Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTTUMGW7)

• DOT Name: Ubiquitin carboxyl-terminal hydrolase 2
• Synonyms: EC 3.4.19.12; 41 kDa ubiquitin-specific protease; Deubiquitinating enzyme 2; Ubiquitin thioesterase 2; Ubiquitin-specific-processing protease 2
• Gene Name: USP2
• Related Disease: Complex neurodevelopmental disorder
• UniProt ID: UBP2_HUMAN
• PDB ID: 2HD5; 2IBI; 3NHE; 3V6C; 3V6E; 5XU8; 5XVE; 6DGF
• EC Number: 3.4.19.12
• Pfam ID: PF00443
• Sequence:
  MSQLSSTLKRYTESARYTDAHYAKSGYGAYTPSSYGANLAASLLEKEKLGFKPVPTSSFL
  TRPRTYGPSSLLDYDRGRPLLRPDITGGGKRAESQTRGTERPLGSGLSGGSGFPYGVTNN
  CLSYLPINAYDQGVTLTQKLDSQSDLARDFSSLRTSDSYRIDPRNLGRSPMLARTRKELC
  TLQGLYQTASCPEYLVDYLENYGRKGSASQVPSQAPPSRVPEIISPTYRPIGRYTLWETG
  KGQAPGPSRSSSPGRDGMNSKSAQGLAGLRNLGNTCFMNSILQCLSNTRELRDYCLQRLY
  MRDLHHGSNAHTALVEEFAKLIQTIWTSSPNDVVSPSEFKTQIQRYAPRFVGYNQQDAQE
  FLRFLLDGLHNEVNRVTLRPKSNPENLDHLPDDEKGRQMWRKYLEREDSRIGDLFVGQLK
  SSLTCTDCGYCSTVFDPFWDLSLPIAKRGYPEVTLMDCMRLFTKEDVLDGDEKPTCCRCR
  GRKRCIKKFSIQRFPKILVLHLKRFSESRIRTSKLTTFVNFPLRDLDLREFASENTNHAV
  YNLYAVSNHSGTTMGGHYTAYCRSPGTGEWHTFNDSSVTPMSSSQVRTSDAYLLFYELAS
  PPSRM
• Function: Hydrolase that deubiquitinates polyubiquitinated target proteins such as MDM2, MDM4 and CCND1. Isoform 1 and isoform 4 possess both ubiquitin-specific peptidase and isopeptidase activities. Deubiquitinates MDM2 without reversing MDM2-mediated p53/TP53 ubiquitination and thus indirectly promotes p53/TP53 degradation and limits p53 activity. Has no deubiquitinase activity against p53/TP53. Prevents MDM2-mediated degradation of MDM4. Plays a role in the G1/S cell-cycle progression in normal and cancer cells. Regulates the circadian clock by modulating its intrinsic circadian rhythm and its capacity to respond to external cues. Associates with clock proteins and deubiquitinates core clock component PER1 but does not affect its overall stability. Regulates the nucleocytoplasmic shuttling and nuclear retention of PER1 and its repressive role on the clock transcription factors CLOCK and BMAL1. Plays a role in the regulation of myogenic differentiation of embryonic muscle cells; [Isoform 4]: Circadian clock output effector that regulates Ca(2+) absorption in the small intestine. Probably functions by regulating protein levels of the membrane scaffold protein NHERF4 in a rhythmic manner, and is therefore likely to control Ca(2+) membrane permeability mediated by the Ca(2+) channel TRPV6 in the intestine.
• Tissue Specificity: Expressed in mesangial cells of the kidney and in different types of glomerulonephritides (at protein level).
• Reactome Pathway:
  Regulation of TNFR1 signaling (R-HSA-5357905)
  TNFR1-induced NF-kappa-B signaling pathway (R-HSA-5357956)
  Ub-specific processing proteases (R-HSA-5689880)
  Regulation of TP53 Degradation (R-HSA-6804757)
  TNFR1-induced proapoptotic signaling (R-HSA-5357786)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Complex neurodevelopmental disorder	DISB9AFI	Limited	Autosomal recessive	[1]

18 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 Ubiquitin carboxyl-terminal hydrolase 2.	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Ubiquitin carboxyl-terminal hydrolase 2.	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Ubiquitin carboxyl-terminal hydrolase 2.	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Ubiquitin carboxyl-terminal hydrolase 2.	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Ubiquitin carboxyl-terminal hydrolase 2.	[6]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Ubiquitin carboxyl-terminal hydrolase 2.	[7]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Ubiquitin carboxyl-terminal hydrolase 2.	[8]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Ubiquitin carboxyl-terminal hydrolase 2.	[9]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Ubiquitin carboxyl-terminal hydrolase 2.	[10]
Malathion	DMXZ84M	Approved	Malathion increases the expression of Ubiquitin carboxyl-terminal hydrolase 2.	[11]
Amphotericin B	DMTAJQE	Approved	Amphotericin B increases the expression of Ubiquitin carboxyl-terminal hydrolase 2.	[12]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Ubiquitin carboxyl-terminal hydrolase 2.	[13]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Ubiquitin carboxyl-terminal hydrolase 2.	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Ubiquitin carboxyl-terminal hydrolase 2.	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Ubiquitin carboxyl-terminal hydrolase 2.	[17]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Ubiquitin carboxyl-terminal hydrolase 2.	[18]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Ubiquitin carboxyl-terminal hydrolase 2.	[19]
GALLICACID	DM6Y3A0	Investigative	GALLICACID decreases the expression of Ubiquitin carboxyl-terminal hydrolase 2.	[20]

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 Ubiquitin carboxyl-terminal hydrolase 2.	[15]

References

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• [2] 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.
• [3] 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.
• [4] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [5] 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.
• [6] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
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• [8] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [9] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [10] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [11] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [12] Differential expression of microRNAs and their predicted targets in renal cells exposed to amphotericin B and its complex with copper (II) ions. Toxicol Mech Methods. 2017 Sep;27(7):537-543. doi: 10.1080/15376516.2017.1333554. Epub 2017 Jun 8.
• [13] 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.
• [14] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [15] 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.
• [16] 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.
• [17] Comparison of transcriptome expression alterations by chronic exposure to low-dose bisphenol A in different subtypes of breast cancer cells. Toxicol Appl Pharmacol. 2019 Dec 15;385:114814. doi: 10.1016/j.taap.2019.114814. Epub 2019 Nov 9.
• [18] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [19] Sulforaphane-induced apoptosis in human leukemia HL-60 cells through extrinsic and intrinsic signal pathways and altering associated genes expression assayed by cDNA microarray. Environ Toxicol. 2017 Jan;32(1):311-328.
• [20] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.