Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8AJG1I)

• DOT Name: RNA-binding E3 ubiquitin-protein ligase MEX3C (MEX3C)
• Synonyms: EC 2.3.2.27; RING finger and KH domain-containing protein 2; RING finger protein 194; RING-type E3 ubiquitin transferase MEX3C
• Gene Name: MEX3C
• Related Disease:
  Atrial fibrillation
  Colorectal carcinoma
  Essential hypertension
  High blood pressure
  Juvenile idiopathic arthritis
  Bladder cancer
  Familial atrial fibrillation
  Immune system disorder
  Neoplasm
  Urinary bladder cancer
  Urinary bladder neoplasm
• UniProt ID: MEX3C_HUMAN
• PDB ID: 5WWW; 5WWX; 5WWZ; 5ZI6
• EC Number: 2.3.2.27
• Pfam ID: PF00013 ; PF13920
• Sequence:
  MPSGSSAALALAAAPAPLPQPPPPPPPPPPPLPPPSGGPELEGDGLLLRERLAALGLDDP
  SPAEPGAPALRAPAAAAQGQARRAAELSPEERAPPGRPGAPEAAELELEEDEEEGEEAEL
  DGDLLEEEELEEAEEEDRSSLLLLSPPAATASQTQQIPGGSLGSVLLPAARFDAREAAAA
  AAAAGVLYGGDDAQGMMAAMLSHAYGPGGCGAAAAALNGEQAALLRRKSVNTTECVPVPS
  SEHVAEIVGRQGCKIKALRAKTNTYIKTPVRGEEPIFVVTGRKEDVAMAKREILSAAEHF
  SMIRASRNKNGPALGGLSCSPNLPGQTTVQVRVPYRVVGLVVGPKGATIKRIQQQTHTYI
  VTPSRDKEPVFEVTGMPENVDRAREEIEMHIAMRTGNYIELNEENDFHYNGTDVSFEGGT
  LGSAWLSSNPVPPSRARMISNYRNDSSSSLGSGSTDSYFGSNRLADFSPTSPFSTGNFWF
  GDTLPSVGSEDLAVDSPAFDSLPTSAQTIWTPFEPVNPLSGFGSDPSGNMKTQRRGSQPS
  TPRLSPTFPESIEHPLARRVRSDPPSTGNHVGLPIYIPAFSNGTNSYSSSNGGSTSSSPP
  ESRRKHDCVICFENEVIAALVPCGHNLFCMECANKICEKRTPSCPVCQTAVTQAIQIHS
• Function: E3 ubiquitin ligase responsible for the post-transcriptional regulation of common HLA-A allotypes. Binds to the 3' UTR of HLA-A2 mRNA, and regulates its levels by promoting mRNA decay. RNA binding is sufficient to prevent translation, but ubiquitin ligase activity is required for mRNA degradation.
• Tissue Specificity: Highest levels found in fetal brain and testis. Also expressed in thymus, salivary gland and uterus. Highly expressed in cells of the innate immune system, in particular activated NK cells. Week expression in the intestine.
• Reactome Pathway: Antigen processing (R-HSA-983168)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Atrial fibrillation	DIS15W6U	Strong	Biomarker	[1]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[2]
Essential hypertension	DIS7WI98	Strong	Biomarker	[3]
High blood pressure	DISY2OHH	Strong	Biomarker	[3]
Juvenile idiopathic arthritis	DISQZGBV	Strong	Biomarker	[4]
Bladder cancer	DISUHNM0	moderate	Altered Expression	[5]
Familial atrial fibrillation	DISL4AGF	moderate	Biomarker	[1]
Immune system disorder	DISAEGPH	moderate	Biomarker	[6]
Neoplasm	DISZKGEW	moderate	Biomarker	[5]
Urinary bladder cancer	DISDV4T7	moderate	Altered Expression	[5]
Urinary bladder neoplasm	DIS7HACE	moderate	Altered Expression	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of RNA-binding E3 ubiquitin-protein ligase MEX3C (MEX3C).	[7]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of RNA-binding E3 ubiquitin-protein ligase MEX3C (MEX3C).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of RNA-binding E3 ubiquitin-protein ligase MEX3C (MEX3C).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of RNA-binding E3 ubiquitin-protein ligase MEX3C (MEX3C).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of RNA-binding E3 ubiquitin-protein ligase MEX3C (MEX3C).	[10]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of RNA-binding E3 ubiquitin-protein ligase MEX3C (MEX3C).	[11]
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of RNA-binding E3 ubiquitin-protein ligase MEX3C (MEX3C).	[12]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of RNA-binding E3 ubiquitin-protein ligase MEX3C (MEX3C).	[13]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of RNA-binding E3 ubiquitin-protein ligase MEX3C (MEX3C).	[14]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of RNA-binding E3 ubiquitin-protein ligase MEX3C (MEX3C).	[15]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of RNA-binding E3 ubiquitin-protein ligase MEX3C (MEX3C).	[16]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of RNA-binding E3 ubiquitin-protein ligase MEX3C (MEX3C).	[17]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of RNA-binding E3 ubiquitin-protein ligase MEX3C (MEX3C).	[18]
Milchsaure	DM462BT	Investigative	Milchsaure affects the expression of RNA-binding E3 ubiquitin-protein ligase MEX3C (MEX3C).	[20]

References

• [1] Multi-ethnic genome-wide association study for atrial fibrillation.Nat Genet. 2018 Jun 11;50(9):1225-1233. doi: 10.1038/s41588-018-0133-9.
• [2] Replication stress links structural and numerical cancer chromosomal instability.Nature. 2013 Feb 28;494(7438):492-496. doi: 10.1038/nature11935.
• [3] Implication of chromosome 18 in hypertension by sibling pair and association analyses: putative involvement of the RKHD2 gene.Hypertension. 2006 Nov;48(5):883-91. doi: 10.1161/01.HYP.0000244085.52918.a0. Epub 2006 Oct 2.
• [4] Gene expression signatures in polyarticular juvenile idiopathic arthritis demonstrate disease heterogeneity and offer a molecular classification of disease subsets.Arthritis Rheum. 2009 Jul;60(7):2113-23. doi: 10.1002/art.24534.
• [5] MEX3C regulates lipid metabolism to promote bladder tumorigenesis through JNK pathway.Onco Targets Ther. 2019 May 1;12:3285-3294. doi: 10.2147/OTT.S199667. eCollection 2019.
• [6] The human RNA-binding protein and E3 ligase MEX-3C binds the MEX-3-recognition element (MRE) motif with high affinity.J Biol Chem. 2017 Sep 29;292(39):16221-16234. doi: 10.1074/jbc.M117.797746. Epub 2017 Aug 14.
• [7] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [8] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [9] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] 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.
• [12] Drinking-water arsenic exposure modulates gene expression in human lymphocytes from a U.S. population. Environ Health Perspect. 2008 Apr;116(4):524-31. doi: 10.1289/ehp.10861.
• [13] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [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] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [16] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [17] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [18] 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.
• [19] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [20] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.