Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTAJSS3D)

• DOT Name: Cyclin-L1 (CCNL1)
• Synonyms: Cyclin-L
• Gene Name: CCNL1
• Related Disease:
  Diabetic retinopathy
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Carcinoma
  Ewing sarcoma
  Head-neck squamous cell carcinoma
  Neoplasm
  Non-insulin dependent diabetes
  Squamous cell carcinoma
  Nasopharyngeal carcinoma
• UniProt ID: CCNL1_HUMAN
• Pfam ID: PF02984 ; PF00134
• Sequence:
  MASGPHSTATAAAAASSAAPSAGGSSSGTTTTTTTTTGGILIGDRLYSEVSLTIDHSLIP
  EERLSPTPSMQDGLDLPSETDLRILGCELIQAAGILLRLPQVAMATGQVLFHRFFYSKSF
  VKHSFEIVAMACINLASKIEEAPRRIRDVINVFHHLRQLRGKRTPSPLILDQNYINTKNQ
  VIKAERRVLKELGFCVHVKHPHKIIVMYLQVLECERNQTLVQTAWNYMNDSLRTNVFVRF
  QPETIACACIYLAARALQIPLPTRPHWFLLFGTTEEEIQEICIETLRLYTRKKPNYELLE
  KEVEKRKVALQEAKLKAKGLNPDGTPALSTLGGFSPASKPSSPREVKAEEKSPISINVKT
  VKKEPEDRQQASKSPYNGVRKDSKRSRNSRSASRSRSRTRSRSRSHTPRRHYNNRRSRSG
  TYSSRSRSRSRSHSESPRRHHNHGSPHLKAKHTRDDLKSSNRHGHKRKKSRSRSQSKSRD
  HSDAAKKHRHERGHHRDRRERSRSFERSHKSKHHGGSRSGHGRHRR
• Function: Involved in pre-mRNA splicing. Functions in association with cyclin-dependent kinases (CDKs). Inhibited by the CDK-specific inhibitor CDKN1A/p21. May play a role in the regulation of RNA polymerase II (pol II). May be a candidate proto-oncogene in head and neck squamous cell carcinomas (HNSCC).
• Tissue Specificity: Widely expressed. Overexpression in primary tumors of head and neck squamous cell carcinomas (HNSCC).

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Diabetic retinopathy	DISHGUJM	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Biomarker	[2]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[2]
Carcinoma	DISH9F1N	Strong	Biomarker	[3]
Ewing sarcoma	DISQYLV3	Strong	Biomarker	[4]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Genetic Variation	[5]
Neoplasm	DISZKGEW	Strong	Biomarker	[5]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[1]
Squamous cell carcinoma	DISQVIFL	Strong	Biomarker	[5]
Nasopharyngeal carcinoma	DISAOTQ0	Limited	Biomarker	[6]

5 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 Cyclin-L1 (CCNL1).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Cyclin-L1 (CCNL1).	[14]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Cyclin-L1 (CCNL1).	[16]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Cyclin-L1 (CCNL1).	[17]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Cyclin-L1 (CCNL1).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Cyclin-L1 (CCNL1).	[8]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Cyclin-L1 (CCNL1).	[9]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Cyclin-L1 (CCNL1).	[10]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Cyclin-L1 (CCNL1).	[11]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of Cyclin-L1 (CCNL1).	[12]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Cyclin-L1 (CCNL1).	[13]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Cyclin-L1 (CCNL1).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Cyclin-L1 (CCNL1).	[18]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Cyclin-L1 (CCNL1).	[19]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Cyclin-L1 (CCNL1).	[20]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Cyclin-L1 (CCNL1).	[21]

References

• [1] Association between LEKR1-CCNL1 and IGSF21-KLHDC7A gene polymorphisms and diabetic retinopathy of type 2 diabetes mellitus in the Chinese Han population.J Gene Med. 2016 Oct;18(10):282-287. doi: 10.1002/jgm.2926.
• [2] A fine balance between CCNL1 and TIMP1 contributes to the development of breast cancer cells.Biochem Biophys Res Commun. 2011 Jun 3;409(2):344-9. doi: 10.1016/j.bbrc.2011.05.021. Epub 2011 May 8.
• [3] Amplification of Cyclin L1 is associated with lymph node metastases in head and neck squamous cell carcinoma (HNSCC).Br J Cancer. 2005 Feb 28;92(4):770-4. doi: 10.1038/sj.bjc.6602400.
• [4] Overexpression of miR?99b?p inhibits Ewing's sarcoma cell lines by targeting CCNL1.Mol Med Rep. 2015 Sep;12(3):3359-3364. doi: 10.3892/mmr.2015.3888. Epub 2015 Jun 3.
• [5] Cyclin L1 (CCNL1) gene alterations in human head and neck squamous cell carcinoma.Br J Cancer. 2006 Apr 10;94(7):1041-4. doi: 10.1038/sj.bjc.6603036.
• [6] Differences in cancer gene copy number alterations between Epstein-Barr virus-positive and Epstein-Barr virus-negative nasopharyngeal carcinoma.Head Neck. 2018 Sep;40(9):1986-1998. doi: 10.1002/hed.25195. Epub 2018 Jun 21.
• [7] 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.
• [8] 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.
• [9] 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.
• [10] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [11] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [12] Rosiglitazone sensitizes MDA-MB-231 breast cancer cells to anti-tumour effects of tumour necrosis factor-alpha, CH11 and CYC202. Endocr Relat Cancer. 2007 Jun;14(2):305-15. doi: 10.1677/ERC-06-0003.
• [13] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [14] 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.
• [15] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [16] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [17] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [18] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [19] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [20] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [21] In vitro effects of aldehydes present in tobacco smoke on gene expression in human lung alveolar epithelial cells. Toxicol In Vitro. 2013 Apr;27(3):1072-81.