Affinage

CBX4

E3 SUMO-protein ligase CBX4 · UniProt O00257

Length
560 aa
Mass
61.4 kDa
Annotated
2026-04-28
100 papers in source corpus 19 papers cited in narrative 19 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CBX4 (Pc2/HPC2) is a Polycomb group protein that functions as a SUMO E3 ligase and transcriptional regulator with diverse roles in chromatin silencing, DNA damage repair, lineage specification, and senescence control. As a SUMO E3 ligase, CBX4 uses two SUMO-interaction motifs and dual catalytic/adapter domains to recruit Ubc9 and substrates—including CtBP, SIP1, HIPK2, Dnmt3a, BMI1, CtIP, Prdm16, and YAP1—to Polycomb bodies, thereby controlling processes ranging from homologous recombination (via CtIP sumoylation enabling DNA end resection) and ionizing-radiation resistance (via BMI1 sumoylation at damage sites) to thermogenic fat programming (via Prdm16 stabilization) (PMID:12679040, PMID:22402492, PMID:28740167, PMID:29539416, PMID:39154499). Independently of its SUMO ligase activity, CBX4 represses transcription by recruiting HDAC3 or HDAC1 to target promoters, and it also possesses ubiquitin E3 ligase activity toward HDAC7 (PMID:27864346, PMID:32113161, PMID:28283560). CBX4 maintains nucleolar heterochromatin to restrain ribosome biogenesis and counteract cellular senescence, is essential for epithelial lineage identity through cooperation with p63, and is itself regulated by CK1α-mediated phosphorylation that triggers its ubiquitin-dependent degradation (PMID:30917318, PMID:26711500, PMID:32111827).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2003 High

    Establishing that a Polycomb group protein could function as a SUMO E3 ligase resolved how sumoylation substrates are brought together with the E2 enzyme Ubc9 at discrete nuclear foci (Polycomb bodies).

    Evidence In vitro sumoylation reconstitution with purified CBX4/Ubc9/CtBP plus live-cell imaging of Polycomb bodies

    PMID:12679040

    Open questions at the time
    • Structural basis of CBX4-Ubc9-substrate ternary complex unresolved
    • Whether SUMO E3 activity is required for canonical PRC1-mediated gene silencing unclear
  2. 2004 High

    Domain mapping revealed that CBX4 uses two mechanistically distinct regions—an N-terminal domain with intrinsic E3 activity and a C-terminal adapter that co-recruits E2 and substrate—explaining how a single protein achieves selective SUMO conjugation.

    Evidence Domain deletion/mutagenesis with in vitro and in vivo sumoylation assays

    PMID:15592428

    Open questions at the time
    • Which domain contacts Ubc9 catalytic cysteine not mapped
    • No crystal structure of either E3-active domain
  3. 2005 High

    Expanding the substrate repertoire to SIP1 and demonstrating that sumoylation disrupts a corepressor interaction (SIP1-CtBP) showed CBX4-mediated SUMO conjugation as a transcriptional regulatory switch rather than a single-substrate phenomenon.

    Evidence In vitro/in vivo sumoylation with site-directed mutagenesis plus E-cadherin promoter reporter assays

    PMID:16061479

    Open questions at the time
    • In vivo chromatin-level effects of SIP1 sumoylation not assessed
    • Interaction with KyoT2/Notch pathway studied only by single lab (PMID:15710417)
  4. 2006 High

    Identification of an autoregulatory feedback loop—HIPK2 phosphorylates CBX4 to activate its SUMO E3 ligase toward HIPK2 itself—demonstrated that DNA damage signaling dynamically tunes CBX4 activity.

    Evidence In vitro kinase/sumoylation assays with phosphosite mutagenesis

    PMID:17018294

    Open questions at the time
    • Which phosphatase reverses HIPK2-mediated CBX4 phosphorylation unknown
    • Physiological conditions activating this loop beyond DNA damage not tested
  5. 2007 High

    Demonstration that CBX4 sumoylates the DNA methyltransferase Dnmt3a linked Polycomb SUMO ligase activity to epigenetic DNA methylation regulation.

    Evidence In vitro sumoylation with purified CBX4 and Dnmt3a plus cellular co-expression

    PMID:17439403

    Open questions at the time
    • Functional consequence of Dnmt3a sumoylation on methyltransferase activity or genomic targeting not determined
    • No in vivo genetic validation
  6. 2010 High

    Discovery of two functional SUMO-interaction motifs (SIMs) in CBX4—especially SIM2—resolved how the enzyme partitions the active SUMO~Ubc9 thioester to Polycomb foci and controls lineage-specific gene expression during ES cell differentiation.

    Evidence SIM mutagenesis with in vivo sumoylation assays, Ubc9 interaction studies, and ES cell differentiation

    PMID:20098713 PMID:20176810

    Open questions at the time
    • Genome-wide targets of SIM-dependent SUMO conjugation in differentiating ES cells not mapped
    • Whether SIM1 and SIM2 engage different SUMO paralogs in vivo remains unclear
  7. 2012 High

    Showing that CBX4 is recruited to DNA damage sites in a PARP-dependent manner and sumoylates BMI1 at K88 to enable its damage-site accumulation placed CBX4 upstream in the Polycomb-mediated DNA damage response.

    Evidence Laser micro-irradiation, in vitro sumoylation, BMI1-K88 mutagenesis, and clonogenic survival assays

    PMID:22402492

    Open questions at the time
    • Which PAR-binding domain on CBX4 mediates PARP-dependent recruitment not identified
    • Relationship between BMI1 sumoylation and ubiquitin ligase activity of PRC1 at damage sites not clarified
  8. 2013 High

    Conditional knockout demonstrated that CBX4 is cell-intrinsically required for thymic epithelial cell proliferation and thymus organogenesis, acting through physical interaction with the transcription factor p63.

    Evidence TEC-specific Cbx4 conditional knockout mice; BrdU assays; Co-IP of Cbx4-p63

    PMID:23362346

    Open questions at the time
    • Whether p63 is a SUMO substrate of CBX4 in TECs not tested
    • Transcriptional targets co-regulated by CBX4-p63 not identified genome-wide
  9. 2015 High

    Domain-specific rescue in Cbx4-null epidermis dissected the contributions of the chromodomain (repression of non-epidermal genes) versus SUMO E3 ligase domain (proliferation control via CDK inhibitor repression), and showed p63 directly regulates Cbx4 transcription, completing a reciprocal regulatory circuit.

    Evidence Cbx4 ablation in mouse skin with domain-mutant rescue; ChIP; RNA-seq; p63 binding at Cbx4 promoter

    PMID:26711500

    Open questions at the time
    • SUMO substrates mediating CDK inhibitor repression in epidermis unidentified
    • Whether chromodomain-dependent gene repression involves canonical PRC1 H2AK119ub not resolved
  10. 2016 High

    Discovery that CBX4 represses Runx2 transcription by recruiting HDAC3 to its promoter—independently of SUMO ligase activity, chromodomain, or PRC1—revealed a non-canonical, HDAC-dependent transcriptional repression function.

    Evidence ChIP, reciprocal Co-IP, domain mutagenesis, and in vivo colorectal cancer metastasis model

    PMID:27864346

    Open questions at the time
    • How CBX4 is targeted to the Runx2 promoter without chromodomain engagement unknown
    • Whether HDAC3 recruitment is a general mechanism or specific to Runx2
  11. 2017 High

    Two parallel advances linked CBX4 to homologous recombination (via CtIP sumoylation enabling DNA end resection) and to memory formation (via ubiquitin-dependent HDAC7 degradation), broadening CBX4's enzymatic repertoire to include ubiquitin E3 ligase activity.

    Evidence CtIP-K896R mutagenesis with HR reporter and resection assays (PMID:28740167); Co-IP and in vivo hippocampal manipulation for HDAC7 ubiquitination (PMID:28283560)

    PMID:28283560 PMID:28740167

    Open questions at the time
    • Whether CBX4 ubiquitin ligase activity uses a RING-dependent mechanism or distinct catalytic site unknown
    • CtIP sumoylation by CBX4 not confirmed in non-cancer cell lines
    • HDAC7 ubiquitination finding from single lab
  12. 2018 High

    Identification of Prdm16 as a CBX4 SUMO substrate in adipocytes—where sumoylation at K917 blocks ubiquitin-mediated Prdm16 degradation—established CBX4 as a regulator of thermogenic fat programming and white fat browning.

    Evidence In vitro sumoylation, K917R mutagenesis, fat-specific Cbx4 knockout/overexpression, and cold-exposure experiments

    PMID:29539416

    Open questions at the time
    • Which ubiquitin ligase targets Prdm16 in competition with SUMO not identified
    • Contribution of other CBX family members in adipocytes not assessed
  13. 2019 High

    Demonstrating that CBX4 maintains nucleolar heterochromatin by recruiting fibrillarin and KAP1 to rDNA loci, thereby restraining rRNA synthesis and ribosome biogenesis, revealed a mechanism linking Polycomb function to senescence control.

    Evidence CBX4 knockout in human mesenchymal stem cells; ChIP at rDNA; RNA-seq; ribosome profiling; mouse osteoarthritis model rescue

    PMID:30917318

    Open questions at the time
    • Whether SUMO ligase activity is required for fibrillarin/KAP1 recruitment not tested
    • Mechanism of CBX4 targeting to rDNA repeats not elucidated
  14. 2020 High

    CK1α was identified as the kinase that phosphorylates CBX4 at T437, triggering CHIP-mediated ubiquitination and degradation, establishing the first defined post-translational pathway controlling CBX4 protein turnover; TNFα stabilizes CBX4 by suppressing this phosphorylation.

    Evidence In vitro kinase assays, T437 mutagenesis, ubiquitination assays identifying K178/K280, and in vivo osteosarcoma model

    PMID:32111827

    Open questions at the time
    • Whether CK1α-mediated degradation operates in non-cancer cell types unknown
    • Context-dependent switch between CBX4-mediated Runx2 repression (colorectal) and activation (osteosarcoma) not mechanistically resolved
  15. 2024 Medium

    Sumoylation of YAP1 by CBX4 at K97/K280 was shown to competitively block S127 phosphorylation, stabilize YAP1, and promote its nuclear entry, linking CBX4's SUMO ligase activity to Hippo pathway inactivation.

    Evidence Sumoylation assays, SUMO-site mutagenesis, high-throughput sequencing, and gastric cancer tumor models

    PMID:39154499

    Open questions at the time
    • Mechanism by which SUMO conjugation blocks LATS-mediated phosphorylation not structurally defined
    • Single lab; independent confirmation needed
    • Whether this applies outside gastric cancer contexts untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • No structural model exists for CBX4 in complex with Ubc9 or any substrate, and the mechanistic basis for substrate selectivity among its growing list of SUMO targets remains undefined; additionally, how SUMO ligase-dependent and HDAC-dependent functions are coordinated at specific genomic loci is unresolved.
  • No crystal or cryo-EM structure of CBX4 E3 ligase domain or CBX4-Ubc9 complex
  • Genome-wide mapping of CBX4-SUMO versus CBX4-HDAC target gene sets not performed
  • Whether ubiquitin E3 ligase activity uses the same or distinct catalytic surface as SUMO E3 activity unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016874 ligase activity 11 GO:0140096 catalytic activity, acting on a protein 9 GO:0140110 transcription regulator activity 3 GO:0042393 histone binding 2
Localization
GO:0005634 nucleus 8 GO:0005694 chromosome 4 GO:0005730 nucleolus 1
Pathway
R-HSA-392499 Metabolism of proteins 9 R-HSA-4839726 Chromatin organization 5 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-1266738 Developmental Biology 2 R-HSA-73894 DNA Repair 2
Partners
BMI1CTBP1CTIPHDAC1HDAC3HIPK2TP63UBC9
Complex memberships
PRC1

Evidence

Reading pass · 19 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 CBX4 (Pc2) functions as a SUMO E3 ligase, dramatically enhancing sumoylation of the corepressor CtBP by recruiting both CtBP and the SUMO E2 enzyme Ubc9 to polycomb bodies, thereby bringing substrate and E2 into proximity. In vitro sumoylation assay with purified components; co-immunoprecipitation; live-cell imaging of polycomb bodies Cell High 12679040
2005 CBX4 (Pc2) acts as a SUMO E3 ligase for Smad-interacting protein 1 (SIP1), sumoylating it at Lys391 and Lys866; sumoylation disrupts SIP1 recruitment of CtBP and attenuates E-cadherin transcriptional repression in a promoter-context-dependent manner. In vivo and in vitro sumoylation assays; co-immunoprecipitation; luciferase reporter assays; site-directed mutagenesis of sumoylation sites The Journal of biological chemistry High 16061479
2006 CBX4 (Pc2) serves as a SUMO E3 ligase for HIPK2; DNA damage-induced phosphorylation of Pc2 at multiple sites (including Thr495) by HIPK2 is required for Pc2-mediated sumoylation of HIPK2, establishing an autoregulatory feedback loop that enhances HIPK2-dependent transcriptional repression. Co-immunoprecipitation; in vitro kinase and sumoylation assays; site-directed mutagenesis; immunofluorescence Molecular cell High 17018294
2007 CBX4 (Cbx4) functions as a SUMO E3 ligase for the de novo DNA methyltransferase Dnmt3a, promoting its SUMO-1 modification at the N-terminal regulatory region including the PWWP domain; purified Cbx4 directly promotes Dnmt3a sumoylation in vitro. Co-immunoprecipitation; in vitro sumoylation assay with purified Cbx4; transfection co-expression The Biochemical journal High 17439403
2010 CBX4 (Pc2) contains two functional SUMO interaction motifs (SIMs) that are required for full E3 ligase activity; the SIMs contribute to Pc2 self-sumoylation, CtBP sumoylation, and enrichment of SUMO at polycomb foci, and interact with the SIM-binding surface of both SUMO1 and SUMO2. Mutagenesis of SIMs; in vivo sumoylation assays; immunofluorescence; SUMO isoform mutant analysis PloS one High 20098713 20176810
2010 CBX4 (Pc2) SIM2 is crucial for its E3 ligase activity by enabling subnuclear partitioning of the active SUMO~Ubc9 thioester intermediate and controlling lineage-specific gene expression during embryonic stem cell differentiation. SIM mutagenesis; in vivo sumoylation assays; Ubc9 interaction studies; ES cell differentiation assays Molecular and cellular biology High 20176810
2004 CBX4 (Pc2) E3 ligase activity requires two distinct domains: a C-terminal adapter domain that recruits both Ubc9 and CtBP, and a second N-terminal domain with intrinsic E3 activity in vitro; adapter function is required to selectively co-recruit E2 and substrate in vivo. Domain deletion and mutagenesis; in vitro sumoylation assays with domain fragments; in vivo sumoylation assays The EMBO journal High 15592428
2012 CBX4 is recruited to DNA damage sites in a PARP-dependent manner (independent of H2AX, RNF8, BMI1, and PI3-related kinases) and acts as a SUMO E3 ligase for BMI1, sumoylating it at lysine 88; this sumoylation is required for BMI1 accumulation at DNA lesions and for cellular resistance to ionizing radiation. Laser micro-irradiation with live-cell imaging; co-immunoprecipitation; in vitro sumoylation; siRNA knockdown with clonogenic survival assay; site-directed mutagenesis of BMI1-K88 Nucleic acids research High 22402492
2017 CBX4 SUMO E3 ligase constitutively sumoylates CtIP at lysine 896, which is required for CtIP recruitment to DNA double-strand breaks and for DNA end resection; CBX4 depletion or non-sumoylatable CtIP-K896R blocks homologous recombination and increases genomic instability; artificial CtIP-SUMO fusion rescues these defects. siRNA depletion; site-directed mutagenesis (K896R); resection assays; HR reporter assay; CtIP-SUMO fusion rescue; laser micro-irradiation imaging Nature communications High 28740167
2016 CBX4 suppresses colorectal carcinoma metastasis by repressing Runx2 transcription through recruiting HDAC3 to the Runx2 promoter, maintaining deacetylated H3K27; this function requires the CBX4-HDAC3 interaction but is independent of its SUMO E3 ligase activity, chromodomain, or PRC1 complex. Co-immunoprecipitation; chromatin immunoprecipitation; domain mutagenesis; migration/invasion assays; in vivo metastasis model Cancer research High 27864346
2020 CBX4 promotes osteosarcoma metastasis by transcriptionally upregulating Runx2 via recruitment of the acetyltransferase GCN5 to the Runx2 promoter; CK1α phosphorylates CBX4 at T437, facilitating its ubiquitination at K178 and K280 and subsequent CHIP-mediated degradation; TNFα reduces this phosphorylation to stabilize CBX4. Co-immunoprecipitation; ChIP; phosphorylation and ubiquitination assays; site-directed mutagenesis; kinase assays; in vivo metastasis model Nature communications High 32111827
2019 CBX4 counteracts human mesenchymal stem cell senescence by recruiting nucleolar proteins fibrillarin (FBL) and KAP1 to rDNA loci, limiting excessive rRNA expression, ribosome biogenesis, and protein translation; CBX4 knockout destabilizes nucleolar heterochromatin and accelerates senescence. CBX4 knockout in hMSCs; RNA-seq; ChIP; co-immunoprecipitation; rRNA quantification; ribosome profiling; mouse osteoarthritis model with CBX4 overexpression Cell reports High 30917318
2018 Cbx4 is a SUMO E3 ligase for Prdm16 in brown/beige adipocytes; Cbx4-mediated sumoylation of Prdm16 at K917 blocks its ubiquitination-mediated degradation, stabilizes Prdm16, augments thermogenic gene expression, and is required for white fat browning; this sumoylation also primes Prdm16 for further stabilization by methyltransferase Ehmt1. In vitro sumoylation assay; site-directed mutagenesis (K917R); ubiquitination assay; fat-specific Cbx4 knockout and overexpression; cold-exposure experiments; thermogenic gene expression analysis Cell reports High 29539416
2013 Cbx4 is essential for thymic epithelial cell (TEC) proliferation and thymus organogenesis; cell-specific deletion shows the defect is intrinsic to TECs; Cbx4 physically interacts with p63 transcription factor, and the two functionally cooperate to maintain TEC stemness and proliferative capacity. Conditional Cbx4 knockout mice; BrdU proliferation assay; co-immunoprecipitation of Cbx4 with p63; histology and flow cytometry of thymic compartments Development (Cambridge, England) High 23362346
2015 Cbx4 maintains epithelial lineage identity and keratinocyte proliferation in developing epidermis by repressing neuronal gene programs and cyclin-dependent kinase inhibitors (p16/p19, p57); its chromodomain and SUMO E3 ligase activities differentially regulate proliferation, differentiation, and nonepidermal gene repression; Cbx4 expression is directly regulated by p63. Cbx4 ablation in mice; domain-specific mutant rescue experiments; ChIP; RNA-seq; p63 binding to Cbx4 promoter The Journal of cell biology High 26711500
2005 CBX4 (HPC2) interacts with the LIM domain protein KyoT2 through its C-terminal fragment; this interaction enables CBX4 to inhibit RBP-J-mediated transcriptional activation by Notch intracellular domain (NIC) and by constitutively active RBP-J-VP16. Yeast two-hybrid; GST pulldown; co-immunoprecipitation; mammalian two-hybrid; luciferase reporter assay FEBS letters Medium 15710417
2017 CBX4 acts as a ubiquitin E3 ligase for HDAC7, mediating its ubiquitin-dependent degradation in the dorsal hippocampus after contextual fear conditioning; this degradation derepresses Nur77 and promotes long-term memory formation. Co-immunoprecipitation; ubiquitination assay identifying CBX4 as E3 for HDAC7; in vivo hippocampal manipulation; contextual fear conditioning behavioral assay The Journal of neuroscience Medium 28283560
2020 CBX4 transcriptionally suppresses KLF6 in clear cell renal cell carcinoma by physically binding HDAC1 and maintaining HDAC1 localization on the KLF6 promoter; disruption of CBX4-HDAC1 interaction attenuates CBX4-mediated tumor growth and migration. Co-immunoprecipitation; ChIP; luciferase reporter assay; domain disruption experiments; in vivo xenograft model EBioMedicine Medium 32113161
2024 CBX4 sumoylates YAP1 at K97 and K280 (SUMO1 modification), which competitively inhibits YAP1-S127 phosphorylation, preserves YAP1 stability, and promotes its cytoplasm-to-nucleus transport, thereby inactivating the Hippo pathway and countering cellular senescence and chemoresistance in gastric cancer; CEBPB transcriptionally downregulates CBX4 in response to low-dose cisplatin. Co-immunoprecipitation; ChIP; sumoylation assays; high-throughput sequencing; site-directed mutagenesis of SUMO sites; in vitro and in vivo tumor models Drug resistance updates Medium 39154499

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1991 PC1 and PC2 are proprotein convertases capable of cleaving proopiomelanocortin at distinct pairs of basic residues. Proceedings of the National Academy of Sciences of the United States of America 596 2023902
1991 Identification of a cDNA encoding a second putative prohormone convertase related to PC2 in AtT20 cells and islets of Langerhans. Proceedings of the National Academy of Sciences of the United States of America 482 1988934
2003 The polycomb protein Pc2 is a SUMO E3. Cell 469 12679040
1992 Distribution and regulation of the prohormone convertases PC1 and PC2 in the rat pituitary. Molecular endocrinology (Baltimore, Md.) 261 1316544
1993 The prohormone convertases PC1 and PC2 mediate distinct endoproteolytic cleavages in a strict temporal order during proopiomelanocortin biosynthetic processing. The Journal of biological chemistry 226 8380577
1994 Proglucagon is processed to glucagon by prohormone convertase PC2 in alpha TC1-6 cells. Proceedings of the National Academy of Sciences of the United States of America 184 8159732
1995 Differential processing of proglucagon by the subtilisin-like prohormone convertases PC2 and PC3 to generate either glucagon or glucagon-like peptide. The Journal of biological chemistry 173 7592866
2007 TAZ promotes PC2 degradation through a SCFbeta-Trcp E3 ligase complex. Molecular and cellular biology 155 17636028
2016 Structure of the polycystic kidney disease TRP channel Polycystin-2 (PC2). Nature structural & molecular biology 148 27991905
2000 Regulation of pancreatic PC1 and PC2 associated with increased glucagon-like peptide 1 in diabetic rats. The Journal of clinical investigation 138 10749575
2005 Pc2-mediated sumoylation of Smad-interacting protein 1 attenuates transcriptional repression of E-cadherin. The Journal of biological chemistry 131 16061479
1994 The developmental expression in rat of proteases furin, PC1, PC2, and carboxypeptidase E: implications for early maturation of proteolytic processing capacity. The Journal of neuroscience : the official journal of the Society for Neuroscience 125 8046441
2020 Targeting the CK1α/CBX4 axis for metastasis in osteosarcoma. Nature communications 123 32111827
2000 Association of HPC2/ELAC2 genotypes and prostate cancer. American journal of human genetics 123 10986046
2012 CBX4-mediated SUMO modification regulates BMI1 recruitment at sites of DNA damage. Nucleic acids research 122 22402492
1995 Proprotein convertases (PC1/PC3 and PC2) in normal and neoplastic human tissues: their use as markers of neuroendocrine differentiation. The Journal of clinical endocrinology and metabolism 117 7829629
1999 The cell biology of the prohormone convertases PC1 and PC2. Progress in nucleic acid research and molecular biology 110 10506829
2019 Maintenance of Nucleolar Homeostasis by CBX4 Alleviates Senescence and Osteoarthritis. Cell reports 108 30917318
1999 The subtilisin/kexin family of precursor convertases. Emphasis on PC1, PC2/7B2, POMC and the novel enzyme SKI-1. Annals of the New York Academy of Sciences 108 10816641
1997 Comparative analysis of expression of the proprotein convertases furin, PACE4, PC1 and PC2 in human lung tumours. British journal of cancer 107 9166946
2006 Phosphorylation-dependent control of Pc2 SUMO E3 ligase activity by its substrate protein HIPK2. Molecular cell 104 17018294
2001 The prohormone convertase enzyme 2 (PC2) is essential for processing pro-islet amyloid polypeptide at the NH2-terminal cleavage site. Diabetes 95 11246872
2002 Isolation and characterization of VGF peptides in rat brain. Role of PC1/3 and PC2 in the maturation of VGF precursor. Journal of neurochemistry 94 12065665
1995 7B2 is a specific intracellular binding protein of the prohormone convertase PC2. Journal of neurochemistry 89 7722516
1995 Differences in pH optima and calcium requirements for maturation of the prohormone convertases PC2 and PC3 indicates different intracellular locations for these events. The Journal of biological chemistry 87 7836407
2007 Polycomb protein Cbx4 promotes SUMO modification of de novo DNA methyltransferase Dnmt3a. The Biochemical journal 85 17439403
2001 Evaluation of linkage and association of HPC2/ELAC2 in patients with familial or sporadic prostate cancer. American journal of human genetics 85 11254448
2006 Impaired NH2-terminal processing of human proislet amyloid polypeptide by the prohormone convertase PC2 leads to amyloid formation and cell death. Diabetes 81 16873681
1994 Developmental expression of the prohormone convertases PC1 and PC2 in mouse pancreatic islets. Endocrinology 81 7925129
2016 CBX4 Suppresses Metastasis via Recruitment of HDAC3 to the Runx2 Promoter in Colorectal Carcinoma. Cancer research 79 27864346
2001 Role of HPC2/ELAC2 in hereditary prostate cancer. Cancer research 79 11522646
1993 Heterologous processing of prosomatostatin in constitutive and regulated secretory pathways. Putative role of the endoproteases furin, PC1, and PC2. The Journal of biological chemistry 79 8095501
2000 Defective prodynorphin processing in mice lacking prohormone convertase PC2. Journal of neurochemistry 77 10987860
1992 Identification and analysis of the gene encoding human PC2, a prohormone convertase expressed in neuroendocrine tissues. Proceedings of the National Academy of Sciences of the United States of America 75 1594602
2007 Pc2 and SUMOylation. Biochemical Society transactions 72 18031231
2003 Biological processing of the cocaine and amphetamine-regulated transcript precursors by prohormone convertases, PC2 and PC1/3. The Journal of biological chemistry 71 12584191
2008 The cellulase/hemicellulase system of the anaerobic fungus Orpinomyces PC-2 and aspects of its applied use. Annals of the New York Academy of Sciences 70 18378601
2006 Implication of polycomb members Bmi-1, Mel-18, and Hpc-2 in the regulation of p16INK4a, p14ARF, h-TERT, and c-Myc expression in primary breast carcinomas. Clinical cancer research : an official journal of the American Association for Cancer Research 68 17145810
2010 A role for non-covalent SUMO interaction motifs in Pc2/CBX4 E3 activity. PloS one 65 20098713
1996 Identification of a transferable sorting domain for the regulated pathway in the prohormone convertase PC2. The Journal of biological chemistry 65 8810291
1995 Characterization of the endopeptidase PC2 activity towards secretogranin II in stably transfected PC12 cells. The Biochemical journal 65 7575410
1995 Comparative proteolytic processing of rat prosomatostatin by the convertases PC1, PC2, furin, PACE4 and PC5 in constitutive and regulated secretory pathways. FEBS letters 65 7720860
1992 The post-translational processing and intracellular sorting of PC2 in the islets of Langerhans. The Journal of biological chemistry 65 1429592
2001 ELAC2/HPC2 involvement in hereditary and sporadic prostate cancer. Cancer research 64 11507049
1996 Glucose-regulated translational control of proinsulin biosynthesis with that of the proinsulin endopeptidases PC2 and PC3 in the insulin-producing MIN6 cell line. Diabetes 62 8522057
2004 Multiple activities contribute to Pc2 E3 function. The EMBO journal 61 15592428
1994 RNA polymerase II cofactor PC2 facilitates activation of transcription by GAL4-AH in vitro. Molecular and cellular biology 61 8196633
1992 Structure and expression of Xenopus prohormone convertase PC2. FEBS letters 61 1633858
2013 Cbx4 regulates the proliferation of thymic epithelial cells and thymus function. Development (Cambridge, England) 59 23362346
2017 CBX4 exhibits oncogenic activities in breast cancer via Notch1 signaling. The international journal of biochemistry & cell biology 58 29229426
1997 Role of the prohormone convertase PC2 in the processing of proglucagon to glucagon. FEBS letters 58 9287128
2008 Polycystin-2 expression is regulated by a PC2-binding domain in the intracellular portion of fibrocystin. The Journal of biological chemistry 56 18782757
1994 Calcium- and pH-dependent aggregation and membrane association of the precursor of the prohormone convertase PC2. The Journal of biological chemistry 56 8034613
2015 Cbx4 maintains the epithelial lineage identity and cell proliferation in the developing stratified epithelium. The Journal of cell biology 54 26711500
1995 Purification and characteristics of the candidate prohormone processing proteases PC2 and PC1/3 from bovine adrenal medulla chromaffin granules. The Journal of biological chemistry 54 7713926
2001 Polymorphisms in the prostate cancer susceptibility gene HPC2/ELAC2 in multiplex families and healthy controls. Cancer research 51 11431329
1994 Levels of the conversion endoproteases PC1 (PC3) and PC2 distinguish between insulin-producing pancreatic islet beta cells and non-beta cells. The Biochemical journal 51 8198551
2013 Hexa-D-arginine treatment increases 7B2•PC2 activity in hyp-mouse osteoblasts and rescues the HYP phenotype. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 49 22886699
1991 Chromosomal assignments of the genes for neuroendocrine convertase PC1 (NEC1) to human 5q15-21, neuroendocrine convertase PC2 (NEC2) to human 20p11.1-11.2, and furin (mouse 7[D1-E2] region). Genomics 49 1765368
2020 LncRNA FOXP4-AS1 Is Involved in Cervical Cancer Progression via Regulating miR-136-5p/CBX4 Axis. OncoTargets and therapy 48 32256085
2019 CBX4 promotes the proliferation and metastasis via regulating BMI-1 in lung cancer. Journal of cellular and molecular medicine 48 31724308
1996 Identification of the thyrotropin-releasing hormone precursor, its processing products, and its coexpression with convertase 1 in primary cultures of hypothalamic neurons: anatomic distribution of PC1 and PC2. Endocrinology 48 8940396
2003 ELAC2/HPC2 polymorphisms, prostate-specific antigen levels, and prostate cancer. Journal of the National Cancer Institute 46 12783937
2000 Regional and cellular localization of the neuroendocrine prohormone convertases PC1 and PC2 in the rat central nervous system. The Journal of comparative neurology 45 10906712
2018 miR-129-5p suppresses breast cancer proliferation by targeting CBX4. Neoplasma 44 29940764
2020 CBX4 transcriptionally suppresses KLF6 via interaction with HDAC1 to exert oncogenic activities in clear cell renal cell carcinoma. EBioMedicine 43 32113161
2004 Differential regulation and xenobiotic induction of tandem P450 monooxygenase genes pc-1 (CYP63A1) and pc-2 (CYP63A2) in the white-rot fungus Phanerochaete chrysosporium. Applied microbiology and biotechnology 43 15378295
2017 DNA end resection requires constitutive sumoylation of CtIP by CBX4. Nature communications 42 28740167
2010 The SUMO E3 ligase activity of Pc2 is coordinated through a SUMO interaction motif. Molecular and cellular biology 41 20176810
1991 Site-directed mutagenesis and expression of PC2 in microinjected Xenopus oocytes. The Journal of biological chemistry 41 1748673
1996 Proinsulin processing in the rat insulinoma cell line INS after overexpression of the endoproteases PC2 or PC3 by recombinant adenovirus. The Biochemical journal 40 8947461
1997 Proinsulin conversion in GH3 cells after coexpression of human proinsulin with the endoproteases PC2 and/or PC3. Diabetes 39 9166668
1996 Differential coexpression of genes encoding prothyrotropin-releasing hormone (pro-TRH) and prohormone convertases (PC1 and PC2) in rat brain neurons: implications for differential processing of pro-TRH. Endocrinology 36 8625894
1996 Role of PC2 in proenkephalin processing: antisense and overexpression studies. Journal of neurochemistry 36 8769847
1998 Structural elements of PC2 required for interaction with its helper protein 7B2. The Journal of biological chemistry 35 9422782
2002 HPC2/ELAC2 polymorphisms and prostate cancer risk: analysis by age of onset of disease. British journal of cancer 34 12373607
2018 Cbx4 Sumoylates Prdm16 to Regulate Adipose Tissue Thermogenesis. Cell reports 33 29539416
2004 Significance of prohormone convertase 2, PC2, mediated initial cleavage at the proglucagon interdomain site, Lys70-Arg71, to generate glucagon. Endocrinology 33 15528303
1992 Processing of adrenocorticotropin by two proteases in bovine intermediate lobe secretory vesicle membranes. A distinct acidic, tetrabasic residue-specific calcium-activated serine protease and a PC2-like enzyme. The Journal of biological chemistry 33 1313803
1996 Peptide biosynthetic processing: distinguishing prohormone convertases PC1 and PC2. Molecular and cellular endocrinology 32 8832576
1998 Proglucagon processing in an islet cell line: effects of PC1 overexpression and PC2 depletion. Endocrinology 31 9528943
2019 MicroRNA-497-5p Induces Cell Cycle Arrest Of Cervical Cancer Cells In S Phase By Targeting CBX4. OncoTargets and therapy 30 31849480
1994 Prohormone convertases PC2 and PC3 in rat neutrophils and macrophages. Parallel changes with proenkephalin-derived peptides induced by LPS in vivo. Neuropeptides 30 7808596
2020 Circular RNA hsa_circ_0008039 promotes proliferation, migration and invasion of breast cancer cells through upregulating CBX4 via sponging miR-515-5p. European review for medical and pharmacological sciences 29 32141558
2008 Expression of PCSK1 (PC1/3), PCSK2 (PC2) and PCSK3 (furin) in mouse small intestine. Regulatory peptides 29 18706454
2021 Inhibiting CBX4 efficiently protects hepatocellular carcinoma cells against sorafenib resistance. British journal of cancer 28 33473171
2015 MicroRNA-195 functions as a tumor suppressor by inhibiting CBX4 in hepatocellular carcinoma. Oncology reports 28 25607636
2009 Pax6 regulates the proglucagon processing enzyme PC2 and its chaperone 7B2. Molecular and cellular biology 28 19223471
2003 The proprotein convertase PC2 is involved in the maturation of prosomatostatin to somatostatin-14 but not in the somatostatin deficit in Alzheimer's disease. Neuroscience 28 14614908
2017 HDAC7 Ubiquitination by the E3 Ligase CBX4 Is Involved in Contextual Fear Conditioning Memory Formation. The Journal of neuroscience : the official journal of the Society for Neuroscience 27 28283560
2024 CBX4 counteracts cellular senescence to desensitize gastric cancer cells to chemotherapy by inducing YAP1 SUMOylation. Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy 25 39154499
2010 Silencing mediated by the Schizosaccharomyces pombe HIRA complex is dependent upon the Hpc2-like protein, Hip4. PloS one 25 20976105
2005 The PcG protein HPC2 inhibits RBP-J-mediated transcription by interacting with LIM protein KyoT2. FEBS letters 25 15710417
1994 Cellular distributions of the prohormone processing enzymes PC1 and PC2. Molecular and cellular neurosciences 25 7704436
1996 Processing of pro-opiomelanocortin in GH3 cells: inhibition by prohormone convertase 2 (PC2) antisense mRNA. Molecular and cellular endocrinology 24 8822269
1994 Expression of the prohormone convertase PC2 correlates with the presence of corticotropin-like intermediate lobe peptide in human adrenocorticotropin-secreting tumors. The Journal of clinical endocrinology and metabolism 24 7962350
1998 Two genes of the anaerobic fungus Orpinomyces sp. strain PC-2 encoding cellulases with endoglucanase activities may have arisen by gene duplication. FEMS microbiology letters 23 9485595
1997 Expression of the proprotein convertases PC1 and PC2 mRNAs in thyrotropin releasing hormone neurons of the rat paraventricular nucleus of hypothalamus. Brain research 22 9247068
1997 Convertase PC2 and the neuroendocrine polypeptide 7B2 are co-induced and processed during neuronal differentiation of P19 embryonal carcinoma cells. DNA and cell biology 22 9364928
1995 The role of prohormone convertases PC1 (PC3) and PC2 in the cell-specific processing of proglucagon. Biochemical and biophysical research communications 22 7864855