Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDBY87B)

• DOT Name: Mediator of RNA polymerase II transcription subunit 25 (MED25)
• Synonyms: Activator interaction domain-containing protein 1; Activator-recruited cofactor 92 kDa component; ARC92; Mediator complex subunit 25; p78
• Gene Name: MED25
• Related Disease:
  Axonal neuropathy
  Congenital cataract-microcephaly-nevus flammeus simplex-severe intellectual disability syndrome
  Corpus callosum, agenesis of
  Type-1/2 diabetes
  Adult glioblastoma
  Alopecia
  Alopecia areata
  Breast cancer
  Breast carcinoma
  Familial hyperinsulinism
  Glioblastoma multiforme
  Glioma
  Hemolytic anemia
  Hepatitis B virus infection
  Herpes simplex infection
  Intellectual disability
  Maturity-onset diabetes of the young
  Neoplasm
  Neuroblastoma
  Non-insulin dependent diabetes
  Prostate neoplasm
  Ulcerative colitis
  Colon cancer
  Colon carcinoma
  Isolated congenital microcephaly
  Autosomal recessive non-syndromic intellectual disability
  Charcot-Marie-Tooth disease type 2B2
  Central core myopathy
• UniProt ID: MED25_HUMAN
• PDB ID: 2KY6; 2L23; 2L6U; 2XNF; 7EMF; 7LBM; 8GXQ; 8GXS
• Pfam ID: PF11232 ; PF11235 ; PF11265
• Sequence:
  MVPGSEGPARAGSVVADVVFVIEGTANLGPYFEGLRKHYLLPAIEYFNGGPPAETDFGGD
  YGGTQYSLVVFNTVDCAPESYVQCHAPTSSAYEFVTWLDGIKFMGGGGESCSLIAEGLST
  ALQLFDDFKKMREQIGQTHRVCLLICNSPPYLLPAVESTTYSGCTTENLVQQIGERGIHF
  SIVSPRKLPALRLLFEKAAPPALLEPLQPPTDVSQDPRHMVLVRGLVLPVGGGSAPGPLQ
  SKQPVPLPPAAPSGATLSAAPQQPLPPVPPQYQVPGNLSAAQVAAQNAVEAAKNQKAGLG
  PRFSPITPLQQAAPGVGPPFSQAPAPQLPPGPPGAPKPPPASQPSLVSTVAPGSGLAPTA
  QPGAPSMAGTVAPGGVSGPSPAQLGAPALGGQQSVSNKLLAWSGVLEWQEKPKPASVDAN
  TKLTRSLPCQVYVNHGENLKTEQWPQKLIMQLIPQQLLTTLGPLFRNSRMVQFHFTNKDL
  ESLKGLYRIMGNGFAGCVHFPHTAPCEVRVLMLLYSSKKKIFMGLIPYDQSGFVNGIRQV
  ITNHKQVQQQKLEQQQRGMGGQQAPPGLGPILEDQARPSQNLLQLRPPQPQPQGTVGASG
  ATGQPQPQGTAQPPPGAPQGPPGAASGPPPPGPILRPQNPGANPQLRSLLLNPPPPQTGV
  PPPQASLHHLQPPGAPALLPPPHQGLGQPQLGPPLLHPPPAQSWPAQLPPRAPLPGQMLL
  SGGPRGPVPQPGLQPSVMEDDILMDLI
• 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. Required for RARA/RXRA-mediated transcription.
• Tissue Specificity: Ubiquitously expressed. Highest levels in brain, heart, kidney, peripheral leukocytes, placenta, skeletal muscle and spleen.
• 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

28 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Axonal neuropathy	DIS5S2BC	Definitive	Biomarker	[1]
Congenital cataract-microcephaly-nevus flammeus simplex-severe intellectual disability syndrome	DISIJQX1	Definitive	Autosomal recessive	[2]
Corpus callosum, agenesis of	DISO9P40	Definitive	Biomarker	[1]
Type-1/2 diabetes	DISIUHAP	Definitive	Altered Expression	[3]
Adult glioblastoma	DISVP4LU	Strong	Altered Expression	[4]
Alopecia	DIS37HU4	Strong	Biomarker	[5]
Alopecia areata	DIS0XXBJ	Strong	Biomarker	[5]
Breast cancer	DIS7DPX1	Strong	Biomarker	[6]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[6]
Familial hyperinsulinism	DISHQKQE	Strong	Biomarker	[7]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[4]
Glioma	DIS5RPEH	Strong	Genetic Variation	[4]
Hemolytic anemia	DIS803XQ	Strong	Biomarker	[8]
Hepatitis B virus infection	DISLQ2XY	Strong	Biomarker	[9]
Herpes simplex infection	DISL1SAV	Strong	Biomarker	[10]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[2]
Maturity-onset diabetes of the young	DISG75M5	Strong	Biomarker	[11]
Neoplasm	DISZKGEW	Strong	Biomarker	[4]
Neuroblastoma	DISVZBI4	Strong	Biomarker	[12]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Biomarker	[11]
Prostate neoplasm	DISHDKGQ	Strong	Altered Expression	[13]
Ulcerative colitis	DIS8K27O	Strong	Biomarker	[14]
Colon cancer	DISVC52G	moderate	Biomarker	[15]
Colon carcinoma	DISJYKUO	moderate	Biomarker	[15]
Isolated congenital microcephaly	DISUXHZ6	moderate	Genetic Variation	[2]
Autosomal recessive non-syndromic intellectual disability	DISJWRZZ	Supportive	Autosomal recessive	[16]
Charcot-Marie-Tooth disease type 2B2	DISNPA2O	Supportive	Autosomal recessive	[17]
Central core myopathy	DIS18AZZ	Limited	Altered Expression	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Mediator of RNA polymerase II transcription subunit 25 (MED25).	[19]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Mediator of RNA polymerase II transcription subunit 25 (MED25).	[20]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Mediator of RNA polymerase II transcription subunit 25 (MED25).	[22]
GALLICACID	DM6Y3A0	Investigative	GALLICACID decreases the expression of Mediator of RNA polymerase II transcription subunit 25 (MED25).	[24]

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 decreases the methylation of Mediator of RNA polymerase II transcription subunit 25 (MED25).	[21]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Mediator of RNA polymerase II transcription subunit 25 (MED25).	[23]

References

• [1] ALS5/SPG11/KIAA1840 mutations cause autosomal recessive axonal Charcot-Marie-Tooth disease. Brain. 2016 Jan;139(Pt 1):73-85. doi: 10.1093/brain/awv320. Epub 2015 Nov 10.
• [2] Homozygous MED25 mutation implicated in eye-intellectual disability syndrome. Hum Genet. 2015 Jun;134(6):577-87. doi: 10.1007/s00439-015-1541-x. Epub 2015 Mar 20.
• [3] Bioactive triterpenoids from the caffeine-rich plants guayusa and mat.Food Res Int. 2019 Jan;115:504-510. doi: 10.1016/j.foodres.2018.10.005. Epub 2018 Oct 4.
• [4] Effects of curcumin-loaded PLGA nanoparticles on the RG2 rat glioma model.Mater Sci Eng C Mater Biol Appl. 2017 Sep 1;78:32-38. doi: 10.1016/j.msec.2017.03.292. Epub 2017 Apr 6.
• [5] Structure and polymorphism of the human gene for the interferon-induced p78 protein (MX1): evidence of association with alopecia areata in the Down syndrome region.Hum Genet. 2000 Jun;106(6):639-45. doi: 10.1007/s004390000318.
• [6] Oxyprenylated Phenylpropanoids Bind to MT1 Melatonin Receptors and Inhibit Breast Cancer Cell Proliferation and Migration.J Nat Prod. 2017 Dec 22;80(12):3324-3329. doi: 10.1021/acs.jnatprod.7b00853. Epub 2017 Nov 16.
• [7] 18F-DOPA PET/CT and 68Ga-DOTANOC PET/CT scans as diagnostic tools in focal congenital hyperinsulinism: a blinded evaluation.Eur J Nucl Med Mol Imaging. 2018 Feb;45(2):250-261. doi: 10.1007/s00259-017-3867-1. Epub 2017 Nov 8.
• [8] Stimulation of Phospholipid Scrambling of the Erythrocyte Membrane by 9-Cis-Retinoic Acid.Cell Physiol Biochem. 2017;41(2):543-554. doi: 10.1159/000457014. Epub 2017 Jan 31.
• [9] Clinical significance of a highly sensitive enzyme immunoassay of hepatitis B surface antigen using a novel electron spin resonance technique.J Med Virol. 2002 Feb;66(2):166-70. doi: 10.1002/jmv.2126.
• [10] Structural Basis for the Interaction between p53 Transactivation Domain and the Mediator Subunit MED25.Molecules. 2018 Oct 22;23(10):2726. doi: 10.3390/molecules23102726.
• [11] MED25 is a mediator component of HNF4-driven transcription leading to insulin secretion in pancreatic beta-cells.PLoS One. 2012;7(8):e44007. doi: 10.1371/journal.pone.0044007. Epub 2012 Aug 30.
• [12] A novel, semi-synthetic diterpenoid 16(R and S)-phenylamino-cleroda-3,13(14), Z-dien-15,16 olide (PGEA-AN) inhibits the growth and cell survival of human neuroblastoma cell line SH-SY5Y by modulating P53 pathway.Mol Cell Biochem. 2018 Dec;449(1-2):105-115. doi: 10.1007/s11010-018-3347-3. Epub 2018 Apr 11.
• [13] PTOV1 antagonizes MED25 in RAR transcriptional activation.Biochem Biophys Res Commun. 2011 Jan 7;404(1):239-44. doi: 10.1016/j.bbrc.2010.11.100. Epub 2010 Nov 24.
• [14] Effects of alpha lipoic acid and its derivative "andrographolid-lipoic acid-1" on ulcerative colitis: A systematic review with meta-analysis of animal studies.J Cell Biochem. 2019 Apr;120(4):4766-4782. doi: 10.1002/jcb.27807. Epub 2018 Oct 26.
• [15] Pharmacologic doses of ascorbic acid repress specificity protein (Sp) transcription factors and Sp-regulated genes in colon cancer cells. Nutr Cancer. 2011;63(7):1133-42. doi: 10.1080/01635581.2011.605984. Epub 2011 Sep 15.
• [16] Homozygous missense mutation in MED25 segregates with syndromic intellectual disability in a large consanguineous family. J Med Genet. 2015 Feb;52(2):123-7. doi: 10.1136/jmedgenet-2014-102793. Epub 2014 Dec 19.
• [17] Charcot-Marie-Tooth Neuropathy Type 2 C RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY. 1998 Sep 24 [updated 2016 Apr 14]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [18] Structural development of a type-1 ryanodine receptor (RyR1) Ca(2+)-release channel inhibitor guided by endoplasmic reticulum Ca(2+) assay.Eur J Med Chem. 2019 Oct 1;179:837-848. doi: 10.1016/j.ejmech.2019.06.076. Epub 2019 Jun 29.
• [19] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [20] 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.
• [21] 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.
• [22] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [23] 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.
• [24] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.