Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTP5LEJE)

• DOT Name: Mediator of RNA polymerase II transcription subunit 13 (MED13)
• Synonyms: Activator-recruited cofactor 250 kDa component; ARC250; Mediator complex subunit 13; Thyroid hormone receptor-associated protein 1; Thyroid hormone receptor-associated protein complex 240 kDa component; Trap240; Vitamin D3 receptor-interacting protein complex component DRIP250; DRIP250
• Gene Name: MED13
• Related Disease:
  Breast cancer
  Breast carcinoma
  Complex neurodevelopmental disorder
  Metabolic disorder
  Colorectal carcinoma
  Hypothyroidism
  Intellectual developmental disorder 61
  Neurodevelopmental disorder
  Ovarian cancer
  Transposition of the great arteries
  Attention deficit hyperactivity disorder
  Constipation
  Eye disorder
  Intellectual disability
  Neoplasm
  Syndromic intellectual disability
  Obesity
• UniProt ID: MED13_HUMAN
• Pfam ID: PF06333 ; PF18296
• Sequence:
  MSASFVPNGASLEDCHCNLFCLADLTGIKWKKYVWQGPTSAPILFPVTEEDPILSSFSRC
  LKADVLGVWRRDQRPGRRELWIFWWGEDPSFADLIHHDLSEEEDGVWENGLSYECRTLLF
  KAVHNLLERCLMNRNFVRIGKWFVKPYEKDEKPINKSEHLSCSFTFFLHGDSNVCTSVEI
  NQHQPVYLLSEEHITLAQQSNSPFQVILCPFGLNGTLTGQAFKMSDSATKKLIGEWKQFY
  PISCCLKEMSEEKQEDMDWEDDSLAAVEVLVAGVRMIYPACFVLVPQSDIPTPSPVGSTH
  CSSSCLGVHQVPASTRDPAMSSVTLTPPTSPEEVQTVDPQSVQKWVKFSSVSDGFNSDST
  SHHGGKIPRKLANHVVDRVWQECNMNRAQNKRKYSASSGGLCEEATAAKVASWDFVEATQ
  RTNCSCLRHKNLKSRNAGQQGQAPSLGQQQQILPKHKTNEKQEKSEKPQKRPLTPFHHRV
  SVSDDVGMDADSASQRLVISAPDSQVRFSNIRTNDVAKTPQMHGTEMANSPQPPPLSPHP
  CDVVDEGVTKTPSTPQSQHFYQMPTPDPLVPSKPMEDRIDSLSQSFPPQYQEAVEPTVYV
  GTAVNLEEDEANIAWKYYKFPKKKDVEFLPPQLPSDKFKDDPVGPFGQESVTSVTELMVQ
  CKKPLKVSDELVQQYQIKNQCLSAIASDAEQEPKIDPYAFVEGDEEFLFPDKKDRQNSER
  EAGKKHKVEDGTSSVTVLSHEEDAMSLFSPSIKQDAPRPTSHARPPSTSLIYDSDLAVSY
  TDLDNLFNSDEDELTPGSKKSANGSDDKASCKESKTGNLDPLSCISTADLHKMYPTPPSL
  EQHIMGFSPMNMNNKEYGSMDTTPGGTVLEGNSSSIGAQFKIEVDEGFCSPKPSEIKDFS
  YVYKPENCQILVGCSMFAPLKTLPSQYLPPIKLPEECIYRQSWTVGKLELLSSGPSMPFI
  KEGDGSNMDQEYGTAYTPQTHTSFGMPPSSAPPSNSGAGILPSPSTPRFPTPRTPRTPRT
  PRGAGGPASAQGSVKYENSDLYSPASTPSTCRPLNSVEPATVPSIPEAHSLYVNLILSES
  VMNLFKDCNFDSCCICVCNMNIKGADVGVYIPDPTQEAQYRCTCGFSAVMNRKFGNNSGL
  FLEDELDIIGRNTDCGKEAEKRFEALRATSAEHVNGGLKESEKLSDDLILLLQDQCTNLF
  SPFGAADQDPFPKSGVISNWVRVEERDCCNDCYLALEHGRQFMDNMSGGKVDEALVKSSC
  LHPWSKRNDVSMQCSQDILRMLLSLQPVLQDAIQKKRTVRPWGVQGPLTWQQFHKMAGRG
  SYGTDESPEPLPIPTFLLGYDYDYLVLSPFALPYWERLMLEPYGSQRDIAYVVLCPENEA
  LLNGAKSFFRDLTAIYESCRLGQHRPVSRLLTDGIMRVGSTASKKLSEKLVAEWFSQAAD
  GNNEAFSKLKLYAQVCRYDLGPYLASLPLDSSLLSQPNLVAPTSQSLITPPQMTNTGNAN
  TPSATLASAASSTMTVTSGVAISTSVATANSTLTTASTSSSSSSNLNSGVSSNKLPSFPP
  FGSMNSNAAGSMSTQANTVQSGQLGGQQTSALQTAGISGESSSLPTQPHPDVSESTMDRD
  KVGIPTDGDSHAVTYPPAIVVYIIDPFTYENTDESTNSSSVWTLGLLRCFLEMVQTLPPH
  IKSTVSVQIIPCQYLLQPVKHEDREIYPQHLKSLAFSAFTQCRRPLPTSTNVKTLTGFGP
  GLAMETALRSPDRPECIRLYAPPFILAPVKDKQTELGETFGEAGQKYNVLFVGYCLSHDQ
  RWILASCTDLYGELLETCIINIDVPNRARRKKSSARKFGLQKLWEWCLGLVQMSSLPWRV
  VIGRLGRIGHGELKDWSCLLSRRNLQSLSKRLKDMCRMCGISAADSPSILSACLVAMEPQ
  GSFVIMPDSVSTGSVFGRSTTLNMQTSQLNTPQDTSCTHILVFPTSASVQVASATYTTEN
  LDLAFNPNNDGADGMGIFDLLDTGDDLDPDIINILPASPTGSPVHSPGSHYPHGGDAGKG
  QSTDRLLSTEPHEEVPNILQQPLALGYFVSTAKAGPLPDWFWSACPQAQYQCPLFLKASL
  HLHVPSVQSDELLHSKHSHPLDSNQTSDVLRFVLEQYNALSWLTCDPATQDRRSCLPIHF
  VVLNQLYNFIMNML
• 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.
• Tissue Specificity: Ubiquitous.
• KEGG Pathway: Thyroid hormone sig.ling pathway (hsa04919)
• Reactome Pathway:
  Generic Transcription Pathway (R-HSA-212436)
  Transcriptional regulation of white adipocyte differentiation (R-HSA-381340)
  PPARA activates gene expression (R-HSA-1989781)

Molecular Interaction Atlas (MIA) of This DOT

17 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	Altered Expression	[1]
Complex neurodevelopmental disorder	DISB9AFI	Definitive	Autosomal dominant	[2]
Metabolic disorder	DIS71G5H	Definitive	Biomarker	[3]
Colorectal carcinoma	DIS5PYL0	Strong	Genetic Variation	[4]
Hypothyroidism	DISR0H6D	Strong	Altered Expression	[5]
Intellectual developmental disorder 61	DIS453EZ	Strong	Autosomal dominant	[6]
Neurodevelopmental disorder	DIS372XH	Strong	Genetic Variation	[6]
Ovarian cancer	DISZJHAP	Strong	Genetic Variation	[7]
Transposition of the great arteries	DISPXJ8X	Strong	Biomarker	[8]
Attention deficit hyperactivity disorder	DISL8MX9	moderate	Biomarker	[6]
Constipation	DISRQXWI	moderate	Biomarker	[6]
Eye disorder	DISB52BH	moderate	Biomarker	[6]
Intellectual disability	DISMBNXP	moderate	Biomarker	[6]
Neoplasm	DISZKGEW	moderate	Altered Expression	[9]
Syndromic intellectual disability	DISH7SDF	Supportive	Autosomal dominant	[6]
Obesity	DIS47Y1K	Limited	Altered Expression	[10]

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 Mediator of RNA polymerase II transcription subunit 13 (MED13).	[11]
Quercetin	DM3NC4M	Approved	Quercetin increases the phosphorylation of Mediator of RNA polymerase II transcription subunit 13 (MED13).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Mediator of RNA polymerase II transcription subunit 13 (MED13).	[18]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Mediator of RNA polymerase II transcription subunit 13 (MED13).	[14]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Mediator of RNA polymerase II transcription subunit 13 (MED13).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Mediator of RNA polymerase II transcription subunit 13 (MED13).	[12]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Mediator of RNA polymerase II transcription subunit 13 (MED13).	[13]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Mediator of RNA polymerase II transcription subunit 13 (MED13).	[15]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Mediator of RNA polymerase II transcription subunit 13 (MED13).	[16]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of Mediator of RNA polymerase II transcription subunit 13 (MED13).	[17]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Mediator of RNA polymerase II transcription subunit 13 (MED13).	[16]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Mediator of RNA polymerase II transcription subunit 13 (MED13).	[19]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Mediator of RNA polymerase II transcription subunit 13 (MED13).	[20]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride decreases the expression of Mediator of RNA polymerase II transcription subunit 13 (MED13).	[21]
OXYBENZONE	DMMZYX6	Investigative	OXYBENZONE increases the expression of Mediator of RNA polymerase II transcription subunit 13 (MED13).	[22]

References

• [1] Expression of CDK8 and CDK8-interacting Genes as Potential Biomarkers in Breast Cancer.Curr Cancer Drug Targets. 2015;15(8):739-49. doi: 10.2174/156800961508151001105814.
• [2] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [3] A cardiac microRNA governs systemic energy homeostasis by regulation of MED13.Cell. 2012 Apr 27;149(3):671-83. doi: 10.1016/j.cell.2012.03.029.
• [4] Frameshift Mutations of HSPA4 and MED13 in Gastric and Colorectal Cancers.Pathol Oncol Res. 2016 Oct;22(4):769-72. doi: 10.1007/s12253-016-0070-9. Epub 2016 Apr 30.
• [5] Regulation of cardiac transcription by thyroid hormone and Med13.J Mol Cell Cardiol. 2019 Apr;129:27-38. doi: 10.1016/j.yjmcc.2019.01.007. Epub 2019 Feb 12.
• [6] De novo mutations in MED13, a component of the Mediator complex, are associated with a novel neurodevelopmental disorder. Hum Genet. 2018 May;137(5):375-388. doi: 10.1007/s00439-018-1887-y. Epub 2018 May 8.
• [7] Mutations in BRIP1 confer high risk of ovarian cancer.Nat Genet. 2011 Oct 2;43(11):1104-7. doi: 10.1038/ng.955.
• [8] Missense mutations and gene interruption in PROSIT240, a novel TRAP240-like gene, in patients with congenital heart defect (transposition of the great arteries). Circulation. 2003 Dec 9;108(23):2843-50. doi: 10.1161/01.CIR.0000103684.77636.CD. Epub 2003 Nov 24.
• [9] Understanding Obesity as a Risk Factor for Uterine Tumors Using Drosophila.Adv Exp Med Biol. 2019;1167:129-155. doi: 10.1007/978-3-030-23629-8_8.
• [10] Cardiac myocyte KLF5 regulates body weight via alteration of cardiac FGF21.Biochim Biophys Acta Mol Basis Dis. 2019 Sep 1;1865(9):2125-2137. doi: 10.1016/j.bbadis.2019.04.010. Epub 2019 Apr 26.
• [11] 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.
• [12] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [13] 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.
• [14] 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.
• [15] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [16] Drug-induced endoplasmic reticulum and oxidative stress responses independently sensitize toward TNF-mediated hepatotoxicity. Toxicol Sci. 2014 Jul;140(1):144-59. doi: 10.1093/toxsci/kfu072. Epub 2014 Apr 20.
• [17] Clinical determinants of response to irinotecan-based therapy derived from cell line models. Clin Cancer Res. 2008 Oct 15;14(20):6647-55.
• [18] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [19] 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.
• [20] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [21] The contact allergen nickel triggers a unique inflammatory and proangiogenic gene expression pattern via activation of NF-kappaB and hypoxia-inducible factor-1alpha. J Immunol. 2007 Mar 1;178(5):3198-207.
• [22] Chromatin modifiers: A new class of pollutants with potential epigenetic effects revealed by in vitro assays and transcriptomic analyses. Toxicology. 2023 Jan 15;484:153413. doi: 10.1016/j.tox.2022.153413. Epub 2022 Dec 26.