Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTWX0D0H)

• DOT Name: E3 ubiquitin-protein ligase RNF14 (RNF14)
• Synonyms: EC 2.3.2.31; Androgen receptor-associated protein 54; HFB30; RING finger protein 14
• Gene Name: RNF14
• Related Disease:
  Barrett esophagus
  Colon cancer
  Colon carcinoma
  Prostate neoplasm
  Prostate cancer
  Prostate carcinoma
• UniProt ID: RNF14_HUMAN
• EC Number: 2.3.2.31
• Pfam ID: PF01485 ; PF05773
• Sequence:
  MSSEDREAQEDELLALASIYDGDEFRKAESVQGGETRIYLDLPQNFKIFVSGNSNECLQN
  SGFEYTICFLPPLVLNFELPPDYPSSSPPSFTLSGKWLSPTQLSALCKHLDNLWEEHRGS
  VVLFAWMQFLKEETLAYLNIVSPFELKIGSQKKVQRRTAQASPNTELDFGGAAGSDVDQE
  EIVDERAVQDVESLSNLIQEILDFDQAQQIKCFNSKLFLCSICFCEKLGSECMYFLECRH
  VYCKACLKDYFEIQIRDGQVQCLNCPEPKCPSVATPGQVKELVEAELFARYDRLLLQSSL
  DLMADVVYCPRPCCQLPVMQEPGCTMGICSSCNFAFCTLCRLTYHGVSPCKVTAEKLMDL
  RNEYLQADEANKRLLDQRYGKRVIQKALEEMESKEWLEKNSKSCPCCGTPIEKLDGCNKM
  TCTGCMQYFCWICMGSLSRANPYKHFNDPGSPCFNRLFYAVDVDDDIWEDEVED
• Function: E3 ubiquitin-protein ligase that plays a key role in the RNF14-RNF25 translation quality control pathway, a pathway that takes place when a ribosome has stalled during translation, and which promotes ubiquitination and degradation of translation factors on stalled ribosomes. Recruited to stalled ribosomes by the ribosome collision sensor GCN1 and mediates 'Lys-6'-linked ubiquitination of target proteins, leading to their degradation. Mediates ubiquitination of EEF1A1/eEF1A and ETF1/eRF1 translation factors on stalled ribosomes, leading to their degradation. Also catalyzes ubiquitination of ribosomal proteins RPL0, RPL1, RPL12, RPS13 and RPS17. Specifically required to resolve RNA-protein cross-links caused by reactive aldehydes, which trigger translation stress by stalling ribosomes: acts by catalying 'Lys-6'-linked ubiquitination of RNA-protein cross-links, leading to their removal by the ATP-dependent unfoldase VCP and subsequent degradation by the proteasome. Independently of its function in the response to stalled ribosomes, acts as a regulator of transcription in Wnt signaling via its interaction with TCF transcription factors (TCF7/TCF1, TCF7L1/TCF3 and TCF7L2/TCF4). May also play a role as a coactivator for androgen- and, to a lesser extent, progesterone-dependent transcription.
• Tissue Specificity: Widely expressed.
• Reactome Pathway: Antigen processing (R-HSA-983168)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Barrett esophagus	DIS416Y7	Strong	Altered Expression	[1]
Colon cancer	DISVC52G	Strong	Biomarker	[2]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[2]
Prostate neoplasm	DISHDKGQ	Strong	Altered Expression	[3]
Prostate cancer	DISF190Y	Limited	Biomarker	[4]
Prostate carcinoma	DISMJPLE	Limited	Biomarker	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of E3 ubiquitin-protein ligase RNF14 (RNF14).	[5]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of E3 ubiquitin-protein ligase RNF14 (RNF14).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of E3 ubiquitin-protein ligase RNF14 (RNF14).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of E3 ubiquitin-protein ligase RNF14 (RNF14).	[8]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of E3 ubiquitin-protein ligase RNF14 (RNF14).	[9]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of E3 ubiquitin-protein ligase RNF14 (RNF14).	[10]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of E3 ubiquitin-protein ligase RNF14 (RNF14).	[8]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of E3 ubiquitin-protein ligase RNF14 (RNF14).	[11]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of E3 ubiquitin-protein ligase RNF14 (RNF14).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of E3 ubiquitin-protein ligase RNF14 (RNF14).	[14]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of E3 ubiquitin-protein ligase RNF14 (RNF14).	[15]
QUERCITRIN	DM1DH96	Investigative	QUERCITRIN decreases the expression of E3 ubiquitin-protein ligase RNF14 (RNF14).	[16]

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 decreases the methylation of E3 ubiquitin-protein ligase RNF14 (RNF14).	[13]

References

• [1] RING finger proteins are involved in the progression of barrett esophagus to esophageal adenocarcinoma: a preliminary study.Gut Liver. 2014 Sep;8(5):487-94. doi: 10.5009/gnl13133. Epub 2014 Feb 24.
• [2] Ring Finger Protein 14 is a new regulator of TCF/-catenin-mediated transcription and colon cancer cell survival.EMBO Rep. 2013 Apr;14(4):347-55. doi: 10.1038/embor.2013.19. Epub 2013 Mar 1.
• [3] A dominant-negative mutant of androgen receptor coregulator ARA54 inhibits androgen receptor-mediated prostate cancer growth.J Biol Chem. 2002 Feb 15;277(7):4609-17. doi: 10.1074/jbc.M108312200. Epub 2001 Oct 22.
• [4] Transgelin functions as a suppressor via inhibition of ARA54-enhanced androgen receptor transactivation and prostate cancer cell growth.Mol Endocrinol. 2007 Feb;21(2):343-58. doi: 10.1210/me.2006-0104. Epub 2006 Nov 2.
• [5] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [6] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [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] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [9] Estradiol and selective estrogen receptor modulators differentially regulate target genes with estrogen receptors alpha and beta. Mol Biol Cell. 2004 Mar;15(3):1262-72. doi: 10.1091/mbc.e03-06-0360. Epub 2003 Dec 29.
• [10] 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.
• [11] 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.
• [12] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [13] 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.
• [14] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [15] 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.
• [16] Molecular mechanisms of quercitrin-induced apoptosis in non-small cell lung cancer. Arch Med Res. 2014 Aug;45(6):445-54.