Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTGF64SM)

• DOT Name: Mediator of RNA polymerase II transcription subunit 7 (MED7)
• Synonyms: hMED7; Activator-recruited cofactor 34 kDa component; ARC34; Cofactor required for Sp1 transcriptional activation subunit 9; CRSP complex subunit 9; Mediator complex subunit 7; RNA polymerase transcriptional regulation mediator subunit 7 homolog; Transcriptional coactivator CRSP33
• Gene Name: MED7
• Related Disease:
  Adenoma
  Breast cancer
  Breast carcinoma
  Cushing disease
  Hypothyroidism
  Neoplasm
  Pseudohypoaldosteronism type 2D
• UniProt ID: MED7_HUMAN
• PDB ID: 7EMF; 7ENA; 7ENC; 7ENJ; 7LBM; 7NVR; 8GXQ; 8GXS
• Pfam ID: PF05983
• Sequence:
  MGEPQQVSALPPPPMQYIKEYTDENIQEGLAPKPPPPIKDSYMMFGNQFQCDDLIIRPLE
  SQGIERLHPMQFDHKKELRKLNMSILINFLDLLDILIRSPGSIKREEKLEDLKLLFVHVH
  HLINEYRPHQARETLRVMMEVQKRQRLETAERFQKHLERVIEMIQNCLASLPDDLPHSEA
  GMRVKTEPMDADDSNNCTGQNEHQRENSGHRRDQIIEKDAALCVLIDEMNERP
• 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:
  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

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adenoma	DIS78ZEV	Strong	Altered Expression	[1]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[2]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[2]
Cushing disease	DISOG6P2	Strong	Altered Expression	[1]
Hypothyroidism	DISR0H6D	Strong	Genetic Variation	[3]
Neoplasm	DISZKGEW	Strong	Altered Expression	[2]
Pseudohypoaldosteronism type 2D	DIS2AO4N	Strong	Biomarker	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Mediator of RNA polymerase II transcription subunit 7 (MED7).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Mediator of RNA polymerase II transcription subunit 7 (MED7).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Mediator of RNA polymerase II transcription subunit 7 (MED7).	[7]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Mediator of RNA polymerase II transcription subunit 7 (MED7).	[8]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Mediator of RNA polymerase II transcription subunit 7 (MED7).	[9]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Mediator of RNA polymerase II transcription subunit 7 (MED7).	[10]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Mediator of RNA polymerase II transcription subunit 7 (MED7).	[11]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Mediator of RNA polymerase II transcription subunit 7 (MED7).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Mediator of RNA polymerase II transcription subunit 7 (MED7).	[12]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Mediator of RNA polymerase II transcription subunit 7 (MED7).	[13]

References

• [1] The Sp transcription factors are involved in the cellular expression of the human glucose-dependent insulinotropic polypeptide receptor gene and overexpressed in adrenals of patients with Cushing's syndrome.J Mol Endocrinol. 2005 Aug;35(1):61-71. doi: 10.1677/jme.1.01765.
• [2] Mediator complex (MED) 7: a biomarker associated with good prognosis in invasive breast cancer, especially ER+ luminal subtypes.Br J Cancer. 2018 Apr;118(8):1142-1151. doi: 10.1038/s41416-018-0041-x. Epub 2018 Mar 28.
• [3] Leveraging Polygenic Functional Enrichment to Improve GWAS Power.Am J Hum Genet. 2019 Jan 3;104(1):65-75. doi: 10.1016/j.ajhg.2018.11.008. Epub 2018 Dec 27.
• [4] Mechanisms and controversies in mutant Cul3-mediated familial hyperkalemic hypertension.Am J Physiol Renal Physiol. 2018 May 1;314(5):F915-F920. doi: 10.1152/ajprenal.00593.2017. Epub 2018 Jan 17.
• [5] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [6] 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.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [9] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [10] 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.
• [11] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [12] 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.
• [13] 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.
• [14] 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.