Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTMVK4K4)

• DOT Name: Cyclin-C (CCNC)
• Synonyms: SRB11 homolog; hSRB11
• Gene Name: CCNC
• Related Disease:
  Breast cancer
  Breast carcinoma
  North Carolina macular dystrophy
  T-cell acute lymphoblastic leukaemia
  Acute lymphocytic leukaemia
  Alzheimer disease
  Bone osteosarcoma
  Colon cancer
  Colon carcinoma
  Colorectal carcinoma
  Hepatocellular carcinoma
  Insulinoma
  Neoplasm
  Non-alcoholic fatty liver disease
  Osteosarcoma
  Renal cell carcinoma
  Thyroid tumor
  Uterine fibroids
  Clear cell renal carcinoma
  Melanoma
  Colon adenocarcinoma
• UniProt ID: CCNC_HUMAN
• PDB ID: 3RGF; 4CRL; 4F6S; 4F6U; 4F6W; 4F70; 4F7J; 4F7L; 4F7N; 4F7S; 4G6L; 5BNJ; 5CEI; 5FGK; 5HBE; 5HBH; 5HBJ; 5HNB; 5HVY; 5I5Z; 5ICP; 5IDN; 5IDP; 5XQX; 5XS2; 6QTG; 6QTJ; 6R3S; 6T41; 6TPA; 6Y0A
• Pfam ID: PF16899 ; PF00134
• Sequence:
  MAGNFWQSSHYLQWILDKQDLLKERQKDLKFLSEEEYWKLQIFFTNVIQALGEHLKLRQQ
  VIATATVYFKRFYARYSLKSIDPVLMAPTCVFLASKVEEFGVVSNTRLIAAATSVLKTRF
  SYAFPKEFPYRMNHILECEFYLLELMDCCLIVYHPYRPLLQYVQDMGQEDMLLPLAWRIV
  NDTYRTDLCLLYPPFMIALACLHVACVVQQKDARQWFAELSVDMEKILEIIRVILKLYEQ
  WKNFDERKEMATILSKMPKPKPPPNSEGEQGPNGSQNSSYSQS
• Function: Component of the Mediator complex, a coactivator involved in regulated gene transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors. Binds to and activates cyclin-dependent kinase CDK8 that phosphorylates the CTD (C-terminal domain) of the large subunit of RNA polymerase II (RNAp II), which may inhibit the formation of a transcription initiation complex.
• Tissue Specificity: Highest levels in pancreas. High levels in heart, liver, skeletal muscle and kidney. Low levels in brain.
• Reactome Pathway:
  NOTCH1 Intracellular Domain Regulates Transcription (R-HSA-2122947)
  Generic Transcription Pathway (R-HSA-212436)
  SMAD2/SMAD3 (R-HSA-2173796)
  Constitutive Signaling by NOTCH1 PEST Domain Mutants (R-HSA-2644606)
  Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants (R-HSA-2894862)
  Transcriptional regulation of white adipocyte differentiation (R-HSA-381340)
  PPARA activates gene expression (R-HSA-1989781)

Molecular Interaction Atlas (MIA) of This DOT

21 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Definitive	Biomarker	[1]
Breast carcinoma	DIS2UE88	Definitive	Biomarker	[1]
North Carolina macular dystrophy	DISMPOAO	Definitive	Genetic Variation	[2]
T-cell acute lymphoblastic leukaemia	DIS17AI2	Definitive	Genetic Variation	[3]
Acute lymphocytic leukaemia	DISPX75S	Strong	Genetic Variation	[4]
Alzheimer disease	DISF8S70	Strong	Biomarker	[5]
Bone osteosarcoma	DIST1004	Strong	Biomarker	[6]
Colon cancer	DISVC52G	Strong	Genetic Variation	[6]
Colon carcinoma	DISJYKUO	Strong	Genetic Variation	[6]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[7]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[8]
Insulinoma	DISIU1JS	Strong	Altered Expression	[9]
Neoplasm	DISZKGEW	Strong	Biomarker	[10]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Altered Expression	[11]
Osteosarcoma	DISLQ7E2	Strong	Biomarker	[6]
Renal cell carcinoma	DISQZ2X8	Strong	Biomarker	[12]
Thyroid tumor	DISLVKMD	Strong	Biomarker	[10]
Uterine fibroids	DISBZRMJ	Strong	Genetic Variation	[13]
Clear cell renal carcinoma	DISBXRFJ	moderate	Biomarker	[14]
Melanoma	DIS1RRCY	moderate	Biomarker	[15]
Colon adenocarcinoma	DISDRE0J	Limited	Altered Expression	[16]

13 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 Cyclin-C (CCNC).	[17]
Arsenic	DMTL2Y1	Approved	Arsenic increases the expression of Cyclin-C (CCNC).	[18]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Cyclin-C (CCNC).	[19]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Cyclin-C (CCNC).	[20]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Cyclin-C (CCNC).	[21]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of Cyclin-C (CCNC).	[22]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of Cyclin-C (CCNC).	[23]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Cyclin-C (CCNC).	[24]
Dihydroxyacetone	DMM1LG2	Approved	Dihydroxyacetone increases the expression of Cyclin-C (CCNC).	[25]
Inecalcitol oral	DMU5SZP	Phase 2	Inecalcitol oral decreases the expression of Cyclin-C (CCNC).	[26]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Cyclin-C (CCNC).	[27]
Paraquat	DMR8O3X	Investigative	Paraquat increases the expression of Cyclin-C (CCNC).	[28]
USNIC ACID	DMGOURX	Investigative	USNIC ACID increases the expression of Cyclin-C (CCNC).	[29]

References

• [1] Inhibition of CDK8 mediator kinase suppresses estrogen dependent transcription and the growth of estrogen receptor positive breast cancer.Oncotarget. 2017 Feb 21;8(8):12558-12575. doi: 10.18632/oncotarget.14894.
• [2] A novel duplication of PRMD13 causes North Carolina macular dystrophy: overexpression of PRDM13 orthologue in drosophila eye reproduces the human phenotype. Hum Mol Genet. 2017 Nov 15;26(22):4367-4374. doi: 10.1093/hmg/ddx322.
• [3] Cyclin C is a haploinsufficient tumour suppressor.Nat Cell Biol. 2014 Nov;16(11):1080-91. doi: 10.1038/ncb3046. Epub 2014 Oct 26.
• [4] Molecular cloning and chromosomal localization of the human cyclin C (CCNC) and cyclin E (CCNE) genes: deletion of the CCNC gene in human tumors.Genomics. 1996 Mar 1;32(2):253-9. doi: 10.1006/geno.1996.0112.
• [5] Cyclin C expression is involved in the pathogenesis of Alzheimer's disease.Neurobiol Aging. 2003 May-Jun;24(3):427-35. doi: 10.1016/s0197-4580(02)00132-x.
• [6] Retroviral cyclin enhances cyclin-dependent kinase-8 activity.J Virol. 2012 May;86(10):5742-51. doi: 10.1128/JVI.07006-11. Epub 2012 Feb 29.
• [7] A molecular dynamics investigation of CDK8/CycC and ligand binding: conformational flexibility and implication in drug discovery.J Comput Aided Mol Des. 2018 Jun;32(6):671-685. doi: 10.1007/s10822-018-0120-3. Epub 2018 May 8.
• [8] Gene expression profiles of hepatoma cell line HLE.World J Gastroenterol. 2003 Apr;9(4):683-7. doi: 10.3748/wjg.v9.i4.683.
• [9] Differential expression of cell-cycle regulators in human beta-cells derived from insulinoma tissue.Metabolism. 2016 May;65(5):736-746. doi: 10.1016/j.metabol.2016.02.007. Epub 2016 Feb 23.
• [10] Synergistic repression of thyroid hyperplasia by cyclin C and Pten.J Cell Sci. 2019 Aug 15;132(16):jcs230029. doi: 10.1242/jcs.230029.
• [11] mTORC1 Down-Regulates Cyclin-Dependent Kinase 8 (CDK8) and Cyclin C (CycC).PLoS One. 2015 Jun 4;10(6):e0126240. doi: 10.1371/journal.pone.0126240. eCollection 2015.
• [12] Multilayer-omics analysis of renal cell carcinoma, including the whole exome, methylome and transcriptome.Int J Cancer. 2014 Sep 15;135(6):1330-42. doi: 10.1002/ijc.28768. Epub 2014 May 2.
• [13] Oncogenic exon 2 mutations in Mediator subunit MED12 disrupt allosteric activation of cyclin C-CDK8/19.J Biol Chem. 2018 Mar 30;293(13):4870-4882. doi: 10.1074/jbc.RA118.001725. Epub 2018 Feb 13.
• [14] Overexpression of miR-15b Promotes Resistance to Sunitinib in Renal Cell Carcinoma.J Cancer. 2019 Jun 9;10(15):3389-3396. doi: 10.7150/jca.31676. eCollection 2019.
• [15] MicroRNA-206 induces G1 arrest in melanoma by inhibition of CDK4 and Cyclin D.Pigment Cell Melanoma Res. 2014 Mar;27(2):275-86. doi: 10.1111/pcmr.12200. Epub 2014 Jan 17.
• [16] Expression and gene amplification of primary (A, B1, D1, D3, and E) and secondary (C and H) cyclins in colon adenocarcinomas and correlation with patient outcome.J Clin Pathol. 2005 May;58(5):509-14. doi: 10.1136/jcp.2004.020347.
• [17] 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.
• [18] Arsenic-induced cell proliferation is associated with enhanced ROS generation, Erk signaling and CyclinA expression. Toxicol Lett. 2010 Oct 5;198(2):263-71. doi: 10.1016/j.toxlet.2010.07.006. Epub 2010 Jul 21.
• [19] The human peroxisome proliferator-activated receptor delta gene is a primary target of 1alpha,25-dihydroxyvitamin D3 and its nuclear receptor. J Mol Biol. 2005 Jun 3;349(2):248-60. doi: 10.1016/j.jmb.2005.03.060. Epub 2005 Apr 7.
• [20] 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.
• [21] Selenite and selenomethionine promote HL-60 cell cycle progression. J Nutr. 2002 Apr;132(4):674-9. doi: 10.1093/jn/132.4.674.
• [22] Cellular response to 5-fluorouracil (5-FU) in 5-FU-resistant colon cancer cell lines during treatment and recovery. Mol Cancer. 2006 May 18;5:20. doi: 10.1186/1476-4598-5-20.
• [23] 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.
• [24] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [25] The sunless tanning agent dihydroxyacetone induces stress response gene expression and signaling in cultured human keratinocytes and reconstructed epidermis. Redox Biol. 2020 Sep;36:101594. doi: 10.1016/j.redox.2020.101594. Epub 2020 May 29.
• [26] Two novel 14-Epi-analogues of 1,25-dihydroxyvitamin D3 inhibit the growth of human breast cancer cells in vitro and in vivo. Cancer Res. 2000 May 15;60(10):2673-9.
• [27] 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.
• [28] Cytotoxicity and gene array analysis of alveolar epithelial A549 cells exposed to paraquat. Chem Biol Interact. 2010 Dec 5;188(3):427-36.
• [29] Effects of usnic acid exposure on human hepatoblastoma HepG2 cells in culture. J Appl Toxicol. 2012 Sep;32(9):722-30.