Affinage

COP1

Caspase recruitment domain-containing protein 16 · UniProt Q5EG05

Length
197 aa
Mass
22.6 kDa
Annotated
2026-06-09
100 papers in source corpus 34 papers cited in narrative 33 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

COP1 (RFWD2) is a RING-finger E3 ubiquitin ligase that controls the abundance of transcription factors and metabolic enzymes by directing them for ubiquitin-mediated proteasomal degradation, acting both autonomously and as the substrate receptor of CUL4-DDB1 (CRL4) complexes (PMID:15103385, PMID:37390815, PMID:37679762). It recognizes substrates through a short VP degron motif, exemplified by direct VP-dependent binding to p27Kip1, ATGL, and FOXO4 (PMID:26254224, PMID:27658392, PMID:33101846), and degron loss—as occurs in prostate-cancer ETV1 translocations—stabilizes substrates (PMID:21572435); alternate non-VP recognition surfaces also operate, as seen for GATA2 (PMID:36251994). COP1 typically directs K48-linked polyubiquitination and degradation of its substrates (PMID:27658392, PMID:35084653), but can also catalyze non-proteolytic K63-linked ubiquitination that instead inhibits enzymatic activity, demonstrated for the plant IAA-amino acid synthetase GH3.5 (PMID:40229271). Its substrate repertoire spans the tumor suppressor p53 (PMID:15103385), the AP-1 factor c-Jun (PMID:21403399), the ETS factors ETV1/4/5 (PMID:21572435, PMID:27335464, PMID:26627735), C/EBPα/β/δ (PMID:23884858, PMID:32795415, PMID:34582788), and additional targets including MTA1, ATGL, GATA2, SIRT1, and UTX (PMID:19805145, PMID:27658392, PMID:36251994, PMID:31125554, PMID:37679762), placing COP1 at the center of growth control, lipid metabolism, inflammation, and development. Through these substrates COP1 can act as a tumor suppressor—mouse hypomorphs develop malignancies with elevated c-Jun, and COP1 loss elevates ETV-driven prostate and lung phenotypes (PMID:21403399, PMID:21572435, PMID:27335464)—or as an oncogenic driver when it degrades p53 or is hijacked by Trib scaffolds to destroy C/EBP family proteins in AML (PMID:20805362, PMID:23884858, PMID:37390815). COP1 activity is tightly regulated: ATM phosphorylates COP1 at Ser387 after DNA damage to trigger autodegradation and nuclear export and thereby stabilize p53 (PMID:16931761), a step reinforced by 14-3-3σ binding to phospho-Ser387 (PMID:21135113, PMID:20843328); Erk1/2 signaling anchors COP1 at the nuclear envelope via the nucleoporin TPR, and Erk inactivation releases it into the nucleoplasm to degrade c-Jun and ETV substrates (PMID:32041890); and the COP9 signalosome competitively displaces COP1 from CRL4, gating assembly of the active CRL4^COP1 ligase (PMID:37390815, PMID:33911083, PMID:31155351). In plants, COP1 integrates light signaling by binding the photoreceptor UVR8 and the transcription factor HY5 through competitive VP-motif interactions resolved structurally (PMID:31304983, PMID:35442727).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2002 Medium

    Established the basic cell-biological properties of mammalian COP1 as a self-ubiquitinating protein with defined nuclear import/export signals, framing how its localization could control activity.

    Evidence Mutagenesis of NLS/NES elements with subcellular fractionation and immunofluorescence

    PMID:12466024

    Open questions at the time
    • Substrates not yet identified
    • Functional consequence of shuttling for substrate degradation not established
  2. 2004 High

    Answered whether COP1 acts as an E3 ligase in mammals by showing it directly ubiquitinates p53 independently of MDM2/Pirh2, defining COP1 as a p53 regulator.

    Evidence Co-IP, in vitro ubiquitination, siRNA knockdown and cell-cycle analysis in human cells

    PMID:15103385

    Open questions at the time
    • Degron on p53 not mapped
    • CRL4 versus autonomous ligase mode not distinguished at this stage
  3. 2006 High

    Resolved how DNA damage relieves COP1-mediated p53 suppression by identifying ATM phosphorylation of Ser387 as the trigger for COP1 autodegradation and relocalization.

    Evidence In vitro kinase assay, S387 mutagenesis, immunofluorescence and Co-IP after ionizing radiation

    PMID:16931761

    Open questions at the time
    • Whether autodegradation is intramolecular or trans not defined
    • Other kinases acting on COP1 unknown
  4. 2010 Medium

    Defined the regulatory logic downstream of Ser387 phosphorylation by showing 14-3-3σ binds phospho-COP1 to enforce nuclear export and self-ubiquitination, and showed GSK3β-primed c-Jun is the degradation-competent form.

    Evidence Co-IP, S387 mutagenesis, nuclear-export and ubiquitination assays; GSK3β inhibitor experiments

    PMID:20843328 PMID:21135113 PMID:24027432

    Open questions at the time
    • Single-lab findings without reciprocal in vivo validation
    • Stoichiometry of 14-3-3σ-COP1 complex unresolved
  5. 2011 High

    Established COP1 as a bona fide tumor suppressor in vivo via c-Jun/AP-1 and as the degrader of ETS factors whose degron loss drives prostate cancer.

    Evidence Mouse hypomorph allelic series and prostate-specific KO with c-Jun and ETV1 epistasis and degron mutagenesis

    PMID:21403399 PMID:21572435

    Open questions at the time
    • Tissue-specific substrate selectivity not fully explained
    • Relative contribution of c-Jun versus ETV substrates to tumor suppression unclear
  6. 2013 High

    Defined Trib-scaffold-dependent substrate recruitment, showing COP1 is hijacked via Trib1/Trib2 to degrade C/EBPα and drive AML, revealing an oncogenic mode of COP1.

    Evidence COP1-binding domain mutagenesis, bone marrow transplantation AML models, ligase-dead COP1 controls

    PMID:20805362 PMID:23884858

    Open questions at the time
    • Structural basis of Trib-COP1 engagement not solved here
    • Whether Trib scaffolds redirect CRL4 assembly not addressed
  7. 2015 High

    Generalized the VP-degron substrate-recognition mechanism and demonstrated tissue-specific physiology, identifying p27Kip1 and ATGL as VP-motif substrates and ETV factors as the effectors of COP1 in lung branching and β-cell insulin secretion.

    Evidence VP-motif interaction mapping, ubiquitination assays, conditional KO mice with ETV genetic rescue

    PMID:25945542 PMID:26254224 PMID:26627735 PMID:27335464

    Open questions at the time
    • Determinants of substrate selectivity among many VP-motif proteins unclear
    • CSN6 cofactor role mechanistically incomplete
  8. 2016 High

    Linked COP1 to lipid metabolism by showing it directs K48-linked degradation of ATGL at Lys100, with COP1 depletion ameliorating hepatic steatosis.

    Evidence K48-specific ubiquitination assay, K100 mutagenesis, adenoviral COP1 depletion in mouse liver

    PMID:27658392

    Open questions at the time
    • Upstream signals controlling hepatic COP1 activity not defined
  9. 2019 High

    Established the structural basis of competitive VP-motif recognition in plant light signaling and broadened the substrate set (SIRT1) and CRL4-regulatory inputs (cryptochromes via Det1).

    Evidence Crystal structures of UVR8/HY5 VP motifs bound to WD40 domain; Co-IP and substrate accumulation assays for SIRT1 and CRY-Det1

    PMID:31125554 PMID:31155351 PMID:31304983

    Open questions at the time
    • Whether mammalian substrates engage WD40 identically not tested
    • CRY/Det1 regulation single-lab in vivo
  10. 2020 High

    Defined spatial regulation of COP1 by Erk1/2 via TPR anchoring and extended physiological roles to microglial inflammation through C/EBPβ and to FOXO4 control downstream of EGF-Akt.

    Evidence Co-IP of COP1-TPR, immunofluorescence redistribution after MEK inhibition; microglial conditional KO with Cebpb epistasis; FOXO4 VP-motif and CSN6 assays

    PMID:32041890 PMID:32795415 PMID:33101846

    Open questions at the time
    • How TPR release is coupled to specific substrate engagement unclear
    • FOXO4 finding single-lab
  11. 2022 High

    Clarified CRL4^COP1 assembly control by CSN/IP6 antagonism and expanded substrate scope to GATA2 (via non-VP BR motifs) and PCDH9.

    Evidence Co-IP, ubiquitination assays, MLN4924 neddylation inhibition, Csn2 knockin mice; GATA2 K419/K424 mutagenesis and xenografts; PCDH9 K48 assays

    PMID:33911083 PMID:35084653 PMID:36251994

    Open questions at the time
    • How non-VP substrates are selected mechanistically unresolved
    • Quantitative balance between autonomous and CRL4-bound COP1 in cells unknown
  12. 2023 High

    Connected metabolic signaling to CRL4^COP1 assembly and substrate range, showing glucose/CK2 O-GlcNAcylation releases CRL4 from CSN to degrade p53 and amplify glycolysis, and identifying a CUL4B-DDB1-COP1 complex degrading UTX.

    Evidence Biochemical reconstitution, peptide inhibitor disruption, conditional p53 KO tumor model; Co-IP and intestinal Cop1 KO CRC model

    PMID:37390815 PMID:37679762

    Open questions at the time
    • Whether other metabolic cues converge on CSN-COP1 switch untested
    • UTX degradation finding single-lab
  13. 2024 High

    Extended COP1 substrate logic to neuronal and immune physiology, showing ETV5 mediates RFWD2-driven synaptic/autism phenotypes and that IL-37d enhances COP1 recruitment to C/EBPβ.

    Evidence RFWD2 knockin mice with ETV5 viral rescue, electrophysiology; Co-IP and ubiquitination with IL-37d treatment in lung carcinoma model

    PMID:38363681 PMID:38503925

    Open questions at the time
    • Mechanism coupling ETV5 degradation to spine density not detailed
    • IL-37d finding single-lab
  14. 2025 High

    Demonstrated a non-proteolytic activity mode, showing COP1 K63-ubiquitinates GH3.5 to inhibit enzyme activity rather than trigger degradation, and links light signaling to chromatin regulation via VIL1.

    Evidence K63-specific in vitro ubiquitination, enzyme-activity and metabolite assays; Co-IP and chromatin loop/H3K27me3 analyses

    PMID:38349881 PMID:40229271

    Open questions at the time
    • Whether mammalian COP1 also performs K63-linked regulatory ubiquitination unknown
    • VIL1-chromatin mechanism partly correlative

Open questions

Synthesis pass · forward-looking unresolved questions
  • How COP1 chooses among autonomous versus CRL4-bound ligase modes and discriminates the large set of VP- and non-VP substrates in a tissue- and signal-specific manner remains unresolved.
  • No unifying model linking localization, CRL4 assembly, and substrate selection
  • Structural basis for non-VP substrate recognition (e.g., GATA2) unsolved
  • Determinants of K48 vs K63 linkage choice undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016874 ligase activity 7 GO:0140096 catalytic activity, acting on a protein 5 GO:0060089 molecular transducer activity 4
Localization
GO:0005634 nucleus 3 GO:0005829 cytosol 2 GO:0005635 nuclear envelope 1 GO:0005654 nucleoplasm 1
Pathway
R-HSA-1643685 Disease 5 R-HSA-392499 Metabolism of proteins 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-1430728 Metabolism 3 R-HSA-168256 Immune System 3 R-HSA-73894 DNA Repair 2
Partners
14-3-3SIGMAC-JUNDDB1ETV1/ETV4/ETV5MTA1P53TPRTRIB1/TRIB2
Complex memberships
COP1-SPA (plant light signaling)CRL4^COP1 (CUL4-DDB1-DET1-COP1)CUL4B-DDB1-COP1

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 COP1 physically interacts with p53 and functions as an E3 ubiquitin ligase for p53 in vitro and in vivo, targeting p53 for ubiquitin-dependent proteasomal degradation independently of MDM2 or Pirh2, thereby inhibiting p53-dependent transcription and apoptosis. Co-immunoprecipitation, in vitro ubiquitination assay, siRNA knockdown, cell cycle analysis Nature High 15103385
2006 Following DNA damage, ATM kinase phosphorylates COP1 on Ser387, triggering rapid COP1 autodegradation and nuclear-to-cytoplasmic redistribution, which disrupts the COP1-p53 complex, abrogates p53 ubiquitination, and allows p53 stabilization. In vitro kinase assay, site-directed mutagenesis, immunofluorescence, co-immunoprecipitation, ionizing radiation treatment Science High 16931761
2011 COP1 constitutively targets c-Jun for ubiquitin-mediated degradation in vivo; Cop1 hypomorphic mice develop spontaneous malignancies with elevated c-Jun, and Cop1-deficient cell proliferation is c-Jun-dependent, establishing COP1 as a tumor suppressor acting through c-Jun/AP-1. Mouse genetic allelic series (hypomorphs), in vivo ubiquitination, western blot, genetic epistasis (c-Jun rescue), bone marrow transplantation The Journal of clinical investigation High 21403399
2011 COP1 ubiquitinates and degrades the ETS transcription factors ETV1, ETV4, and ETV5; prostate cancer translocations remove the COP1-binding degron motifs from ETV1, rendering it ~50-fold more stable; COP1 deficiency in mouse prostate elevates ETV1 and produces hyperplasia and early PIN. Ubiquitination assays, co-immunoprecipitation, site-directed mutagenesis of degron motifs, mouse prostate-specific KO, protein stability assays Nature High 21572435
2002 Mammalian COP1 binds ubiquitinated proteins in vivo and is itself ubiquitinated; it contains a leucine-rich nuclear export signal (NES) in the coiled-coil domain and a novel bipartite NLS bridged by the RING finger; disruption of the RING finger abolishes nuclear import. Mutagenesis, subcellular fractionation, immunofluorescence, co-immunoprecipitation BMC cell biology Medium 12466024
2009 COP1 interacts with MTA1 and acts as its E3 ubiquitin ligase targeting it for proteasomal degradation; the RING motif is required for this activity. MTA1 in turn promotes COP1 autoubiquitination, creating a feedback loop; ionizing radiation disrupts this to stabilize MTA1. Co-immunoprecipitation, in vitro ubiquitination assay, RING-motif mutagenesis, siRNA knockdown, ionizing radiation treatment Proceedings of the National Academy of Sciences of the United States of America High 19805145
2010 COP1 functions as an E3 ubiquitin ligase for c-Jun in mammalian cancer cells; depletion of COP1 reduces c-Jun poly-ubiquitination and stabilizes c-Jun protein, contributing to invasive breast cancer; GSK3β phosphorylation of c-Jun is required for efficient COP1-mediated degradation. siRNA knockdown, co-immunoprecipitation, ubiquitination assay, GSK3β inhibitors, overexpression rescue Neoplasia Medium 24027432
2010 14-3-3σ binds phosphorylated COP1 at Ser387 after DNA damage and promotes COP1 nuclear export through COP1's NES, leading to enhanced COP1 self-ubiquitination and preventing COP1-mediated p53 nuclear exclusion and degradation. Co-immunoprecipitation, immunofluorescence, site-directed mutagenesis (S387), nuclear export assay, ubiquitination assay Cancer research Medium 20843328 21135113
2010 Trib2 contains a C-terminal COP1-binding domain; the COP1-binding site is required for Trib2 to degrade C/EBPα and induce AML; COP1 knockdown inhibits Trib2-mediated C/EBPα degradation, establishing COP1 as the E3 ligase recruited by Trib2 to degrade C/EBPα. Structure-function mutagenesis, in vivo bone marrow transplantation, COP1 knockdown, protein stability assay Blood High 20805362
2013 COP1 acts as a ubiquitin ligase for C/EBPα and promotes its degradation in vivo; Trib1 is essential as a scaffold for this process; coexpression of COP1 accelerates Trib1-induced AML, and a ligase-deficient COP1 mutant abrogates leukemogenesis. Mouse bone marrow transplantation, in vivo ubiquitination assay, ligase-dead mutant, co-immunoprecipitation Blood High 23884858
2015 COP1 directly interacts with the VP motif of p27Kip1 and functions as its E3 ubiquitin ligase, accelerating ubiquitin-mediated degradation of p27 to promote cancer cell proliferation. Co-immunoprecipitation, in vitro ubiquitination assay, VP motif interaction analysis, COP1 overexpression/knockdown Oncotarget Medium 26254224
2015 COP1 (RFWD2) degrades ETV4 and ETV5 at the protein level in the developing lung epithelium; genetic deletion of Etv4/Etv5 rescues the branching morphogenesis defect of Rfwd2 lung-epithelium-specific KO mice, establishing epistasis. Conditional knockout mice, genetic epistasis (Etv loss-of-function rescue), protein-level analysis, western blot Proceedings of the National Academy of Sciences of the United States of America High 27335464
2015 COP1 in pancreatic β-cells targets ETV1, ETV4, and ETV5 for degradation; β-cell-specific COP1 KO mice develop diabetes due to insulin granule docking defects fully rescued by genetic deletion of Etv1, Etv4, and Etv5. β-cell-specific conditional KO mice, genetic epistasis (triple ETV KO rescue), protein stability assays, insulin secretion assays, electron microscopy Cell High 26627735
2016 COP1 binds the VP motif of ATGL and targets it for K48-linked polyubiquitination predominantly at Lys100, leading to proteasomal degradation; COP1 depletion in vivo ameliorates high-fat diet-induced liver steatosis. Co-immunoprecipitation, ubiquitination assay with K48-linkage specificity, site-directed mutagenesis (K100), adenovirus-mediated COP1 depletion in mouse liver Diabetes High 27658392
2020 COP1 ubiquitin ligase controls c/EBPβ protein levels in microglia; COP1 deficiency leads to rapid c/EBPβ accumulation driving pro-inflammatory gene expression and complement-mediated neurotoxicity; single allele deletion of Cebpb prevents the phenotype in COP1-KO microglia. COP1 conditional KO in microglia, genetic epistasis (Cebpb heterozygous rescue), co-culture neurotoxicity assay, antibody blocking, mouse tau neurodegeneration model Cell High 32795415
2021 COP1 deletion in cancer cells stabilizes C/ebpδ protein by blocking its proteasomal degradation; Trib2 functions as a scaffold linking COP1 and C/ebpδ, leading to C/ebpδ polyubiquitination; COP1 suppresses macrophage chemoattractant gene expression through this mechanism. In vivo CRISPR KO screen, proteomics, co-immunoprecipitation, ubiquitination assay, transcriptomics Cell High 34582788
2020 COP1 directly interacts with FOXO4 through a VP motif on FOXO4 and promotes its ubiquitin-mediated proteasomal degradation; CSN6 enhances COP1 E3 ligase activity toward FOXO4, coupling EGF-PKB/Akt signaling to FOXO4 stability. Co-immunoprecipitation, ubiquitination assay, VP motif interaction mapping, siRNA knockdown Advanced science Medium 33101846
2015 CSN6 interacts with p27Kip1 and facilitates COP1-mediated ubiquitin-dependent degradation of p27; COP1 promotes nuclear export of p27, accelerating its cytoplasmic degradation. Co-immunoprecipitation, ubiquitination assay, nuclear export analysis, COP1 overexpression/knockdown Cell cycle Medium 25945542
2019 COP1 physically interacts with and ubiquitinates SIRT1, promoting its proteasomal degradation under lipotoxic conditions; TRB3 recruits COP1 to SIRT1 to facilitate this ubiquitination. Co-immunoprecipitation, western blot, ubiquitination assay, high-fat diet mouse model Experimental cell research Medium 31125554
2020 Erk1/2 inactivation causes COP1 to be released from the nuclear envelope (where it is anchored via interaction with TPR, a nuclear pore component) into the nucleoplasm, leading to rapid degradation of COP1 substrates c-Jun, ETV4, and ETV5. siRNA knockdown, immunofluorescence, co-immunoprecipitation (COP1-TPR), MEK inhibitor treatment, ectopic expression rescue Proceedings of the National Academy of Sciences of the United States of America High 32041890
2022 COP1 drives GATA2 ubiquitination at K419/K424 for proteasomal degradation; GATA2 uses alternate BR1/BR2 motifs (not the canonical VP degron) to bind COP1; COP1-mediated GATA2 degradation suppresses AR expression, PCa cell growth, and castration resistance. Ubiquitination assay, site-directed mutagenesis (K419/K424), co-immunoprecipitation, COP1 overexpression/KO in cell and xenograft models Proceedings of the National Academy of Sciences of the United States of America High 36251994
2023 Glucose-dependent CK2 O-GlcNAcylation impairs CK2 phosphorylation of CSN2, releasing CRL4 from the deneddylase CSN to assemble CRL4COP1 E3 ligase, which targets p53 for degradation and derepresses glycolytic enzymes, amplifying the Warburg effect. Biochemical reconstitution, co-immunoprecipitation, peptide inhibitor (P28) disruption of COP1-p53, conditional p53 KO mouse model, mass spectrometry Molecular cell High 37390815
2021 COP1 and COP9 signalosome (CSN) antagonize each other for CRL4 assembly; IP6 assists CSN to compete with COP1 for CRL4, and disrupting IP6-CSN binding leads to increased CRL4COP1 assembly and ETV5 ubiquitination; ETV5 stabilization by CRL neddylation inhibition rescues hyperinsulinemia phenotypes. Co-immunoprecipitation, ubiquitination assay, neddylation inhibitor (MLN4924), knockin mice (Csn2K70E), human islet validation Nature communications High 33911083
2019 Mammalian cryptochromes negatively regulate CRL4COP1 by interacting with Det1 (a subunit unique to CRL4COP1), preventing COP1 from joining the CRL4 complex and allowing COP1 substrates to accumulate; this mechanism suppresses glucocorticoid receptor transcriptional networks. Co-immunoprecipitation, substrate accumulation assay, cell-based and mouse liver functional assays Current biology Medium 31155351
2013 COP1 interacts with FIP200 (a key autophagy regulator) in the cytoplasm; this interaction is enhanced by UV irradiation, and ectopic COP1 expression reduces a specific form of FIP200 protein. Yeast two-hybrid screen, GST pulldown, split-GFP colocalization, western blot BMC biochemistry Low 23289756
2022 COP1 directly interacts with PCDH9 and promotes its K48-linked polyubiquitination and proteasomal degradation in glioma cells. Yeast two-hybrid screen, co-immunoprecipitation, immunofluorescence co-localization, ubiquitination assay with K48 linkage specificity Molecular neurobiology Medium 35084653
2023 COP1 forms a CUL4B-DDB1-COP1 E3 ligase complex that targets UTX (KDM6A histone demethylase) for degradation; COP1 deficiency in mouse intestinal tissue causes UTX accumulation and restricts colorectal tumorigenesis. Co-immunoprecipitation, immunoblot, conditional Cop1 KO mouse intestinal model, AOM/DSS-induced CRC model Experimental hematology & oncology Medium 37679762
2025 COP1 mediates K63-linked polyubiquitination of GH3.5 (an IAA-amino acid synthetase) without affecting its protein stability, instead inhibiting its enzymatic activity; this suppresses IAA conjugation to amino acids in darkness to promote hypocotyl elongation. In vitro ubiquitination assay with K63-linkage specificity, enzyme activity assay, co-immunoprecipitation, IAA metabolite quantification, genetic analysis Nature communications High 40229271
2024 COP1 physically interacts with VIL1/VERNALIZATION5 (a Polycomb protein) and regulates light-dependent chromatin loop formation at growth-promoting genes; COP1 governs H3K27me3 deposition through VIL1 to repress these genes in darkness. Co-immunoprecipitation, chromatin loop assay (ChIA-PET/3C), histone modification analysis, genetic epistasis Proceedings of the National Academy of Sciences of the United States of America Medium 38349881
2019 Crystal structures of VP motifs from UVR8 and HY5 bound to COP1's WD40 domain revealed competitive binding; photoactivated UVR8 uses high-affinity cooperative binding of its VP motif and photosensing core to displace HY5 from COP1, preventing HY5 ubiquitination. Crystal structure determination, quantitative binding assays, reverse genetics The EMBO journal High 31304983
2022 Cryo-EM structure of UV-B-activated UVR8 in complex with COP1 revealed two-interface interactions; both interfaces are required for UVR8 to competitively displace HY5 from COP1-SPA; RUP2 dissociates UVR8 from COP1-SPA and facilitates UVR8 redimerization. Cryo-EM structure determination, in vitro reconstitution of UV-B signaling pathway, competitive binding assay Science advances High 35442727
2024 RFWD2 (COP1) overexpression in mice causes autistic-like behaviors accompanied by reduced dendritic spine density and abnormal synaptic function in mPFC pyramidal neurons; impaired social behaviors are rescued by ETV5 expression in mPFC, establishing ETV5 as a key substrate mediating RFWD2 synaptic function. Knockin mouse model, behavioral assays, dendritic spine analysis, electrophysiology, ETV5 viral rescue Molecular psychiatry High 38503925
2024 IL-37d promotes C/EBPβ ubiquitination degradation by facilitating COP1 recruitment to C/EBPβ, and also disrupts C/EBPβ DNA binding, thereby reducing neutrophil ATP generation and spontaneous migration. Co-immunoprecipitation, ubiquitination assay, Lewis lung carcinoma mouse model, IL-37d recombinant protein treatment Cell reports Medium 38363681

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 The ubiquitin ligase COP1 is a critical negative regulator of p53. Nature 589 15103385
2012 The photomorphogenic repressors COP1 and DET1: 20 years later. Trends in plant science 486 22705257
2008 COP1 and ELF3 control circadian function and photoperiodic flowering by regulating GI stability. Molecular cell 325 19061637
2005 COP1 - from plant photomorphogenesis to mammalian tumorigenesis. Trends in cell biology 275 16198569
2005 HFR1 is targeted by COP1 E3 ligase for post-translational proteolysis during phytochrome A signaling. Genes & development 237 15741320
2018 Photoreceptor-mediated regulation of the COP1/SPA E3 ubiquitin ligase. Current opinion in plant biology 211 29775763
1994 Regulatory hierarchy of photomorphogenic loci: allele-specific and light-dependent interaction between the HY5 and COP1 loci. The Plant cell 201 8038602
2017 The activities of the E3 ubiquitin ligase COP1/SPA, a key repressor in light signaling. Current opinion in plant biology 184 28433946
2021 In vivo CRISPR screens identify the E3 ligase Cop1 as a modulator of macrophage infiltration and cancer immunotherapy target. Cell 173 34582788
2013 Conversion from CUL4-based COP1-SPA E3 apparatus to UVR8-COP1-SPA complexes underlies a distinct biochemical function of COP1 under UV-B. Proceedings of the National Academy of Sciences of the United States of America 156 24067658
2019 COP1 and BBXs-HY5-mediated light signal transduction in plants. The New phytologist 152 31664720
2011 COP1 is a tumour suppressor that causes degradation of ETS transcription factors. Nature 152 21572435
2020 Ubiquitin Ligase COP1 Suppresses Neuroinflammation by Degrading c/EBPβ in Microglia. Cell 131 32795415
2020 The Photomorphogenic Central Repressor COP1: Conservation and Functional Diversification during Evolution. Plant communications 131 33367240
2017 COP1 conveys warm temperature information to hypocotyl thermomorphogenesis. The New phytologist 129 28418582
2019 Plant photoreceptors and their signaling components compete for COP1 binding via VP peptide motifs. The EMBO journal 128 31304983
2015 Seedlings Transduce the Depth and Mechanical Pressure of Covering Soil Using COP1 and Ethylene to Regulate EBF1/EBF2 for Soil Emergence. Current biology : CB 122 26748855
2016 COP1 is required for UV-B-induced nuclear accumulation of the UVR8 photoreceptor. Proceedings of the National Academy of Sciences of the United States of America 119 27407149
2006 ATM engages autodegradation of the E3 ubiquitin ligase COP1 after DNA damage. Science (New York, N.Y.) 118 16931761
2011 Cop1 constitutively regulates c-Jun protein stability and functions as a tumor suppressor in mice. The Journal of clinical investigation 114 21403399
2004 COP1, the negative regulator of p53, is overexpressed in breast and ovarian adenocarcinomas. Cancer research 110 15492238
2012 Spotlight on the role of COP1 in tumorigenesis. Nature reviews. Cancer 104 22673153
2010 Transformation by Tribbles homolog 2 (Trib2) requires both the Trib2 kinase domain and COP1 binding. Blood 104 20805362
2010 AtBBX21 and COP1 genetically interact in the regulation of shade avoidance. The Plant journal : for cell and molecular biology 103 21070414
2015 CUL4 forms an E3 ligase with COP1 and SPA to promote light-induced degradation of PIF1. Nature communications 102 26037329
2014 COP1 E3 ligase protects HYL1 to retain microRNA biogenesis. Nature communications 92 25532508
2002 AtMYB21, a gene encoding a flower-specific transcription factor, is regulated by COP1. The Plant journal : for cell and molecular biology 92 11967090
2011 Nuclear localization and interaction with COP1 are required for STO/BBX24 function during photomorphogenesis. Plant physiology 81 21685177
2017 The F-box protein FKF1 inhibits dimerization of COP1 in the control of photoperiodic flowering. Nature communications 79 29273730
2009 E3 ubiquitin ligase COP1 regulates the stability and functions of MTA1. Proceedings of the National Academy of Sciences of the United States of America 73 19805145
2013 COP1 targets C/EBPα for degradation and induces acute myeloid leukemia via Trib1. Blood 70 23884858
1998 New COP1-binding motifs involved in ER retrieval. The EMBO journal 69 9843492
2016 Ubiquitin Ligase COP1 Controls Hepatic Fat Metabolism by Targeting ATGL for Degradation. Diabetes 58 27658392
1996 det1, cop1, and cop9 mutations cause inappropriate expression of several gene sets. The Plant cell 58 8953766
2010 14-3-3sigma exerts tumor-suppressor activity mediated by regulation of COP1 stability. Cancer research 54 21135113
2015 β-Cell Insulin Secretion Requires the Ubiquitin Ligase COP1. Cell 51 26627735
2020 COP1 promotes ABA-induced stomatal closure by modulating the abundance of ABI/HAB and AHG3 phosphatases. The New phytologist 49 33048351
2010 Interplay between MDM2, MDMX, Pirh2 and COP1: the negative regulators of p53. Molecular biology reports 48 20333547
2013 COP1 and GSK3β cooperate to promote c-Jun degradation and inhibit breast cancer cell tumorigenesis. Neoplasia (New York, N.Y.) 45 24027432
2023 Glucose-induced CRL4COP1-p53 axis amplifies glycometabolism to drive tumorigenesis. Molecular cell 43 37390815
2020 Role of the COP1 protein in cancer development and therapy. Seminars in cancer biology 43 32027978
2018 COP1/DET1/ETS axis regulates ERK transcriptome and sensitivity to MAPK inhibitors. The Journal of clinical investigation 42 29360641
2018 The COP1 Target SHI-RELATED SEQUENCE5 Directly Activates Photomorphogenesis-Promoting Genes. The Plant cell 42 30150309
2021 DET1-mediated COP1 regulation avoids HY5 activity over second-site gene targets to tune plant photomorphogenesis. Molecular plant 41 33711490
2010 Nuclear export regulation of COP1 by 14-3-3σ in response to DNA damage. Molecular cancer 39 20843328
2016 miR-214 promotes apoptosis and sensitizes breast cancer cells to doxorubicin by targeting the RFWD2-p53 cascade. Biochemical and biophysical research communications 38 27422604
2015 MicroRNA-214 Promotes Apoptosis in Canine Hemangiosarcoma by Targeting the COP1-p53 Axis. PloS one 37 26335793
2022 Structural insight into UV-B-activated UVR8 bound to COP1. Science advances 35 35442727
2016 The Ubiquitin Ligase COP1 Promotes Glioma Cell Proliferation by Preferentially Downregulating Tumor Suppressor p53. Molecular neurobiology 35 27534417
2016 Constitutive photomorphogenesis protein 1 (COP1) and COP9 signalosome, evolutionarily conserved photomorphogenic proteins as possible targets of melatonin. Journal of pineal research 33 27121162
2020 EGF Relays Signals to COP1 and Facilitates FOXO4 Degradation to Promote Tumorigenesis. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 32 33101846
2015 Regulating the stability and localization of CDK inhibitor p27(Kip1) via CSN6-COP1 axis. Cell cycle (Georgetown, Tex.) 32 25945542
2016 E3 ubiquitin ligase RFWD2 controls lung branching through protein-level regulation of ETV transcription factors. Proceedings of the National Academy of Sciences of the United States of America 31 27335464
2015 COP1 enhances ubiquitin-mediated degradation of p27Kip1 to promote cancer cell growth. Oncotarget 31 26254224
2002 An initial biochemical and cell biological characterization of the mammalian homologue of a central plant developmental switch, COP1. BMC cell biology 31 12466024
2022 Organ-specific COP1 control of BES1 stability adjusts plant growth patterns under shade or warmth. Developmental cell 30 35901789
2016 The role of COP1 in repression of photoperiodic flowering. F1000Research 30 26949521
2018 The ubiquitin ligase COP1 regulates cell cycle and apoptosis by affecting p53 function in human breast cancer cell lines. Breast cancer (Tokyo, Japan) 29 29516369
2021 IP6-assisted CSN-COP1 competition regulates a CRL4-ETV5 proteolytic checkpoint to safeguard glucose-induced insulin secretion. Nature communications 28 33911083
2023 CUL4B-DDB1-COP1-mediated UTX downregulation promotes colorectal cancer progression. Experimental hematology & oncology 27 37679762
2011 Good COP1 or bad COP1? In vivo veritas. The Journal of clinical investigation 27 21403396
2024 Light regulates nuclear detainment of intron-retained transcripts through COP1-spliceosome to modulate photomorphogenesis. Nature communications 26 38879536
2017 COP1 integrates light signals to ROP2 for cell cycle activation. Plant signaling & behavior 25 28805486
2019 TRB3 stimulates SIRT1 degradation and induces insulin resistance by lipotoxicity via COP1. Experimental cell research 24 31125554
2019 Cryptochromes-Mediated Inhibition of the CRL4Cop1-Complex Assembly Defines an Evolutionary Conserved Signaling Mechanism. Current biology : CB 23 31155351
2012 Involvement of COP1 in ethylene- and light-regulated hypocotyl elongation. Planta 22 22890836
2018 Nitrate Reductases Are Relocalized to the Nucleus by AtSIZ1 and Their Levels Are Negatively Regulated by COP1 and Ammonium. International journal of molecular sciences 19 29662028
2020 Light controls stamen elongation via cryptochromes, phytochromes and COP1 through HY5 and HYH. The Plant journal : for cell and molecular biology 18 32142184
2019 PEDF promotes nuclear degradation of ATGL through COP1. Biochemical and biophysical research communications 18 30926171
2015 Light signaling induces anthocyanin biosynthesis via AN3 mediated COP1 expression. Plant signaling & behavior 18 26357851
2022 PIFs- and COP1-HY5-mediated temperature signaling in higher plants. Stress biology 17 37676326
2015 CSN6 deregulation impairs genome integrity in a COP1-dependent pathway. Oncotarget 17 25957415
2001 PML and COP1--two proteins with much in common. Trends in biochemical sciences 16 11165511
2016 Mutant p53 protects ETS2 from non-canonical COP1/DET1 dependent degradation. Oncotarget 15 26871468
2023 Effect of COP1 in Promoting the Tumorigenesis of Gastric Cancer by Down-Regulation of CDH18 via PI3K/AKT Signal Pathway. Analytical cellular pathology (Amsterdam) 14 37025097
2013 The COP1 E3-ligase interacts with FIP200, a key regulator of mammalian autophagy. BMC biochemistry 14 23289756
2023 SmCIP7, a COP1 interactive protein, positively regulates anthocyanin accumulation and fruit size in eggplant. International journal of biological macromolecules 13 36801296
2023 Propagated Circulating Tumor Cells Uncover the Potential Role of NFκB, EMT, and TGFβ Signaling Pathways and COP1 in Metastasis. Cancers 12 36980717
2022 A COP1-GATA2 axis suppresses AR signaling and prostate cancer. Proceedings of the National Academy of Sciences of the United States of America 12 36251994
2021 Functional comparison of the WD-repeat domains of SPA1 and COP1 in suppression of photomorphogenesis. Plant, cell & environment 12 34251043
2020 Erk1/2 inactivation promotes a rapid redistribution of COP1 and degradation of COP1 substrates. Proceedings of the National Academy of Sciences of the United States of America 12 32041890
2020 Regulation of COP1 Function by Brassinosteroid Signaling. Frontiers in plant science 12 32849709
2024 COP1 controls light-dependent chromatin remodeling. Proceedings of the National Academy of Sciences of the United States of America 11 38349881
2024 The E3 ubiquitin ligase COP1 regulates salt tolerance via GIGANTEA degradation in roots. Plant, cell & environment 11 38741272
2021 The E3 ligase COP1 promotes ERα signaling and suppresses EMT in breast cancer. Oncogene 11 34716429
2016 COP1 is downregulated in renal cell carcinoma (RCC) and inhibits the migration of RCC ACHN cells in vitro. Molecular medicine reports 10 27278120
2019 COP1 regulates the stability of CAM7 to promote photomorphogenic growth. Plant direct 9 31245782
2015 Expression and regulation of COP1 in chronic lymphocytic leukemia cells for promotion of cell proliferation and tumorigenicity. Oncology reports 9 26717976
1998 Molecular cloning and sequencing of the cDNA of cop1 gene from Pisum sativum. Biochimica et biophysica acta 9 9512668
2025 Inactivation of GH3.5 by COP1-mediated K63-linked ubiquitination promotes seedling hypocotyl elongation. Nature communications 8 40229271
2023 Discovery and Development of Quinazolinones and Quinazolinediones for Ameliorating Nonalcoholic Fatty Liver Disease (NAFLD) by Modulating COP1-ATGL Axis. Journal of medicinal chemistry 8 38100045
2021 Targeting RFWD2 as an Effective Strategy to Inhibit Cellular Proliferation and Overcome Drug Resistance to Proteasome Inhibitor in Multiple Myeloma. Frontiers in cell and developmental biology 8 33968945
2016 Isolation of three B-box zinc finger proteins that interact with STF1 and COP1 defines a HY5/COP1 interaction network involved in light control of development in soybean. Biochemical and biophysical research communications 8 27524234
2024 IL-37d enhances COP1-mediated C/EBPβ degradation to suppress spontaneous neutrophil migration and tumor progression. Cell reports 7 38363681
2024 Increased gene dosage of RFWD2 causes autistic-like behaviors and aberrant synaptic formation and function in mice. Molecular psychiatry 7 38503925
2024 Shade-induced ROS/NO reinforce COP1-mediated diffuse cell growth. Proceedings of the National Academy of Sciences of the United States of America 7 39382994
2023 Co-action of COP1, SPA and cryptochrome in light signal transduction and photomorphogenesis of the moss Physcomitrium patens. The Plant journal : for cell and molecular biology 7 36710658
2022 COP1 Acts as a Ubiquitin Ligase for PCDH9 Ubiquitination and Degradation in Human Glioma. Molecular neurobiology 7 35084653
2019 Photoreceptor signaling: when COP1 meets VPs. The EMBO journal 7 31432520
2024 Rapid increase of C/EBPα p42 induces growth arrest of acute myeloid leukemia (AML) cells by Cop1 deletion in Trib1-expressing AML. Leukemia 6 39367171

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