Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7WUD5R)

• DOT Name: COMM domain-containing protein 1 (COMMD1)
• Synonyms: Protein Murr1
• Gene Name: COMMD1
• Related Disease:
  Arthritis
  Rheumatoid arthritis
  Advanced cancer
  Allergy
  Autism
  Autism spectrum disorder
  B-cell lymphoma
  Chorioamnionitis
  Colitis
  Copper metabolism disorder
  Cystic fibrosis
  Epithelial ovarian cancer
  Head-neck squamous cell carcinoma
  Hepatitis
  Hepatitis A virus infection
  Hepatocellular carcinoma
  HIV infectious disease
  Inflammatory bowel disease
  Liver cirrhosis
  Menkes disease
  Neoplasm
  Ovarian cancer
  Ovarian neoplasm
  Prostate cancer
  Prostate carcinoma
  Ulcerative colitis
  Pulmonary emphysema
  Neuroblastoma
  Proliferative diabetic retinopathy
• UniProt ID: COMD1_HUMAN
• PDB ID: 2H2M; 8F2R; 8F2U
• Pfam ID: PF07258 ; PF17221
• Sequence:
  MAAGELEGGKPLSGLLNALAQDTFHGYPGITEELLRSQLYPEVPPEEFRPFLAKMRGILK
  SIASADMDFNQLEAFLTAQTKKQGGITSDQAAVISKFWKSHKTKIRESLMNQSRWNSGLR
  GLSWRVDGKSQSRHSAQIHTPVAIIELELGKYGQESEFLCLEFDEVKVNQILKTLSEVEE
  SISTLISQPN
• Function: Proposed scaffold protein that is implicated in diverse physiological processes and whose function may be in part linked to its ability to regulate ubiquitination of specific cellular proteins. Can modulate activity of cullin-RING E3 ubiquitin ligase (CRL) complexes by displacing CAND1; in vitro promotes CRL E3 activity and dissociates CAND1 from CUL1 and CUL2. Promotes ubiquitination of NF-kappa-B subunit RELA and its subsequent proteasomal degradation. Down-regulates NF-kappa-B activity. Involved in the regulation of membrane expression and ubiquitination of SLC12A2. Modulates Na(+) transport in epithelial cells by regulation of apical cell surface expression of amiloride-sensitive sodium channel (ENaC) subunits and by promoting their ubiquitination presumably involving NEDD4L. Promotes the localization of SCNN1D to recycling endosomes. Promotes CFTR cell surface expression through regulation of its ubiquitination. Down-regulates SOD1 activity by interfering with its homodimerization. Plays a role in copper ion homeostasis. Involved in copper-dependent ATP7A trafficking between the trans-Golgi network and vesicles in the cell periphery; the function is proposed to depend on its association within the CCC complex and cooperation with the WASH complex on early endosomes. Can bind one copper ion per monomer. May function to facilitate biliary copper excretion within hepatocytes. Binds to phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2). Involved in the regulation of HIF1A-mediated transcription; competes with ARNT/Hif-1-beta for binding to HIF1A resulting in decreased DNA binding and impaired transcriptional activation by HIF-1. Negatively regulates neuroblastoma G1/S phase cell cycle progression and cell proliferation by stimulating ubiquitination of NF-kappa-B subunit RELA and NF-kappa-B degradation in a FAM107A- and actin-dependent manner.
• Tissue Specificity: Ubiquitous. Highest expression in the liver, with lower expression in brain, lung, placenta, pancreas, small intestine, heart, skeletal muscle, kidney and placenta. Down-regulated in cancer tissues.
• Reactome Pathway: Neddylation (R-HSA-8951664)

Molecular Interaction Atlas (MIA) of This DOT

29 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Arthritis	DIST1YEL	Definitive	Genetic Variation	[1]
Rheumatoid arthritis	DISTSB4J	Definitive	Altered Expression	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Allergy	DIS48ZAP	Strong	Biomarker	[3]
Autism	DISV4V1Z	Strong	Biomarker	[4]
Autism spectrum disorder	DISXK8NV	Strong	Altered Expression	[4]
B-cell lymphoma	DISIH1YQ	Strong	Biomarker	[5]
Chorioamnionitis	DISL1D9U	Strong	Altered Expression	[6]
Colitis	DISAF7DD	Strong	Biomarker	[7]
Copper metabolism disorder	DISXHPKM	Strong	Biomarker	[8]
Cystic fibrosis	DIS2OK1Q	Strong	Biomarker	[9]
Epithelial ovarian cancer	DIS56MH2	Strong	Altered Expression	[2]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Altered Expression	[10]
Hepatitis	DISXXX35	Strong	Biomarker	[11]
Hepatitis A virus infection	DISUMFQV	Strong	Biomarker	[11]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[12]
HIV infectious disease	DISO97HC	Strong	Biomarker	[13]
Inflammatory bowel disease	DISGN23E	Strong	Genetic Variation	[7]
Liver cirrhosis	DIS4G1GX	Strong	Biomarker	[14]
Menkes disease	DISJJV50	Strong	Biomarker	[15]
Neoplasm	DISZKGEW	Strong	Altered Expression	[10]
Ovarian cancer	DISZJHAP	Strong	Altered Expression	[2]
Ovarian neoplasm	DISEAFTY	Strong	Altered Expression	[2]
Prostate cancer	DISF190Y	Strong	Altered Expression	[16]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[16]
Ulcerative colitis	DIS8K27O	Strong	Genetic Variation	[7]
Pulmonary emphysema	DIS5M7HZ	moderate	Biomarker	[17]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[18]
Proliferative diabetic retinopathy	DISQZ13G	Limited	Genetic Variation	[19]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Clioquinol	DM746BZ	Withdrawn from market	COMM domain-containing protein 1 (COMMD1) affects the response to substance of Clioquinol.	[30]

9 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 COMM domain-containing protein 1 (COMMD1).	[20]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of COMM domain-containing protein 1 (COMMD1).	[21]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of COMM domain-containing protein 1 (COMMD1).	[22]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of COMM domain-containing protein 1 (COMMD1).	[23]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of COMM domain-containing protein 1 (COMMD1).	[24]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of COMM domain-containing protein 1 (COMMD1).	[25]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of COMM domain-containing protein 1 (COMMD1).	[26]
MG-132	DMKA2YS	Preclinical	MG-132 increases the expression of COMM domain-containing protein 1 (COMMD1).	[27]
BRN-3548355	DM4KXT0	Investigative	BRN-3548355 increases the expression of COMM domain-containing protein 1 (COMMD1).	[29]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of COMM domain-containing protein 1 (COMMD1).	[28]

References

• [1] Hypoxia-Sensitive COMMD1 Integrates Signaling and Cellular Metabolism in Human Macrophages and Suppresses Osteoclastogenesis.Immunity. 2017 Jul 18;47(1):66-79.e5. doi: 10.1016/j.immuni.2017.06.018.
• [2] Nuclear COMMD1 Is Associated with Cisplatin Sensitivity in Ovarian Cancer.PLoS One. 2016 Oct 27;11(10):e0165385. doi: 10.1371/journal.pone.0165385. eCollection 2016.
• [3] Liver-specific Commd1 knockout mice are susceptible to hepatic copper accumulation.PLoS One. 2011;6(12):e29183. doi: 10.1371/journal.pone.0029183. Epub 2011 Dec 22.
• [4] Loss of COMMD1 and copper overload disrupt zinc homeostasis and influence an autism-associated pathway at glutamatergic synapses.Biometals. 2014 Aug;27(4):715-30. doi: 10.1007/s10534-014-9764-1. Epub 2014 Jul 10.
• [5] Deregulation of COMMD1 is associated with poor prognosis in diffuse large B-cell lymphoma.PLoS One. 2014 Mar 13;9(3):e91031. doi: 10.1371/journal.pone.0091031. eCollection 2014.
• [6] Copper metabolism domain-containing 1 represses the mediators involved in the terminal effector pathways of human labour and delivery.Mol Hum Reprod. 2016 Apr;22(4):299-310. doi: 10.1093/molehr/gav075. Epub 2016 Jan 4.
• [7] Copper metabolism domain-containing 1 represses genes that promote inflammation and protects mice from colitis and colitis-associated cancer.Gastroenterology. 2014 Jul;147(1):184-195.e3. doi: 10.1053/j.gastro.2014.04.007. Epub 2014 Apr 13.
• [8] Canine models of copper toxicosis for understanding mammalian copper metabolism.Mamm Genome. 2012 Feb;23(1-2):62-75. doi: 10.1007/s00335-011-9378-7. Epub 2011 Dec 7.
• [9] COMMD1 modulates noxious inflammation in cystic fibrosis.Int J Biochem Cell Biol. 2013 Nov;45(11):2402-9. doi: 10.1016/j.biocel.2013.07.012. Epub 2013 Jul 24.
• [10] Downregulation of COMMD1 by miR-205 promotes a positive feedback loop for amplifying inflammatory- and stemness-associated properties of cancer cells.Cell Death Differ. 2016 May;23(5):841-52. doi: 10.1038/cdd.2015.147. Epub 2015 Nov 20.
• [11] Copper-induced hepatitis: the COMMD1 deficient dog as a translational animal model for human chronic hepatitis.Vet Q. 2011 Mar;31(1):49-60. doi: 10.1080/01652176.2011.563146.
• [12] COMMD7 Regulates NF-B Signaling Pathway in Hepatocellular Carcinoma Stem-like Cells.Mol Ther Oncolytics. 2018 Dec 14;12:112-123. doi: 10.1016/j.omto.2018.12.006. eCollection 2019 Mar 29.
• [13] Soluble Factors Secreted by Endothelial Cells Allow for Productive and Latent HIV-1 Infection in Resting CD4(+) T Cells.AIDS Res Hum Retroviruses. 2017 Feb;33(2):110-120. doi: 10.1089/AID.2016.0058. Epub 2016 Oct 5.
• [14] Distinct Wilson's disease mutations in ATP7B are associated with enhanced binding to COMMD1 and reduced stability of ATP7B.Gastroenterology. 2007 Oct;133(4):1316-26. doi: 10.1053/j.gastro.2007.07.020. Epub 2007 Jul 25.
• [15] The copper-transporting capacity of ATP7A mutants associated with Menkes disease is ameliorated by COMMD1 as a result of improved protein expression.Cell Mol Life Sci. 2012 Jan;69(1):149-63. doi: 10.1007/s00018-011-0743-1. Epub 2011 Jun 11.
• [16] Clusterin facilitates COMMD1 and I-kappaB degradation to enhance NF-kappaB activity in prostate cancer cells.Mol Cancer Res. 2010 Jan;8(1):119-30. doi: 10.1158/1541-7786.MCR-09-0277. Epub 2010 Jan 12.
• [17] The copper dependent-lysyl oxidases contribute to the pathogenesis of pulmonary emphysema in chronic obstructive pulmonary disease patients.J Trace Elem Med Biol. 2017 Dec;44:247-255. doi: 10.1016/j.jtemb.2017.08.011. Epub 2017 Sep 1.
• [18] A novel nuclear complex of DRR1, F-actin and COMMD1 involved in NF-B degradation and cell growth suppression in neuroblastoma.Oncogene. 2017 Oct 12;36(41):5745-5756. doi: 10.1038/onc.2017.181. Epub 2017 Jun 12.
• [19] Multiethnic Genome-Wide Association Study of Diabetic Retinopathy Using Liability Threshold Modeling of Duration of Diabetes and Glycemic Control.Diabetes. 2019 Feb;68(2):441-456. doi: 10.2337/db18-0567. Epub 2018 Nov 28.
• [20] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [21] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [22] 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.
• [23] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [24] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [25] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [26] 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.
• [27] The Antitumor Peptide CIGB-552 Increases COMMD1 and Inhibits Growth of Human Lung Cancer Cells. J Amino Acids. 2013;2013:251398. doi: 10.1155/2013/251398. Epub 2013 Jan 16.
• [28] 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.
• [29] Gene expression profiles in HPV-immortalized human cervical cells treated with the nicotine-derived carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. Chem Biol Interact. 2009 Feb 12;177(3):173-80. doi: 10.1016/j.cbi.2008.10.051. Epub 2008 Nov 6.
• [30] Population-based in vitro hazard and concentration-response assessment of chemicals: the 1000 genomes high-throughput screening study. Environ Health Perspect. 2015 May;123(5):458-66. doi: 10.1289/ehp.1408775. Epub 2015 Jan 13.