Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6J2K12)

• DOT Name: E3 ubiquitin-protein ligase COP1 (COP1)
• Synonyms: EC 2.3.2.27; Constitutive photomorphogenesis protein 1 homolog; hCOP1; RING finger and WD repeat domain protein 2; RING finger protein 200; RING-type E3 ubiquitin transferase RFWD2
• Gene Name: COP1
• Related Disease:
  Acute myelogenous leukaemia
  Adenocarcinoma
  Autism
  Bladder cancer
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Clear cell renal carcinoma
  Gastric cancer
  Glioma
  Hepatitis C virus infection
  Hepatocellular carcinoma
  Multiple sclerosis
  Neoplasm
  Pancreatic cancer
  Relapsing-remitting multiple sclerosis
  Renal cell carcinoma
  Small lymphocytic lymphoma
  Stomach cancer
  Type-1/2 diabetes
  Urinary bladder cancer
  Urinary bladder neoplasm
  Amyotrophic lateral sclerosis
  Invasive ductal breast carcinoma
• UniProt ID: COP1_HUMAN
• PDB ID: 5HQG; 5IGQ
• EC Number: 2.3.2.27
• Pfam ID: PF00400 ; PF13923
• Sequence:
  MSGSRQAGSGSAGTSPGSSAASSVTSASSSLSSSPSPPSVAVSAAALVSGGVAQAAGSGG
  LGGPVRPVLVAPAVSGSGGGAVSTGLSRHSCAARPSAGVGGSSSSLGSGSRKRPLLAPLC
  NGLINSYEDKSNDFVCPICFDMIEEAYMTKCGHSFCYKCIHQSLEDNNRCPKCNYVVDNI
  DHLYPNFLVNELILKQKQRFEEKRFKLDHSVSSTNGHRWQIFQDWLGTDQDNLDLANVNL
  MLELLVQKKKQLEAESHAAQLQILMEFLKVARRNKREQLEQIQKELSVLEEDIKRVEEMS
  GLYSPVSEDSTVPQFEAPSPSHSSIIDSTEYSQPPGFSGSSQTKKQPWYNSTLASRRKRL
  TAHFEDLEQCYFSTRMSRISDDSRTASQLDEFQECLSKFTRYNSVRPLATLSYASDLYNG
  SSIVSSIEFDRDCDYFAIAGVTKKIKVYEYDTVIQDAVDIHYPENEMTCNSKISCISWSS
  YHKNLLASSDYEGTVILWDGFTGQRSKVYQEHEKRCWSVDFNLMDPKLLASGSDDAKVKL
  WSTNLDNSVASIEAKANVCCVKFSPSSRYHLAFGCADHCVHYYDLRNTKQPIMVFKGHRK
  AVSYAKFVSGEEIVSASTDSQLKLWNVGKPYCLRSFKGHINEKNFVGLASNGDYIACGSE
  NNSLYLYYKGLSKTLLTFKFDTVKSVLDKDRKEDDTNEFVSAVCWRALPDGESNVLIAAN
  SQGTIKVLELV
• Function: E3 ubiquitin-protein ligase that mediates ubiquitination and subsequent proteasomal degradation of target proteins. E3 ubiquitin ligases accept ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates. Involved in JUN ubiquitination and degradation. Directly involved in p53 (TP53) ubiquitination and degradation, thereby abolishing p53-dependent transcription and apoptosis. Ubiquitinates p53 independently of MDM2 or RCHY1. Probably mediates E3 ubiquitin ligase activity by functioning as the essential RING domain subunit of larger E3 complexes. In contrast, it does not constitute the catalytic RING subunit in the DCX DET1-COP1 complex that negatively regulates JUN, the ubiquitin ligase activity being mediated by RBX1. Involved in 14-3-3 protein sigma/SFN ubiquitination and proteasomal degradation, leading to AKT activation and promotion of cell survival. Ubiquitinates MTA1 leading to its proteasomal degradation. Upon binding to TRIB1, ubiquitinates CEBPA, which lacks a canonical COP1-binding motif (Probable).
• Tissue Specificity: Ubiquitously expressed at low level. Expressed at higher level in testis, placenta, skeletal muscle and heart.
• KEGG Pathway:
  p53 sig.ling pathway (hsa04115)
  Ubiquitin mediated proteolysis (hsa04120)
• Reactome Pathway:
  Neddylation (R-HSA-8951664)
  Autodegradation of the E3 ubiquitin ligase COP1 (R-HSA-349425)

Molecular Interaction Atlas (MIA) of This DOT

24 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Definitive	Altered Expression	[1]
Adenocarcinoma	DIS3IHTY	Strong	Biomarker	[2]
Autism	DISV4V1Z	Strong	Biomarker	[3]
Bladder cancer	DISUHNM0	Strong	Altered Expression	[4]
Breast cancer	DIS7DPX1	Strong	Biomarker	[5]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[5]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[6]
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[2]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[7]
Glioma	DIS5RPEH	Strong	Altered Expression	[8]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[9]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[10]
Multiple sclerosis	DISB2WZI	Strong	Biomarker	[11]
Neoplasm	DISZKGEW	Strong	Genetic Variation	[12]
Pancreatic cancer	DISJC981	Strong	Altered Expression	[13]
Relapsing-remitting multiple sclerosis	DISSXFCF	Strong	Biomarker	[14]
Renal cell carcinoma	DISQZ2X8	Strong	Biomarker	[2]
Small lymphocytic lymphoma	DIS30POX	Strong	Biomarker	[15]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[7]
Type-1/2 diabetes	DISIUHAP	Strong	Biomarker	[16]
Urinary bladder cancer	DISDV4T7	Strong	Altered Expression	[4]
Urinary bladder neoplasm	DIS7HACE	Strong	Altered Expression	[4]
Amyotrophic lateral sclerosis	DISF7HVM	moderate	Biomarker	[17]
Invasive ductal breast carcinoma	DIS43J58	Limited	Altered Expression	[18]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of E3 ubiquitin-protein ligase COP1 (COP1).	[19]

3 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of E3 ubiquitin-protein ligase COP1 (COP1).	[20]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of E3 ubiquitin-protein ligase COP1 (COP1).	[21]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of E3 ubiquitin-protein ligase COP1 (COP1).	[22]

References

• [1] Myeloid leukemia factor 1 stabilizes tumor suppressor C/EBP to prevent Trib1-driven acute myeloid leukemia.Blood Adv. 2017 Sep 1;1(20):1682-1693. doi: 10.1182/bloodadvances.2017007054. eCollection 2017 Sep 12.
• [2] COP1 is downregulated in renal cell carcinoma (RCC) and inhibits the migration of RCC ACHN cells invitro.Mol Med Rep. 2016 Aug;14(2):1371-8. doi: 10.3892/mmr.2016.5373. Epub 2016 Jun 7.
• [3] Autism genome-wide copy number variation reveals ubiquitin and neuronal genes.Nature. 2009 May 28;459(7246):569-73. doi: 10.1038/nature07953. Epub 2009 Apr 28.
• [4] High expression of constitutive photomorphogenic 1 (COP1) is associated with poor prognosis in bladder cancer.Tumour Biol. 2016 Jul;37(7):8917-22. doi: 10.1007/s13277-015-4765-4. Epub 2016 Jan 11.
• [5] The ubiquitin ligase COP1 regulates cell cycle and apoptosis by affecting p53 function in human breast cancer cell lines.Breast Cancer. 2018 Sep;25(5):529-538. doi: 10.1007/s12282-018-0849-5. Epub 2018 Mar 7.
• [6] COP1 and GSK3 cooperate to promote c-Jun degradation and inhibit breast cancer cell tumorigenesis.Neoplasia. 2013 Sep;15(9):1075-85. doi: 10.1593/neo.13966.
• [7] Loss of COP1 expression determines poor prognosisin patients with gastric cancer.Oncol Rep. 2013 Oct;30(4):1971-5. doi: 10.3892/or.2013.2664. Epub 2013 Aug 8.
• [8] The Ubiquitin Ligase COP1 Promotes Glioma Cell Proliferation by Preferentially Downregulating Tumor Suppressor p53.Mol Neurobiol. 2017 Sep;54(7):5008-5016. doi: 10.1007/s12035-016-0033-x. Epub 2016 Aug 17.
• [9] Hepatitis C virus replication and Golgi function in brefeldin a-resistant hepatoma-derived cells.PLoS One. 2013 Sep 18;8(9):e74491. doi: 10.1371/journal.pone.0074491. eCollection 2013.
• [10] Definition of ubiquitination modulator COP1 as a novel therapeutic target in human hepatocellular carcinoma.Cancer Res. 2010 Nov 1;70(21):8264-9. doi: 10.1158/0008-5472.CAN-10-0749. Epub 2010 Oct 19.
• [11] Release of interleukin-10 and neurotrophic factors in the choroid plexus: possible inductors of neurogenesis following copolymer-1 immunization after cerebral ischemia.Neural Regen Res. 2018 Oct;13(10):1743-1752. doi: 10.4103/1673-5374.238615.
• [12] COP1/DET1/ETS axis regulates ERK transcriptome and sensitivity to MAPK inhibitors.J Clin Invest. 2018 Apr 2;128(4):1442-1457. doi: 10.1172/JCI94840. Epub 2018 Mar 5.
• [13] 14-3-3sigma exerts tumor-suppressor activity mediated by regulation of COP1 stability.Cancer Res. 2011 Feb 1;71(3):884-94. doi: 10.1158/0008-5472.CAN-10-2518. Epub 2010 Dec 6.
• [14] Glatiramer Acetate: from Bench to Bed and Back.Isr Med Assoc J. 2019 Mar;21(3):151-157.
• [15] Constitutively Photomorphogenic 1 Reduces the Sensitivity of Chronic Lymphocytic Leukemia Cells to Fludarabine Through Promotion of Ubiquitin-Mediated P53 Degradation.Cell Physiol Biochem. 2018;50(6):2314-2328. doi: 10.1159/000495092. Epub 2018 Nov 13.
• [16] TRB3 stimulates SIRT1 degradation and induces insulin resistance by lipotoxicity via COP1.Exp Cell Res. 2019 Sep 1;382(1):111428. doi: 10.1016/j.yexcr.2019.05.009. Epub 2019 May 21.
• [17] Limited effects of glatiramer acetate in the high-copy number hSOD1-G93A mouse model of ALS.Exp Neurol. 2007 Aug;206(2):288-95. doi: 10.1016/j.expneurol.2007.05.007. Epub 2007 May 18.
• [18] COP1D, an alternatively spliced constitutive photomorphogenic-1 (COP1) product, stabilizes UV stress-induced c-Jun through inhibition of full-length COP1.Oncogene. 2008 Apr 10;27(17):2401-11. doi: 10.1038/sj.onc.1210892. Epub 2007 Oct 29.
• [19] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [20] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [21] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [22] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.