Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6P1ZVP)

• DOT Name: CDK2-associated and cullin domain-containing protein 1 (CACUL1)
• Synonyms: Cdk-associated cullin 1
• Gene Name: CACUL1
• Related Disease:
  Colorectal neoplasm
  Parkinson disease
  Type-1 diabetes
  Acute myelogenous leukaemia
  Adult lymphoma
  Advanced cancer
  Alzheimer disease
  Breast cancer
  Breast carcinoma
  Colorectal carcinoma
  Coronary heart disease
  Dementia
  Epithelial ovarian cancer
  Ewing sarcoma
  Gastric cancer
  Lung cancer
  Lung carcinoma
  Lymphoma
  Myocardial infarction
  Neoplasm
  Non-small-cell lung cancer
  Ovarian cancer
  Ovarian neoplasm
  Pediatric lymphoma
  Plasma cell myeloma
  Prostate cancer
  Prostate carcinoma
  Stomach cancer
  Stroke
  X-linked intellectual disability
  Adenovirus infection
  Cardiovascular disease
  High blood pressure
  Pancreatic cancer
  Type-1/2 diabetes
  Colorectal adenoma
  Inflammation
  Malignant pleural mesothelioma
  Melanoma
• UniProt ID: CACL1_HUMAN
• Pfam ID: PF00888
• Sequence:
  MEESMEEEEGGSYEAMMDDQNHNNWEAAVDGFRQPLPPPPPPSSIPAPAREPPGGQLLAV
  PAVSVDRKGPKEGLPMGPQPPPEANGVIMMLKSCDAAAAVAKAAPAPTASSTININTSTS
  KFLMNVITIEDYKSTYWPKLDGAIDQLLTQSPGDYIPISYEQIYSCVYKCVCQQHSEQMY
  SDLIKKITNHLERVSKELQASPPDLYIERFNIALGQYMGALQSIVPLFIYMNKFYIETKL
  NRDLKDDLIKLFTEHVAEKHIYSLMPLLLEAQSTPFQVTPSTMANIVKGLYTLRPEWVQM
  APTLFSKFIPNILPPAVESELSEYAAQDQKFQRELIQNGFTRGDQSRKRAGDELAYNSSS
  ACASSRGYR
• Function: Cell cycle associated protein capable of promoting cell proliferation through the activation of CDK2 at the G1/S phase transition.
• Tissue Specificity: Ubiquitously expressed with highest expression in the mammary gland and large intestine. Highly expressed in cancer tissues and cancer cell lines. During cell cycle progression expression is high in G1/S, low in the middle of S phase, and increases again in S/G2 phase.

Molecular Interaction Atlas (MIA) of This DOT

39 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Colorectal neoplasm	DISR1UCN	Definitive	Biomarker	[1]
Parkinson disease	DISQVHKL	Definitive	Genetic Variation	[2]
Type-1 diabetes	DIS7HLUB	Definitive	Altered Expression	[3]
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[4]
Adult lymphoma	DISK8IZR	Strong	Biomarker	[4]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[5]
Alzheimer disease	DISF8S70	Strong	Altered Expression	[6]
Breast cancer	DIS7DPX1	Strong	Biomarker	[7]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[7]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[8]
Coronary heart disease	DIS5OIP1	Strong	Genetic Variation	[9]
Dementia	DISXL1WY	Strong	Biomarker	[10]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[11]
Ewing sarcoma	DISQYLV3	Strong	Biomarker	[12]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[13]
Lung cancer	DISCM4YA	Strong	Biomarker	[14]
Lung carcinoma	DISTR26C	Strong	Biomarker	[14]
Lymphoma	DISN6V4S	Strong	Biomarker	[4]
Myocardial infarction	DIS655KI	Strong	Genetic Variation	[15]
Neoplasm	DISZKGEW	Strong	Biomarker	[16]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[17]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[11]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[11]
Pediatric lymphoma	DIS51BK2	Strong	Biomarker	[4]
Plasma cell myeloma	DIS0DFZ0	Strong	Altered Expression	[18]
Prostate cancer	DISF190Y	Strong	Biomarker	[19]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[19]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[13]
Stroke	DISX6UHX	Strong	Genetic Variation	[15]
X-linked intellectual disability	DISYJBY3	Strong	Genetic Variation	[20]
Adenovirus infection	DISUYSBZ	moderate	Biomarker	[21]
Cardiovascular disease	DIS2IQDX	moderate	Genetic Variation	[22]
High blood pressure	DISY2OHH	moderate	Genetic Variation	[23]
Pancreatic cancer	DISJC981	moderate	Biomarker	[24]
Type-1/2 diabetes	DISIUHAP	Disputed	Genetic Variation	[25]
Colorectal adenoma	DISTSVHM	Limited	Genetic Variation	[26]
Inflammation	DISJUQ5T	Limited	Biomarker	[27]
Malignant pleural mesothelioma	DIST2R60	Limited	Biomarker	[28]
Melanoma	DIS1RRCY	Limited	Altered Expression	[29]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of CDK2-associated and cullin domain-containing protein 1 (CACUL1).	[30]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of CDK2-associated and cullin domain-containing protein 1 (CACUL1).	[34]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of CDK2-associated and cullin domain-containing protein 1 (CACUL1).	[36]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of CDK2-associated and cullin domain-containing protein 1 (CACUL1).	[31]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of CDK2-associated and cullin domain-containing protein 1 (CACUL1).	[32]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of CDK2-associated and cullin domain-containing protein 1 (CACUL1).	[33]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of CDK2-associated and cullin domain-containing protein 1 (CACUL1).	[35]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of CDK2-associated and cullin domain-containing protein 1 (CACUL1).	[37]

References

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• [4] CRL4(DCAF2) negatively regulates IL-23 production in dendritic cells and limits the development of psoriasis.J Exp Med. 2018 Aug 6;215(8):1999-2017. doi: 10.1084/jem.20180210. Epub 2018 Jul 17.
• [5] Coronary artery calcium and the competing long-term risk of cardiovascular vs. cancer mortality: the CAC Consortium.Eur Heart J Cardiovasc Imaging. 2019 Apr 1;20(4):389-395. doi: 10.1093/ehjci/jey176.
• [6] Expression of the newly identified gene CAC1 in the hippocampus of Alzheimer's disease patients.J Mol Neurosci. 2012 Jun;47(2):207-18. doi: 10.1007/s12031-012-9717-5. Epub 2012 Mar 14.
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• [11] It is not all about BRCA: Cullin-Ring ubiquitin Ligases in ovarian cancer.Br J Cancer. 2015 Jan 6;112(1):9-13. doi: 10.1038/bjc.2014.594. Epub 2014 Dec 9.
• [12] WEE1 accumulation and deregulation of S-phase proteins mediate MLN4924 potent inhibitory effect on Ewing sarcoma cells.Oncogene. 2013 Mar 14;32(11):1441-51. doi: 10.1038/onc.2012.153. Epub 2012 May 28.
• [13] Helicobacter pylori promotes invasion and metastasis of gastric cancer cells through activation of AP-1 and up-regulation of CACUL1.Int J Biochem Cell Biol. 2013 Nov;45(11):2666-78. doi: 10.1016/j.biocel.2013.08.015. Epub 2013 Sep 1.
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• [16] Cullin7 promotes epithelialmesenchymal transition of esophageal carcinoma via the ERKSNAI2 signaling pathway.Mol Med Rep. 2018 Apr;17(4):5362-5367. doi: 10.3892/mmr.2018.8503. Epub 2018 Jan 26.
• [17] DCUN1D1 facilitates tumor metastasis by activating FAK signaling and up-regulates PD-L1 in non-small-cell lung cancer.Exp Cell Res. 2019 Jan 15;374(2):304-314. doi: 10.1016/j.yexcr.2018.12.001. Epub 2018 Dec 4.
• [18] Measuring cereblon as a biomarker of response or resistance to lenalidomide and pomalidomide requires use of standardized reagents and understanding of gene complexity.Br J Haematol. 2014 Jan;164(2):233-44. doi: 10.1111/bjh.12622. Epub 2013 Oct 28.
• [19] Clinical significance of SCCRO (DCUN1D1) in prostate cancer and its proliferation-inhibiting effect on Lncap cells.Eur Rev Med Pharmacol Sci. 2017 Oct;21(19):4283-4291.
• [20] Lack of Cul4b, an E3 ubiquitin ligase component, leads to embryonic lethality and abnormal placental development.PLoS One. 2012;7(5):e37070. doi: 10.1371/journal.pone.0037070. Epub 2012 May 14.
• [21] Adenovirus E1B 55-Kilodalton Protein Targets SMARCAL1 for Degradation during Infection and Modulates Cellular DNA Replication.J Virol. 2019 Jun 14;93(13):e00402-19. doi: 10.1128/JVI.00402-19. Print 2019 Jul 1.
• [22] All-cause and cause-specific mortality in individuals with zero and minimal coronary artery calcium: A long-term, competing risk analysis in the Coronary Artery Calcium Consortium.Atherosclerosis. 2020 Feb;294:72-79. doi: 10.1016/j.atherosclerosis.2019.11.008. Epub 2019 Nov 16.
• [23] Relation of Coronary Artery Calcium and Extra-Coronary Aortic Calcium to Incident Hypertension (from the Multi-Ethnic Study of Atherosclerosis).Am J Cardiol. 2018 Jan 15;121(2):210-216. doi: 10.1016/j.amjcard.2017.10.018. Epub 2017 Oct 24.
• [24] Chk1 inhibitor SCH 900776 enhances the antitumor activity of MLN4924 on pancreatic cancer.Cell Cycle. 2018;17(2):191-199. doi: 10.1080/15384101.2017.1405194. Epub 2018 Jan 3.
• [25] Low short-term and long-term cardiovascular and all-cause mortality in absence of coronary artery calcium: A 22-year follow-up observational study from large cohort.J Diabetes Complications. 2019 Sep;33(9):616-622. doi: 10.1016/j.jdiacomp.2019.05.015. Epub 2019 May 30.
• [26] Coexistence of Colorectal Adenomas and Coronary Calcification in Asymptomatic Men and Women.J Clin Gastroenterol. 2018 Jul;52(6):508-514. doi: 10.1097/MCG.0000000000000824.
• [27] Stabilization of HIF through inhibition of Cullin-2 neddylation is protective in mucosal inflammatory responses.FASEB J. 2015 Jan;29(1):208-15. doi: 10.1096/fj.14-259663. Epub 2014 Oct 17.
• [28] Combined Inhibition of NEDD8-Activating Enzyme and mTOR Suppresses NF2 Loss-Driven Tumorigenesis.Mol Cancer Ther. 2017 Aug;16(8):1693-1704. doi: 10.1158/1535-7163.MCT-16-0821. Epub 2017 May 3.
• [29] Cul1 promotes melanoma cell proliferation by promoting DEPTOR degradation and enhancing cap-dependent translation.Oncol Rep. 2016 Feb;35(2):1049-56. doi: 10.3892/or.2015.4442. Epub 2015 Nov 23.
• [30] 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.
• [31] 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.
• [32] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [33] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [34] 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.
• [35] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [36] 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.
• [37] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.