Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTF06FRP)

• DOT Name: E3 ubiquitin-protein ligase RNF114 (RNF114)
• Synonyms: EC 2.3.2.27; RING finger protein 114; RING-type E3 ubiquitin transferase RNF114; Zinc finger protein 228; Zinc finger protein 313
• Gene Name: RNF114
• Related Disease:
  Neoplasm
  Palmoplantar pustulosis
  Pemphigus
  Systemic lupus erythematosus
  Psoriasis
• UniProt ID: RN114_HUMAN
• EC Number: 2.3.2.27
• Pfam ID: PF05605 ; PF13445 ; PF18574
• Sequence:
  MAAQQRDCGGAAQLAGPAAEADPLGRFTCPVCLEVYEKPVQVPCGHVFCSACLQECLKPK
  KPVCGVCRSALAPGVRAVELERQIESTETSCHGCRKNFFLSKIRSHVATCSKYQNYIMEG
  VKATIKDASLQPRNVPNRYTFPCPYCPEKNFDQEGLVEHCKLFHSTDTKSVVCPICASMP
  WGDPNYRSANFREHIQRRHRFSYDTFVDYDVDEEDMMNQVLQRSIIDQ
• Function: E3 ubiquitin-protein ligase that promotes the ubiquitination of various substrates. In turn, participates in the regulation of many biological processes including cell cycle, apoptosis, osteoclastogenesis as well as innate or adaptive immunity. Acts as a negative regulator of NF-kappa-B-dependent transcription by promoting the ubiquitination and stabilization of the NF-kappa-B inhibitor TNFAIP3. May promote the ubiquitination of TRAF6 as well. Acts also as a negative regulator of T-cell activation. Inhibits cellular dsRNA responses and interferon production by targeting MAVS component for proteasomal degradation. Ubiquitinates the CDK inhibitor CDKN1A leading to its degradationand probably also CDKN1B and CDKN1C. This activity stimulates cell cycle G1-to-S phase transition and suppresses cellular senescence. May play a role in spermatogenesis.
• Tissue Specificity: Expressed in numerous tissues, including skin, CD4 lymphocytes and dendritic cells. Highest levels in testis.
• Reactome Pathway: Antigen processing (R-HSA-983168)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neoplasm	DISZKGEW	Strong	Altered Expression	[1]
Palmoplantar pustulosis	DISCNSWD	Strong	Biomarker	[2]
Pemphigus	DISZAZ6M	Strong	Altered Expression	[3]
Systemic lupus erythematosus	DISI1SZ7	Strong	Genetic Variation	[4]
Psoriasis	DIS59VMN	Limited	Biomarker	[5]

15 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 E3 ubiquitin-protein ligase RNF114 (RNF114).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of E3 ubiquitin-protein ligase RNF114 (RNF114).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of E3 ubiquitin-protein ligase RNF114 (RNF114).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of E3 ubiquitin-protein ligase RNF114 (RNF114).	[9]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of E3 ubiquitin-protein ligase RNF114 (RNF114).	[10]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of E3 ubiquitin-protein ligase RNF114 (RNF114).	[11]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of E3 ubiquitin-protein ligase RNF114 (RNF114).	[12]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of E3 ubiquitin-protein ligase RNF114 (RNF114).	[13]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of E3 ubiquitin-protein ligase RNF114 (RNF114).	[14]
Selenium	DM25CGV	Approved	Selenium increases the expression of E3 ubiquitin-protein ligase RNF114 (RNF114).	[15]
Menadione	DMSJDTY	Approved	Menadione affects the expression of E3 ubiquitin-protein ligase RNF114 (RNF114).	[12]
Afimoxifene	DMFORDT	Phase 2	Afimoxifene decreases the expression of E3 ubiquitin-protein ligase RNF114 (RNF114).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of E3 ubiquitin-protein ligase RNF114 (RNF114).	[17]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of E3 ubiquitin-protein ligase RNF114 (RNF114).	[18]
Milchsaure	DM462BT	Investigative	Milchsaure affects the expression of E3 ubiquitin-protein ligase RNF114 (RNF114).	[19]

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 affects the methylation of E3 ubiquitin-protein ligase RNF114 (RNF114).	[16]

References

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• [2] A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1.Nat Genet. 2010 Nov;42(11):985-90. doi: 10.1038/ng.694. Epub 2010 Oct 17.
• [3] Usefulness of miRNA-338-3p in the diagnosis of pemphigus and its correlation with disease severity.PeerJ. 2018 Aug 3;6:e5388. doi: 10.7717/peerj.5388. eCollection 2018.
• [4] GWAS identifies novel SLE susceptibility genes and explains the association of the HLA region.Genes Immun. 2014 Sep;15(6):347-54. doi: 10.1038/gene.2014.23. Epub 2014 May 29.
• [5] Regulation of RANKL-induced osteoclastogenesis by RING finger protein RNF114.J Orthop Res. 2018 Jan;36(1):159-166. doi: 10.1002/jor.23654. Epub 2017 Jul 31.
• [6] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [7] 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.
• [8] 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.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [11] Identification of novel ER-alpha target genes in breast cancer cells: gene- and cell-selective co-regulator recruitment at target promoters determines the response to 17beta-estradiol and tamoxifen. Mol Cell Endocrinol. 2010 Jan 15;314(1):90-100.
• [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] Methotrexate modulates folate phenotype and inflammatory profile in EA.hy 926 cells. Eur J Pharmacol. 2014 Jun 5;732:60-7.
• [14] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [15] 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.
• [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] 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.
• [18] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [19] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.