Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTPF83PG)

• DOT Name: Cullin-2 (CUL2)
• Synonyms: CUL-2
• Gene Name: CUL2
• Related Disease:
  Breast carcinoma
  Inflammatory bowel disease
  Acute myelogenous leukaemia
  Breast cancer
  Hepatocellular carcinoma
  Polycythemia
  Retinoblastoma
  Acute leukaemia
  Adenocarcinoma
  Carcinoma
  Carcinoma of esophagus
  Colon cancer
  Colorectal carcinoma
  Esophageal cancer
  Human papillomavirus infection
  Neoplasm of esophagus
  Squamous cell carcinoma
• UniProt ID: CUL2_HUMAN
• PDB ID: 4WQO; 5N4W; 6R6H; 6R7F; 6R7H; 6R7I; 6R7N; 7PLO; 8JAL; 8JAQ; 8JAR; 8JAS; 8JAU; 8JAV; 8QU8
• Pfam ID: PF00888 ; PF10557
• Sequence:
  MSLKPRVVDFDETWNKLLTTIKAVVMLEYVERATWNDRFSDIYALCVAYPEPLGERLYTE
  TKIFLENHVRHLHKRVLESEEQVLVMYHRYWEEYSKGADYMDCLYRYLNTQFIKKNKLTE
  ADLQYGYGGVDMNEPLMEIGELALDMWRKLMVEPLQAILIRMLLREIKNDRGGEDPNQKV
  IHGVINSFVHVEQYKKKFPLKFYQEIFESPFLTETGEYYKQEASNLLQESNCSQYMEKVL
  GRLKDEEIRCRKYLHPSSYTKVIHECQQRMVADHLQFLHAECHNIIRQEKKNDMANMYVL
  LRAVSTGLPHMIQELQNHIHDEGLRATSNLTQENMPTLFVESVLEVHGKFVQLINTVLNG
  DQHFMSALDKALTSVVNYREPKSVCKAPELLAKYCDNLLKKSAKGMTENEVEDRLTSFIT
  VFKYIDDKDVFQKFYARMLAKRLIHGLSMSMDSEEAMINKLKQACGYEFTSKLHRMYTDM
  SVSADLNNKFNNFIKNQDTVIDLGISFQIYVLQAGAWPLTQAPSSTFAIPQELEKSVQMF
  ELFYSQHFSGRKLTWLHYLCTGEVKMNYLGKPYVAMVTTYQMAVLLAFNNSETVSYKELQ
  DSTQMNEKELTKTIKSLLDVKMINHDSEKEDIDAESSFSLNMNFSSKRTKFKITTSMQKD
  TPQEMEQTRSAVDEDRKMYLQAAIVRIMKARKVLRHNALIQEVISQSRARFNPSISMIKK
  CIEVLIDKQYIERSQASADEYSYVA
• Function: Core component of multiple cullin-RING-based ECS (ElonginB/C-CUL2/5-SOCS-box protein) E3 ubiquitin-protein ligase complexes, which mediate the ubiquitination of target proteins. CUL2 may serve as a rigid scaffold in the complex and may contribute to catalysis through positioning of the substrate and the ubiquitin-conjugating enzyme. The E3 ubiquitin-protein ligase activity of the complex is dependent on the neddylation of the cullin subunit and is inhibited by the association of the deneddylated cullin subunit with TIP120A/CAND1. The functional specificity of the ECS complex depends on the substrate recognition component. ECS(VHL) mediates the ubiquitination of hypoxia-inducible factor (HIF). A number of ECS complexes (containing either KLHDC2, KLHDC3, KLHDC10, APPBP2, FEM1A, FEM1B or FEM1C as substrate-recognition component) are part of the DesCEND (destruction via C-end degrons) pathway, which recognizes a C-degron located at the extreme C terminus of target proteins, leading to their ubiquitination and degradation. ECS complexes and ARIH1 collaborate in tandem to mediate ubiquitination of target proteins. ECS(LRR1) ubiquitinates MCM7 and promotes CMG replisome disassembly by VCP and chromatin extraction during S-phase.
• KEGG Pathway:
  HIF-1 sig.ling pathway (hsa04066)
  Ubiquitin mediated proteolysis (hsa04120)
  Pathways in cancer (hsa05200)
  Re.l cell carcinoma (hsa05211)
• Reactome Pathway:
  Neddylation (R-HSA-8951664)
  Regulation of expression of SLITs and ROBOs (R-HSA-9010553)
  Antigen processing (R-HSA-983168)
  Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha (R-HSA-1234176)

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast carcinoma	DIS2UE88	Definitive	Altered Expression	[1]
Inflammatory bowel disease	DISGN23E	Definitive	Biomarker	[2]
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[3]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[1]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[4]
Polycythemia	DIS8B6VW	Strong	Biomarker	[5]
Retinoblastoma	DISVPNPB	Strong	Biomarker	[6]
Acute leukaemia	DISDQFDI	Limited	Genetic Variation	[7]
Adenocarcinoma	DIS3IHTY	Limited	Altered Expression	[8]
Carcinoma	DISH9F1N	Limited	Genetic Variation	[7]
Carcinoma of esophagus	DISS6G4D	Limited	Biomarker	[8]
Colon cancer	DISVC52G	Limited	Genetic Variation	[7]
Colorectal carcinoma	DIS5PYL0	Limited	Genetic Variation	[7]
Esophageal cancer	DISGB2VN	Limited	Biomarker	[8]
Human papillomavirus infection	DISX61LX	Limited	Altered Expression	[9]
Neoplasm of esophagus	DISOLKAQ	Limited	Biomarker	[8]
Squamous cell carcinoma	DISQVIFL	Limited	Altered Expression	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Cullin-2 (CUL2).	[10]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Cullin-2 (CUL2).	[11]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Cullin-2 (CUL2).	[12]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Cullin-2 (CUL2).	[14]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Cullin-2 (CUL2).	[15]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of Cullin-2 (CUL2).	[16]
Clozapine	DMFC71L	Approved	Clozapine increases the expression of Cullin-2 (CUL2).	[17]
Benzatropine	DMF7EXL	Approved	Benzatropine increases the expression of Cullin-2 (CUL2).	[17]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Cullin-2 (CUL2).	[18]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Cullin-2 (CUL2).	[19]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Cullin-2 (CUL2).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Cullin-2 (CUL2).	[13]

References

• [1] Association of mRNA expression levels of Cullin family members with prognosis in breast cancer: An online database analysis.Medicine (Baltimore). 2019 Aug;98(31):e16625. doi: 10.1097/MD.0000000000016625.
• [2] Deep resequencing of GWAS loci identifies independent rare variants associated with inflammatory bowel disease.Nat Genet. 2011 Oct 9;43(11):1066-73. doi: 10.1038/ng.952.
• [3] CUEDC2, a novel interacting partner of the SOCS1 protein, plays important roles in the leukaemogenesis of acute myeloid leukaemia.Cell Death Dis. 2018 Jul 10;9(7):774. doi: 10.1038/s41419-018-0812-6.
• [4] Twist1 Regulates Vimentin through Cul2 Circular RNA to Promote EMT in Hepatocellular Carcinoma.Cancer Res. 2018 Aug 1;78(15):4150-4162. doi: 10.1158/0008-5472.CAN-17-3009. Epub 2018 May 29.
• [5] An integrated computational approach can classify VHL missense mutations according to risk of clear cell renal carcinoma.Hum Mol Genet. 2014 Nov 15;23(22):5976-88. doi: 10.1093/hmg/ddu321. Epub 2014 Jun 26.
• [6] Human papillomavirus type 16 E7 oncoprotein associates with the cullin 2 ubiquitin ligase complex, which contributes to degradation of the retinoblastoma tumor suppressor.J Virol. 2007 Sep;81(18):9737-47. doi: 10.1128/JVI.00881-07. Epub 2007 Jul 3.
• [7] Mutational analysis of hypoxia-related genes HIF1alpha and CUL2 in common human cancers.APMIS. 2009 Dec;117(12):880-5. doi: 10.1111/j.1600-0463.2009.02550.x.
• [8] CUL2 and STK11 as novel response-predictive genes for neoadjuvant radiochemotherapy in esophageal cancer.Pharmacogenomics. 2010 Aug;11(8):1105-13. doi: 10.2217/pgs.10.76.
• [9] Human Papillomavirus 16 E7 Stabilizes APOBEC3A Protein by Inhibiting Cullin 2-Dependent Protein Degradation.J Virol. 2018 Mar 14;92(7):e01318-17. doi: 10.1128/JVI.01318-17. Print 2018 Apr 1.
• [10] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [11] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [12] 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.
• [13] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [14] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [15] 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.
• [16] 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.
• [17] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [18] Regulation of gene expression and inhibition of experimental prostate cancer bone metastasis by dietary genistein. Neoplasia. 2004 Jul-Aug;6(4):354-63. doi: 10.1593/neo.03478.
• [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] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.