Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTMTZD47)

• DOT Name: Cullin-5 (CUL5)
• Synonyms: CUL-5; Vasopressin-activated calcium-mobilizing receptor 1; VACM-1
• Gene Name: CUL5
• Related Disease:
  Adenocarcinoma
  Ataxia-telangiectasia
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Diabetic kidney disease
  Hepatitis B virus infection
  Hepatocellular carcinoma
  HIV infectious disease
  Language disorder
  Liver cancer
  Lung cancer
  Lung carcinoma
  Neoplasm
  Rheumatoid arthritis
  Small lymphocytic lymphoma
  Small-cell lung cancer
  Clear cell renal carcinoma
  Renal cell carcinoma
• UniProt ID: CUL5_HUMAN
• PDB ID: 3DPL; 3DQV; 4JGH; 4N9F; 6V9I; 7ONI; 8EI2; 8FVJ
• Pfam ID: PF00888 ; PF10557
• Sequence:
  MATSNLLKNKGSLQFEDKWDFMRPIVLKLLRQESVTKQQWFDLFSDVHAVCLWDDKGPAK
  IHQALKEDILEFIKQAQARVLSHQDDTALLKAYIVEWRKFFTQCDILPKPFCQLEITLMG
  KQGSNKKSNVEDSIVRKLMLDTWNESIFSNIKNRLQDSAMKLVHAERLGEAFDSQLVIGV
  RESYVNLCSNPEDKLQIYRDNFEKAYLDSTERFYRTQAPSYLQQNGVQNYMKYADAKLKE
  EEKRALRYLETRRECNSVEALMECCVNALVTSFKETILAECQGMIKRNETEKLHLMFSLM
  DKVPNGIEPMLKDLEEHIISAGLADMVAAAETITTDSEKYVEQLLTLFNRFSKLVKEAFQ
  DDPRFLTARDKAYKAVVNDATIFKLELPLKQKGVGLKTQPESKCPELLANYCDMLLRKTP
  LSKKLTSEEIEAKLKEVLLVLKYVQNKDVFMRYHKAHLTRRLILDISADSEIEENMVEWL
  REVGMPADYVNKLARMFQDIKVSEDLNQAFKEMHKNNKLALPADSVNIKILNAGAWSRSS
  EKVFVSLPTELEDLIPEVEEFYKKNHSGRKLHWHHLMSNGIITFKNEVGQYDLEVTTFQL
  AVLFAWNQRPREKISFENLKLATELPDAELRRTLWSLVAFPKLKRQVLLYEPQVNSPKDF
  TEGTLFSVNQEFSLIKNAKVQKRGKINLIGRLQLTTERMREEENEGIVQLRILRTQEAII
  QIMKMRKKISNAQLQTELVEILKNMFLPQKKMIKEQIEWLIEHKYIRRDESDINTFIYMA
• Function: Core component of multiple SCF-like ECS (Elongin-Cullin 2/5-SOCS-box protein) E3 ubiquitin-protein ligase complexes, which mediate the ubiquitination and subsequent proteasomal degradation of target proteins. As a scaffold protein may contribute to catalysis through positioning of the substrate and the ubiquitin-conjugating enzyme. The functional specificity of the E3 ubiquitin-protein ligase complex depends on the variable substrate recognition component. ECS(SOCS1) seems to direct ubiquitination of JAK2. ECS(KLHDC1) complex is part of the DesCEND (destruction via C-end degrons) pathway and mediates ubiquitination and degradation of truncated SELENOS selenoprotein produced by failed UGA/Sec decoding, which ends with a glycine. As part of a multisubunit complex composed of elongin BC complex (ELOB and ELOC), elongin A/ELOA, RBX1 and CUL5; polyubiquitinates monoubiquitinated POLR2A. May form a cell surface vasopressin receptor ; (Microbial infection) Seems to be involved in proteasomal degradation of p53/TP53 stimulated by adenovirus E1B-55 kDa protein.
• KEGG Pathway:
  Ubiquitin mediated proteolysis (hsa04120)
  Human immunodeficiency virus 1 infection (hsa05170)
• Reactome Pathway:
  Downregulation of ERBB2 signaling (R-HSA-8863795)
  Neddylation (R-HSA-8951664)
  Inactivation of CSF3 (G-CSF) signaling (R-HSA-9705462)
  Antigen processing (R-HSA-983168)
  Vif-mediated degradation of APOBEC3G (R-HSA-180585)

Molecular Interaction Atlas (MIA) of This DOT

19 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adenocarcinoma	DIS3IHTY	Strong	Altered Expression	[1]
Ataxia-telangiectasia	DISP3EVR	Strong	Genetic Variation	[2]
Breast cancer	DIS7DPX1	Strong	Biomarker	[3]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[3]
Breast neoplasm	DISNGJLM	Strong	Therapeutic	[4]
Diabetic kidney disease	DISJMWEY	Strong	Altered Expression	[5]
Hepatitis B virus infection	DISLQ2XY	Strong	Altered Expression	[6]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[6]
HIV infectious disease	DISO97HC	Strong	Biomarker	[7]
Language disorder	DISTLKP7	Strong	Genetic Variation	[2]
Liver cancer	DISDE4BI	Strong	Altered Expression	[1]
Lung cancer	DISCM4YA	Strong	Biomarker	[8]
Lung carcinoma	DISTR26C	Strong	Biomarker	[8]
Neoplasm	DISZKGEW	Strong	Biomarker	[9]
Rheumatoid arthritis	DISTSB4J	Strong	Genetic Variation	[10]
Small lymphocytic lymphoma	DIS30POX	Strong	Biomarker	[11]
Small-cell lung cancer	DISK3LZD	moderate	Biomarker	[12]
Clear cell renal carcinoma	DISBXRFJ	Limited	Biomarker	[9]
Renal cell carcinoma	DISQZ2X8	Limited	Biomarker	[9]

15 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 Cullin-5 (CUL5).	[13]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Cullin-5 (CUL5).	[14]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Cullin-5 (CUL5).	[15]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Cullin-5 (CUL5).	[16]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Cullin-5 (CUL5).	[17]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Cullin-5 (CUL5).	[18]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Cullin-5 (CUL5).	[19]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of Cullin-5 (CUL5).	[20]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Cullin-5 (CUL5).	[21]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Cullin-5 (CUL5).	[4]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Cullin-5 (CUL5).	[23]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Cullin-5 (CUL5).	[24]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Cullin-5 (CUL5).	[25]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Cullin-5 (CUL5).	[26]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Cullin-5 (CUL5).	[27]

References

• [1] Cullin-5, a ubiquitin ligase scaffold protein, is significantly underexpressed in endometrial adenocarcinomas and is a target of miR-182.Oncol Rep. 2016 Apr;35(4):2461-5. doi: 10.3892/or.2016.4605. Epub 2016 Feb 1.
• [2] Runs of homozygosity associated with speech delay in autism in a taiwanese han population: evidence for the recessive model.PLoS One. 2013 Aug 16;8(8):e72056. doi: 10.1371/journal.pone.0072056. eCollection 2013.
• [3] 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.
• [4] Resveratrol enhances anti-proliferative effect of VACM-1/cul5 in T47D cancer cells. Cell Biol Toxicol. 2011 Apr;27(2):95-105. doi: 10.1007/s10565-010-9173-3. Epub 2010 Oct 15.
• [5] C-peptide increases the expression of vasopressin-activated calcium-mobilizing receptor gene through a G protein-dependent pathway.Eur J Endocrinol. 2005 Jan;152(1):135-41. doi: 10.1530/eje.1.01823.
• [6] Downregulation of MicroRNA-145 Caused by Hepatitis B Virus X Protein Promotes Expression of CUL5 and Contributes to Pathogenesis of Hepatitis B Virus-Associated Hepatocellular Carcinoma.Cell Physiol Biochem. 2015;37(4):1547-59. doi: 10.1159/000438522. Epub 2015 Oct 30.
• [7] ARIH2 Is a Vif-Dependent Regulator of CUL5-Mediated APOBEC3G Degradation in HIV Infection.Cell Host Microbe. 2019 Jul 10;26(1):86-99.e7. doi: 10.1016/j.chom.2019.05.008. Epub 2019 Jun 25.
• [8] The CUL5 ubiquitin ligase complex mediates resistance to CDK9 and MCL1 inhibitors in lung cancer cells.Elife. 2019 Jul 11;8:e44288. doi: 10.7554/eLife.44288.
• [9] Cullin 5 is a novel candidate tumor suppressor in renal cell carcinoma involved in the maintenance of genome stability.Oncogenesis. 2019 Jan 9;8(1):4. doi: 10.1038/s41389-018-0110-2.
• [10] Genetic influences on susceptibility to rheumatoid arthritis in African-Americans.Hum Mol Genet. 2019 Mar 1;28(5):858-874. doi: 10.1093/hmg/ddy395.
• [11] Analysis of 11q22-q23 deletion target genes in B-cell chronic lymphocytic leukaemia: evidence for a pathogenic role of NPAT, CUL5, and PPP2R1B.Eur J Cancer. 2007 May;43(8):1328-35. doi: 10.1016/j.ejca.2007.02.005. Epub 2007 Apr 20.
• [12] Cullin5 deficiency promotes small-cell lung cancer metastasis by stabilizing integrin 1.J Clin Invest. 2019 Mar 1;129(3):972-987. doi: 10.1172/JCI122779. Epub 2019 Jan 28.
• [13] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [14] Effect of all-trans retinoic acid on sodium/iodide symporter expression, radioiodine uptake and gene expression profiles in a human anaplastic thyroid carcinoma cell line. Nucl Med Biol. 2006 Oct;33(7):875-82. doi: 10.1016/j.nucmedbio.2006.07.004.
• [15] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [16] 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.
• [17] 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.
• [18] 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.
• [19] Arsenic trioxide induces different gene expression profiles of genes related to growth and apoptosis in glioma cells dependent on the p53 status. Mol Biol Rep. 2008 Sep;35(3):421-9.
• [20] Transcriptional profiling of MCF7 breast cancer cells in response to 5-Fluorouracil: relationship with cell cycle changes and apoptosis, and identification of novel targets of p53. Int J Cancer. 2006 Sep 1;119(5):1164-75.
• [21] 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.
• [22] Resveratrol enhances anti-proliferative effect of VACM-1/cul5 in T47D cancer cells. Cell Biol Toxicol. 2011 Apr;27(2):95-105. doi: 10.1007/s10565-010-9173-3. Epub 2010 Oct 15.
• [23] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [24] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [25] Epigenetic influences of low-dose bisphenol A in primary human breast epithelial cells. Toxicol Appl Pharmacol. 2010 Oct 15;248(2):111-21.
• [26] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [27] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.