Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTNBK390)

• DOT Name: Ubiquitin-conjugating enzyme E2 R1 (CDC34)
• Synonyms: EC 2.3.2.23; (E3-independent) E2 ubiquitin-conjugating enzyme R1; EC 2.3.2.24; E2 ubiquitin-conjugating enzyme R1; Ubiquitin-conjugating enzyme E2-32 kDa complementing; Ubiquitin-conjugating enzyme E2-CDC34; Ubiquitin-protein ligase R1
• Gene Name: CDC34
• Related Disease:
  Bone osteosarcoma
  Osteosarcoma
  Advanced cancer
  B-cell acute lymphoblastic leukaemia
  Carcinoma of esophagus
  Childhood acute lymphoblastic leukemia
  Esophageal cancer
  Esophageal squamous cell carcinoma
  Hepatocellular carcinoma
  Herpes simplex infection
  leukaemia
  Leukemia
  Lung cancer
  Lung carcinoma
  Neoplasm of esophagus
  Papillary renal cell carcinoma
  Neoplasm
• UniProt ID: UB2R1_HUMAN
• PDB ID: 2OB4; 3RZ3; 4MDK; 7M2K
• EC Number: 2.3.2.23; 2.3.2.24
• Pfam ID: PF00179
• Sequence:
  MARPLVPSSQKALLLELKGLQEEPVEGFRVTLVDEGDLYNWEVAIFGPPNTYYEGGYFKA
  RLKFPIDYPYSPPAFRFLTKMWHPNIYETGDVCISILHPPVDDPQSGELPSERWNPTQNV
  RTILLSVISLLNEPNTFSPANVDASVMYRKWKESKGKDREYTDIIRKQVLGTKVDAERDG
  VKVPTTLAEYCVKTKAPAPDEGSDLFYDDYYEDGEVEEEADSCFGDDEDDSGTEES
• Function: Accepts ubiquitin from the E1 complex and catalyzes its covalent attachment to other proteins. In vitro catalyzes 'Lys-48'-linked polyubiquitination. Cooperates with the E2 UBCH5C and the SCF(FBXW11) E3 ligase complex for the polyubiquitination of NFKBIA leading to its subsequent proteasomal degradation. Performs ubiquitin chain elongation building ubiquitin chains from the UBE2D3-primed NFKBIA-linked ubiquitin. UBE2D3 acts as an initiator E2, priming the phosphorylated NFKBIA target at positions 'Lys-21' and/or 'Lys-22' with a monoubiquitin. Cooperates with the SCF(SKP2) E3 ligase complex to regulate cell proliferation through ubiquitination and degradation of MYBL2 and KIP1. Involved in ubiquitin conjugation and degradation of CREM isoform ICERIIgamma and ATF15 resulting in abrogation of ICERIIgamma- and ATF5-mediated repression of cAMP-induced transcription during both meiotic and mitotic cell cycles. Involved in the regulation of the cell cycle G2/M phase through its targeting of the WEE1 kinase for ubiquitination and degradation. Also involved in the degradation of beta-catenin. Is target of human herpes virus 1 protein ICP0, leading to ICP0-dependent dynamic interaction with proteasomes.
• Tissue Specificity: Expressed in testes during spermatogenesis to regulate repression of cAMP-induced transcription.
• KEGG Pathway: Ubiquitin mediated proteolysis (hsa04120)
• Reactome Pathway:
  FCERI mediated NF-kB activation (R-HSA-2871837)
  CLEC7A (Dectin-1) signaling (R-HSA-5607764)
  Synthesis of active ubiquitin (R-HSA-8866652)
  Antigen processing (R-HSA-983168)
  Downstream TCR signaling (R-HSA-202424)

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bone osteosarcoma	DIST1004	Definitive	Biomarker	[1]
Osteosarcoma	DISLQ7E2	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[2]
B-cell acute lymphoblastic leukaemia	DISKLOKC	Strong	Altered Expression	[3]
Carcinoma of esophagus	DISS6G4D	Strong	Biomarker	[4]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Strong	Altered Expression	[3]
Esophageal cancer	DISGB2VN	Strong	Biomarker	[4]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[5]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[6]
Herpes simplex infection	DISL1SAV	Strong	Biomarker	[7]
leukaemia	DISS7D1V	Strong	Altered Expression	[3]
Leukemia	DISNAKFL	Strong	Altered Expression	[3]
Lung cancer	DISCM4YA	Strong	Altered Expression	[8]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[8]
Neoplasm of esophagus	DISOLKAQ	Strong	Biomarker	[4]
Papillary renal cell carcinoma	DIS25HBV	Strong	Biomarker	[9]
Neoplasm	DISZKGEW	Disputed	Altered Expression	[10]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Methotrexate	DM2TEOL	Approved	Ubiquitin-conjugating enzyme E2 R1 (CDC34) affects the response to substance of Methotrexate.	[24]
Fluorouracil	DMUM7HZ	Approved	Ubiquitin-conjugating enzyme E2 R1 (CDC34) affects the response to substance of Fluorouracil.	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Ubiquitin-conjugating enzyme E2 R1 (CDC34).	[11]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the methylation of Ubiquitin-conjugating enzyme E2 R1 (CDC34).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Ubiquitin-conjugating enzyme E2 R1 (CDC34).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Ubiquitin-conjugating enzyme E2 R1 (CDC34).	[13]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Ubiquitin-conjugating enzyme E2 R1 (CDC34).	[14]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Ubiquitin-conjugating enzyme E2 R1 (CDC34).	[15]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of Ubiquitin-conjugating enzyme E2 R1 (CDC34).	[16]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Ubiquitin-conjugating enzyme E2 R1 (CDC34).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Ubiquitin-conjugating enzyme E2 R1 (CDC34).	[18]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Ubiquitin-conjugating enzyme E2 R1 (CDC34).	[19]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Ubiquitin-conjugating enzyme E2 R1 (CDC34).	[21]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Ubiquitin-conjugating enzyme E2 R1 (CDC34).	[22]
2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE	DMNQL17	Investigative	2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE increases the expression of Ubiquitin-conjugating enzyme E2 R1 (CDC34).	[18]
acrolein	DMAMCSR	Investigative	acrolein decreases the expression of Ubiquitin-conjugating enzyme E2 R1 (CDC34).	[23]

References

• [1] miR-671-5p Inhibits Tumor Proliferation by Blocking Cell Cycle in Osteosarcoma.DNA Cell Biol. 2019 Sep;38(9):996-1004. doi: 10.1089/dna.2019.4870. Epub 2019 Aug 8.
• [2] Egr-1 and serum response factor are involved in growth factors- and serum-mediated induction of E2-EPF UCP expression that regulates the VHL-HIF pathway.J Cell Biochem. 2008 Nov 1;105(4):1117-27. doi: 10.1002/jcb.21914.
• [3] Expression and localization of the CDC34 ubiquitin-conjugating enzyme in pediatric acute lymphoblastic leukemia.Cell Growth Differ. 2001 Aug;12(8):427-33.
• [4] Role of interleukin 1 beta in esophageal squamous cell carcinoma.J Mol Med (Berl). 2012 Jan;90(1):89-100. doi: 10.1007/s00109-011-0809-4. Epub 2011 Sep 13.
• [5] The predictive role of E2-EPF ubiquitin carrier protein in esophageal squamous cell carcinoma.J Mol Med (Berl). 2009 Mar;87(3):307-20. doi: 10.1007/s00109-008-0430-3. Epub 2008 Dec 16.
• [6] Enhanced expression of mRNAs of antisecretory factor-1, gp96, DAD1 and CDC34 in human hepatocellular carcinomas.Biochim Biophys Acta. 2001 Apr 30;1536(1):1-12. doi: 10.1016/s0925-4439(01)00026-6.
• [7] Herpes simplex virus 1 mutant in which the ICP0 HUL-1 E3 ubiquitin ligase site is disrupted stabilizes cdc34 but degrades D-type cyclins and exhibits diminished neurotoxicity.J Virol. 2003 Dec;77(24):13194-202. doi: 10.1128/jvi.77.24.13194-13202.2003.
• [8] Skeletal muscle mRNA levels for cathepsin B, but not components of the ubiquitin-proteasome pathway, are increased in patients with lung cancer referred for thoracotomy.Clin Sci (Lond). 2002 Mar;102(3):353-61.
• [9] Deregulation of E2-EPF ubiquitin carrier protein in papillary renal cell carcinoma.Am J Pathol. 2011 Feb;178(2):853-60. doi: 10.1016/j.ajpath.2010.10.033.
• [10] Niclosamide Induces Cell Cycle Arrest in G1 Phase in Head and Neck Squamous Cell Carcinoma Through Let-7d/CDC34 Axis.Front Pharmacol. 2019 Jan 9;9:1544. doi: 10.3389/fphar.2018.01544. eCollection 2018.
• [11] 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.
• [12] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [13] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [14] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [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] 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.
• [17] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [18] Responses of genes involved in cell cycle control to diverse DNA damaging chemicals in human lung adenocarcinoma A549 cells. Cancer Cell Int. 2005 Aug 24;5:28. doi: 10.1186/1475-2867-5-28.
• [19] 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.
• [20] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [21] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [22] Molecular signatures of cytotoxic effects in human embryonic kidney 293?cells treated with single and mixture of ochratoxin A and citrinin. Food Chem Toxicol. 2019 Jan;123:374-384. doi: 10.1016/j.fct.2018.11.015. Epub 2018 Nov 11.
• [23] Acrolein decreases endothelial cell migration and insulin sensitivity through induction of let-7a. Toxicol Sci. 2014 Aug 1;140(2):271-82. doi: 10.1093/toxsci/kfu087. Epub 2014 May 8.
• [24] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.