Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTNAD2S4)

DOT Name COP9 signalosome complex subunit 8 (COPS8)
Synonyms SGN8; Signalosome subunit 8; COP9 homolog; hCOP9; JAB1-containing signalosome subunit 8
Gene Name COPS8
Related Disease
Advanced cancer ( )
Breast cancer ( )
Breast carcinoma ( )
Cardiovascular disease ( )
Neoplasm ( )
Thyroid tumor ( )
Kidney cancer ( )
Renal carcinoma ( )
UniProt ID
CSN8_HUMAN
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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PDB ID
4D10; 4D18; 4WSN; 6R6H; 6R7F; 6R7H; 6R7I; 6R7N; 8H38; 8H3A; 8H3F
Pfam ID
PF10075
Sequence
MPVAVMAESAFSFKKLLDQCENQELEAPGGIATPPVYGQLLALYLLHNDMNNARYLWKRI
PPAIKSANSELGGIWSVGQRIWQRDFPGIYTTINAHQWSETVQPIMEALRDATRRRAFAL
VSQAYTSIIADDFAAFVGLPVEEAVKGILEQGWQADSTTRMVLPRKPVAGALDVSFNKFI
PLSEPAPVPPIPNEQQLARLTDYVAFLEN
Function
Component of the COP9 signalosome complex (CSN), a complex involved in various cellular and developmental processes. The CSN complex is an essential regulator of the ubiquitin (Ubl) conjugation pathway by mediating the deneddylation of the cullin subunits of SCF-type E3 ligase complexes, leading to decrease the Ubl ligase activity of SCF-type complexes such as SCF, CSA or DDB2. The complex is also involved in phosphorylation of p53/TP53, c-jun/JUN, IkappaBalpha/NFKBIA, ITPK1 and IRF8/ICSBP, possibly via its association with CK2 and PKD kinases. CSN-dependent phosphorylation of TP53 and JUN promotes and protects degradation by the Ubl system, respectively.
Reactome Pathway
Formation of TC-NER Pre-Incision Complex (R-HSA-6781823 )
Cargo recognition for clathrin-mediated endocytosis (R-HSA-8856825 )
Neddylation (R-HSA-8951664 )
DNA Damage Recognition in GG-NER (R-HSA-5696394 )

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
Advanced cancer DISAT1Z9 Strong Biomarker [1]
Breast cancer DIS7DPX1 Strong Genetic Variation [2]
Breast carcinoma DIS2UE88 Strong Genetic Variation [2]
Cardiovascular disease DIS2IQDX Strong Genetic Variation [3]
Neoplasm DISZKGEW Strong Altered Expression [4]
Thyroid tumor DISLVKMD Strong Genetic Variation [5]
Kidney cancer DISBIPKM Limited Biomarker [6]
Renal carcinoma DISER9XT Limited Biomarker [6]
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⏷ Show the Full List of 8 Disease(s)
Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
12 Drug(s) Affected the Gene/Protein Processing of This DOT
Drug Name Drug ID Highest Status Interaction REF
Valproate DMCFE9I Approved Valproate increases the expression of COP9 signalosome complex subunit 8 (COPS8). [7]
Tretinoin DM49DUI Approved Tretinoin decreases the expression of COP9 signalosome complex subunit 8 (COPS8). [8]
Acetaminophen DMUIE76 Approved Acetaminophen increases the expression of COP9 signalosome complex subunit 8 (COPS8). [9]
Doxorubicin DMVP5YE Approved Doxorubicin decreases the expression of COP9 signalosome complex subunit 8 (COPS8). [10]
Ivermectin DMDBX5F Approved Ivermectin decreases the expression of COP9 signalosome complex subunit 8 (COPS8). [11]
Hydrogen peroxide DM1NG5W Approved Hydrogen peroxide affects the expression of COP9 signalosome complex subunit 8 (COPS8). [12]
Vorinostat DMWMPD4 Approved Vorinostat increases the expression of COP9 signalosome complex subunit 8 (COPS8). [13]
Selenium DM25CGV Approved Selenium decreases the expression of COP9 signalosome complex subunit 8 (COPS8). [14]
Diethylstilbestrol DMN3UXQ Approved Diethylstilbestrol decreases the expression of COP9 signalosome complex subunit 8 (COPS8). [15]
Trichostatin A DM9C8NX Investigative Trichostatin A decreases the expression of COP9 signalosome complex subunit 8 (COPS8). [18]
Formaldehyde DM7Q6M0 Investigative Formaldehyde decreases the expression of COP9 signalosome complex subunit 8 (COPS8). [19]
Milchsaure DM462BT Investigative Milchsaure increases the expression of COP9 signalosome complex subunit 8 (COPS8). [20]
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⏷ Show the Full List of 12 Drug(s)
2 Drug(s) Affected the Post-Translational Modifications of This DOT
Drug Name Drug ID Highest Status Interaction REF
Benzo(a)pyrene DMN7J43 Phase 1 Benzo(a)pyrene decreases the methylation of COP9 signalosome complex subunit 8 (COPS8). [16]
Bisphenol A DM2ZLD7 Investigative Bisphenol A increases the methylation of COP9 signalosome complex subunit 8 (COPS8). [17]
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References

1 Roles of COP9 signalosome in cancer.Cell Cycle. 2011 Sep 15;10(18):3057-66. doi: 10.4161/cc.10.18.17320. Epub 2011 Sep 15.
2 COPS5 amplification and overexpression confers tamoxifen-resistance in ER-positive breast cancer by degradation of NCoR.Nat Commun. 2016 Jul 4;7:12044. doi: 10.1038/ncomms12044.
3 Role of the COP9 Signalosome (CSN) in Cardiovascular Diseases.Biomolecules. 2019 Jun 5;9(6):217. doi: 10.3390/biom9060217.
4 Analysis of RNA expression of normal and cancer tissues reveals high correlation of COP9 gene expression with respiratory chain complex components. BMC Genomics. 2016 Dec 1;17(1):983.
5 Subunit 6 of the COP9 signalosome promotes tumorigenesis in mice through stabilization of MDM2 and is upregulated in human cancers.J Clin Invest. 2011 Mar;121(3):851-65. doi: 10.1172/JCI44111. Epub 2011 Feb 7.
6 Mutation screening of ACKR3 and COPS8 in kidney cancer cases from the CONFIRM study.Fam Cancer. 2017 Jul;16(3):411-416. doi: 10.1007/s10689-016-9961-x.
7 Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
8 Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
9 Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
10 Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
11 Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
12 Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
13 Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
14 Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
15 Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
16 Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
17 DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
18 A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
19 Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
20 Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.