene assay Journal of biomedical science Medium 18398700
2008 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. siRNA knockdown, DNA microarray, reporter gene assay with promoter deletions, chromatin immunoprecipitation (ChIP), gel mobility shift assay (EMSA), Western blot Experimental cell research High 18281035
2012 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. Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, co-transfection, subcellular localization (fluorescence microscopy), protein stability assay PloS one Medium 22844532
2001 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. Yeast two-hybrid, co-immunoprecipitation from S. pombe lysates, complementation assay with human MM-1, drug hypersensitivity assay Differentiation; research in biological diversity Medium 11683500
2024 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. Drosophila genetic screen (RNAi modifier screen), in vivo imaging, biochemical microtubule co-sedimentation, NMJ morphology analysis, Tau-aggregate quantification, behavioral memory assay bioRxivpreprint Medium bio_10.1101_2024.10.14.618171
2026 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. PFDN5 overexpression and CRISPR/Cas9 knockout, in vitro functional assays, xenograft in vivo model, protein array, bioinformatics, Western blot Journal of translational medicine Medium 42032729

Source papers

Stage 0 corpus · 25 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 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. Experimental hematology 132 12691914
1998 MM-1, a novel c-Myc-associating protein that represses transcriptional activity of c-Myc. The Journal of biological chemistry 101 9792694
2001 A novel transrepression pathway of c-Myc. Recruitment of a transcriptional corepressor complex to c-Myc by MM-1, a c-Myc-binding protein. The Journal of biological chemistry 87 11585818
2001 MM-1, a c-Myc-binding protein, is a candidate for a tumor suppressor in leukemia/lymphoma and tongue cancer. The Journal of biological chemistry 63 11567024
1989 Characterization of a novel myeloma cell line, MM.1. The Journal of laboratory and clinical medicine 55 2926241
2007 MM-1 facilitates degradation of c-Myc by recruiting proteasome and a novel ubiquitin E3 ligase. International journal of oncology 34 17786314
2008 Hepatitis C virus ARFP/F protein interacts with cellular MM-1 protein and enhances the gene trans-activation activity of c-Myc. Journal of biomedical science 33 18398700
2013 Complete Genome Sequence of the γ-Hexachlorocyclohexane-Degrading Bacterium Sphingomonas sp. Strain MM-1. Genome announcements 30 23682148
2012 Kinetics of arsenite oxidation by Variovorax sp. MM-1 isolated from a soil and identification of arsenite oxidase gene. Journal of hazardous materials 30 23290483
2008 Negative regulation of the Wnt signal by MM-1 through inhibiting expression of the wnt4 gene. Experimental cell research 26 18281035
2011 The lin genes for γ-hexachlorocyclohexane degradation in Sphingomonas sp. MM-1 proved to be dispersed across multiple plasmids. Bioscience, biotechnology, and biochemistry 25 21389627
2012 Rabring7 degrades c-Myc through complex formation with MM-1. PloS one 24 22844532
2004 Repression of the c-fms gene in fibroblast cells by c-Myc-MM-1-TIF1beta complex. FEBS letters 20 15304350
2006 Distinct localizations and repression activities of MM-1 isoforms toward c-Myc. Journal of cellular biochemistry 15 16173081
2000 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. International journal of hematology 7 10979215
1997 Role of glucocorticoid on interleukin-6-induced cellular functions in the mouse macrophage cell line (Mm 1). Biochimica et biophysica acta 6 9223622
2017 New nucleoside hydrolase with transribosylation activity from Agromyces sp. MM-1 and its application for enzymatic synthesis of 2'-O-methylribonucleosides. Journal of bioscience and bioengineering 5 28826816
1985 Specific inhibition by prostaglandin D2 and its metabolites of lysozyme synthesis in mouse macrophage-like cell line, Mm-1. Biochimica et biophysica acta 5 3855662
2001 Bob1, a Gim5/MM-1/Pfd5 homolog, interacts with the MAP kinase kinase Byr1 to regulate sexual differentiation in the fission yeast, Schizosaccharomyces pombe. Differentiation; research in biological diversity 4 11683500
2024 Activating Esterase D by PFD5 exerts antiviral effect through inhibiting glutathionization of LAMP1 during Senecavirus A infection. Microbial pathogenesis 2 39603569
2024 Identification of Genes Associated with Familial Focal Segmental Glomerulosclerosis Through Transcriptomics and In Silico Analysis, Including RPL27, TUBB6, and PFDN5. International journal of molecular sciences 1 39519211
2015 Establishment and mutation analysis of a novel malignant peritoneal mesothelioma cell line, TU-MM-1, using whole genome sequencing. Human cell 1 26070481
2026 Virulent phages MM-1 and MM-2 attack enterohemorrhagic Escherichia coli and Salmonella enterica strains. International journal of medical microbiology : IJMM 0 41990421
2026 PFDN5 synergizes with anti-PD1 therapy to promote triple-negative breast cancer cell death through JAK2/STAT3/c-Myc signaling axis. Journal of translational medicine 0 42032729
2005 Molecular cloning, expression and chromosomal localization of mouse MM-1. Molecular biology reports 0 16328889

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