Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6M6CQ8)

• DOT Name: Mediator of RNA polymerase II transcription subunit 18 (MED18)
• Synonyms: Mediator complex subunit 18; p28b
• Gene Name: MED18
• Related Disease:
  Aortic aneurysm
  Breast cancer
  Breast carcinoma
  Cystic fibrosis
  Ehlers-Danlos syndrome
  Fragile X syndrome
  Gerstmann-Straussler-Scheinker syndrome
  Intellectual disability
  Neoplasm
  Noonan syndrome
  Osteogenesis imperfecta
  Rett syndrome
  Advanced cancer
• UniProt ID: MED18_HUMAN
• PDB ID: 7EMF; 7ENA; 7ENC; 7ENJ; 7LBM; 7NVR; 8GXQ; 8GXS
• Pfam ID: PF09637
• Sequence:
  MEAPPVTMMPVTGGTINMMEYLLQGSVLDHSLESLIHRLRGLCDNMEPETFLDHEMVFLL
  KGQQASPFVLRARRSMDRAGAPWHLRYLGQPEMGDKNRHALVRNCVDIATSENLTDFLME
  MGFRMDHEFVAKGHLFRKGIMKIMVYKIFRILVPGNTDSTEALSLSYLVELSVVAPAGQD
  MVSDDMKNFAEQLKPLVHLEKIDPKRLM
• Function: Component of the Mediator complex, a coactivator involved in the regulated 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.
• Reactome Pathway:
  Transcriptional regulation of white adipocyte differentiation (R-HSA-381340)
  PPARA activates gene expression (R-HSA-1989781)

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Aortic aneurysm	DISQ5KRA	Strong	Biomarker	[1]
Breast cancer	DIS7DPX1	Strong	Genetic Variation	[2]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[2]
Cystic fibrosis	DIS2OK1Q	Strong	Biomarker	[3]
Ehlers-Danlos syndrome	DISSVBRR	Strong	Genetic Variation	[4]
Fragile X syndrome	DISE8W3A	Strong	Genetic Variation	[5]
Gerstmann-Straussler-Scheinker syndrome	DISIO6KC	Strong	Genetic Variation	[6]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[7]
Neoplasm	DISZKGEW	Strong	Biomarker	[8]
Noonan syndrome	DIS7Q7DN	Strong	Biomarker	[9]
Osteogenesis imperfecta	DIS7XQSD	Strong	Genetic Variation	[10]
Rett syndrome	DISGG5UV	Strong	Biomarker	[7]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Mediator of RNA polymerase II transcription subunit 18 (MED18).	[12]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Mediator of RNA polymerase II transcription subunit 18 (MED18).	[13]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Mediator of RNA polymerase II transcription subunit 18 (MED18).	[15]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Mediator of RNA polymerase II transcription subunit 18 (MED18).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Mediator of RNA polymerase II transcription subunit 18 (MED18).	[17]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Mediator of RNA polymerase II transcription subunit 18 (MED18).	[18]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone affects the splicing of Mediator of RNA polymerase II transcription subunit 18 (MED18).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic increases the methylation of Mediator of RNA polymerase II transcription subunit 18 (MED18).	[14]

References

• [1] Cardiovascular malformations caused by NOTCH1 mutations do not keep left: data on 428 probands with left-sided CHD and their families.Genet Med. 2016 Sep;18(9):914-23. doi: 10.1038/gim.2015.193. Epub 2016 Jan 28.
• [2] Incorporating truncating variants in PALB2, CHEK2, and ATM into the BOADICEA breast cancer risk model.Genet Med. 2016 Dec;18(12):1190-1198. doi: 10.1038/gim.2016.31. Epub 2016 Apr 14.
• [3] Cystic fibrosis on the African continent.Genet Med. 2016 Jul;18(7):653-62. doi: 10.1038/gim.2015.157. Epub 2015 Dec 10.
• [4] Targeted next-generation sequencing makes new molecular diagnoses and expands genotype-phenotype relationship in Ehlers-Danlos syndrome.Genet Med. 2016 Nov;18(11):1119-1127. doi: 10.1038/gim.2016.14. Epub 2016 Mar 24.
• [5] Identification of microsatellite markers <1Mb from the FMR1 CGG repeat and development of a single-tube tetradecaplex PCR panel of highly polymorphic markers for preimplantation genetic diagnosis of fragile X syndrome.Genet Med. 2016 Sep;18(9):869-75. doi: 10.1038/gim.2015.185. Epub 2016 Jan 7.
• [6] Molecular diagnosis of glycogen storage disease and disorders with overlapping clinical symptoms by massive parallel sequencing.Genet Med. 2016 Oct;18(10):1037-43. doi: 10.1038/gim.2015.217. Epub 2016 Feb 25.
• [7] Mutations in JMJD1C are involved in Rett syndrome and intellectual disability. Genet Med. 2016 Apr;18(4):378-85. doi: 10.1038/gim.2015.100. Epub 2015 Jul 16.
• [8] Long non-coding RNA SNHG3 promotes progression of gastric cancer by regulating neighboring MED18 gene methylation.Cell Death Dis. 2019 Sep 18;10(10):694. doi: 10.1038/s41419-019-1940-3.
• [9] Genotype and phenotype in patients with Noonan syndrome and a RIT1 mutation.Genet Med. 2016 Dec;18(12):1226-1234. doi: 10.1038/gim.2016.32. Epub 2016 Apr 21.
• [10] Cesarean delivery is not associated with decreased at-birth fracture rates in osteogenesis imperfecta.Genet Med. 2016 Jun;18(6):570-6. doi: 10.1038/gim.2015.131. Epub 2015 Oct 1.
• [11] Low risk of solid tumors in persons with Down syndrome.Genet Med. 2016 Nov;18(11):1151-1157. doi: 10.1038/gim.2016.23. Epub 2016 Mar 31.
• [12] 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.
• [13] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
• [14] Epigenetic changes in individuals with arsenicosis. Chem Res Toxicol. 2011 Feb 18;24(2):165-7. doi: 10.1021/tx1004419. Epub 2011 Feb 4.
• [15] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [16] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [17] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [18] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [19] Analysis of the prostate cancer cell line LNCaP transcriptome using a sequencing-by-synthesis approach. BMC Genomics. 2006 Sep 29;7:246. doi: 10.1186/1471-2164-7-246.