Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT06BFRQ)

• DOT Name: G2/M phase-specific E3 ubiquitin-protein ligase (G2E3)
• Synonyms: EC 2.3.2.26; G2/M phase-specific HECT-type E3 ubiquitin transferase
• Gene Name: G2E3
• Related Disease: Advanced cancer
• UniProt ID: G2E3_HUMAN
• EC Number: 2.3.2.26
• Pfam ID: PF00632 ; PF13771
• Sequence:
  MNESKPGDSQNLACVFCRKHDDCPNKYGEKKTKEKWNLTVHYYCLLMSSGIWQRGKEEEG
  VYGFLIEDIRKEVNRASKLKCCVCKKNGASIGCVAPRCKRSYHFPCGLQRECIFQFTGNF
  ASFCWDHRPVQIITSNNYRESLPCTICLEFIEPIPSYNILRSPCCKNAWFHRDCLQVQAI
  NAGVFFFRCTICNNSDIFQKEMLRMGIHIPEKDASWELEENAYQELLQHYERCDVRRCRC
  KEGRDYNAPDSKWEIKRCQCCGSSGTHLACSSLRSWEQNWECLECRGIIYNSGEFQKAKK
  HVLPNSNNVGITDCLLEESSPKLPRQSPGSQSKDLLRQGSKFRRNVSTLLIELGFQIKKK
  TKRLYINKANIWNSALDAFRNRNFNPSYAIEVAYVIENDNFGSEHPGSKQEFLSLLMQHL
  ENSSLFEGSLSKNLSLNSQALKENLYYEAGKMLAISLVHGGPSPGFFSKTLFNCLVYGPE
  NTQPILDDVSDFDVAQIIIRINTATTVADLKSIINECYNYLELIGCLRLITTLSDKYMLV
  KDILGYHVIQRVHTPFESFKQGLKTLGVLEKIQAYPEAFCSILCHKPESLSAKILSELFT
  VHTLPDVKALGFWNSYLQAVEDGKSTTTMEDILIFATGCSSIPPAGFKPTPSIECLHVDF
  PVGNKCNNCLAIPITNTYKEFQENMDFTIRNTLRLEKEESSHYIGH
• Function: E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates. Essential in early embryonic development to prevent apoptotic death.
• Tissue Specificity: Predominantly expressed in brain, liver, kidney, testes and ovary.

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Limited	Biomarker	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of G2/M phase-specific E3 ubiquitin-protein ligase (G2E3).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of G2/M phase-specific E3 ubiquitin-protein ligase (G2E3).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of G2/M phase-specific E3 ubiquitin-protein ligase (G2E3).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of G2/M phase-specific E3 ubiquitin-protein ligase (G2E3).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of G2/M phase-specific E3 ubiquitin-protein ligase (G2E3).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of G2/M phase-specific E3 ubiquitin-protein ligase (G2E3).	[7]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of G2/M phase-specific E3 ubiquitin-protein ligase (G2E3).	[8]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of G2/M phase-specific E3 ubiquitin-protein ligase (G2E3).	[9]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of G2/M phase-specific E3 ubiquitin-protein ligase (G2E3).	[10]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of G2/M phase-specific E3 ubiquitin-protein ligase (G2E3).	[11]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of G2/M phase-specific E3 ubiquitin-protein ligase (G2E3).	[12]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of G2/M phase-specific E3 ubiquitin-protein ligase (G2E3).	[11]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of G2/M phase-specific E3 ubiquitin-protein ligase (G2E3).	[13]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol decreases the expression of G2/M phase-specific E3 ubiquitin-protein ligase (G2E3).	[14]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of G2/M phase-specific E3 ubiquitin-protein ligase (G2E3).	[15]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of G2/M phase-specific E3 ubiquitin-protein ligase (G2E3).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of G2/M phase-specific E3 ubiquitin-protein ligase (G2E3).	[9]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of G2/M phase-specific E3 ubiquitin-protein ligase (G2E3).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of G2/M phase-specific E3 ubiquitin-protein ligase (G2E3).	[17]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of G2/M phase-specific E3 ubiquitin-protein ligase (G2E3).	[18]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of G2/M phase-specific E3 ubiquitin-protein ligase (G2E3).	[19]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of G2/M phase-specific E3 ubiquitin-protein ligase (G2E3).	[8]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A increases the expression of G2/M phase-specific E3 ubiquitin-protein ligase (G2E3).	[20]

References

• [1] Screening analysis of ubiquitin ligases reveals G2E3 as a potential target for chemosensitizing cancer cells.Oncotarget. 2015 Jan 20;6(2):617-32. doi: 10.18632/oncotarget.2710.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [4] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [5] 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.
• [6] 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.
• [7] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [8] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [9] 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.
• [10] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [11] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [12] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [13] 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.
• [14] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [15] Clinical determinants of response to irinotecan-based therapy derived from cell line models. Clin Cancer Res. 2008 Oct 15;14(20):6647-55.
• [16] Synergistic effect of JQ1 and rapamycin for treatment of human osteosarcoma. Int J Cancer. 2015 May 1;136(9):2055-64.
• [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] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [19] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [20] Persistence of epigenomic effects after recovery from repeated treatment with two nephrocarcinogens. Front Genet. 2018 Dec 3;9:558.