Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTPXA60S)

• DOT Name: E3 ubiquitin-protein ligase RNF26 (RNF26)
• Synonyms: EC 2.3.2.27; RING finger protein 26
• Gene Name: RNF26
• Related Disease:
  Advanced cancer
  Colorectal carcinoma
  Gastric cancer
  Malignant uterine tumour
  Stomach cancer
• UniProt ID: RNF26_HUMAN
• EC Number: 2.3.2.27
• Pfam ID: PF13920
• Sequence:
  MEAVYLVVNGLGLVLDVLTLVLDLNFLLVSSLLASLAWLLAFVYNLPHTVLTSLLHLGRG
  VLLSLLALIEAVVRFTCGGLQALCTLLYSCCSGLESLKLLGHLASHGALRSREILHRGVL
  NVVSSGHALLRQACDICAIAMSLVAYVINSLVNICLIGTQNLFSLVLALWDAVTGPLWRM
  TDVVAAFLAHISSSAVAMAILLWTPCQLALELLASAARLLASFVLVNLTGLVLLACVLAV
  TVTVLHPDFTLRLATQALSQLHARPSYHRLREDVMRLSRLALGSEAWRRVWSRSLQLASW
  PNRGGAPGAPQGDPMRVFSVRTRRQDTLPEAGRRSEAEEEEARTIRVTPVRGRERLNEEE
  PPGGQDPWKLLKEQEERKKCVICQDQSKTVLLLPCRHLCLCQACTEILMRHPVYHRNCPL
  CRRGILQTLNVYL
• Function: E3 ubiquitin-protein ligase that plays a key role in endosome organization by retaining vesicles in the perinuclear cloud. Acts as a platform for perinuclear positioning of the endosomal system by mediating ubiquitination of SQSTM1 through interaction with the ubiquitin conjugating enzyme UBE2J1. Ubiquitinated SQSTM1 attracts specific vesicle-associated adapters, forming a molecular bridge that restrains cognate vesicles in the perinuclear region and organizes the endosomal pathway for efficient cargo transport. Also acts as a regulator of type I interferon production in response to viral infection by mediating the formation of 'Lys-11'-linked polyubiquitin chains on TMEM173/STING, leading to stabilize TMEM173/STING. Also required to limit type I interferon response by promoting autophagic degradation of IRF3.
• Tissue Specificity: Ubiquitous. Up-regulated in several cancer cell lines.

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[1]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[1]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[1]
Malignant uterine tumour	DIS3QDT8	Strong	Altered Expression	[1]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of E3 ubiquitin-protein ligase RNF26 (RNF26).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of E3 ubiquitin-protein ligase RNF26 (RNF26).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of E3 ubiquitin-protein ligase RNF26 (RNF26).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of E3 ubiquitin-protein ligase RNF26 (RNF26).	[5]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of E3 ubiquitin-protein ligase RNF26 (RNF26).	[6]
Marinol	DM70IK5	Approved	Marinol increases the expression of E3 ubiquitin-protein ligase RNF26 (RNF26).	[7]
Aspirin	DM672AH	Approved	Aspirin increases the expression of E3 ubiquitin-protein ligase RNF26 (RNF26).	[8]
Sulindac	DM2QHZU	Approved	Sulindac decreases the expression of E3 ubiquitin-protein ligase RNF26 (RNF26).	[8]
APR-246	DMNFADH	Phase 2	APR-246 affects the expression of E3 ubiquitin-protein ligase RNF26 (RNF26).	[9]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of E3 ubiquitin-protein ligase RNF26 (RNF26).	[11]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of E3 ubiquitin-protein ligase RNF26 (RNF26).	[12]

1 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 increases the methylation of E3 ubiquitin-protein ligase RNF26 (RNF26).	[10]

References

• [1] Molecular cloning and characterization of RNF26 on human chromosome 11q23 region, encoding a novel RING finger protein with leucine zipper.Biochem Biophys Res Commun. 2001 Apr 13;282(4):1038-44. doi: 10.1006/bbrc.2001.4671.
• [2] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [3] 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.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [6] 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.
• [7] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [8] Expression profile analysis of colon cancer cells in response to sulindac or aspirin. Biochem Biophys Res Commun. 2002 Mar 29;292(2):498-512.
• [9] Mutant p53 reactivation by PRIMA-1MET induces multiple signaling pathways converging on apoptosis. Oncogene. 2010 Mar 4;29(9):1329-38. doi: 10.1038/onc.2009.425. Epub 2009 Nov 30.
• [10] 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.
• [11] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [12] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.