Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTSIZ1I7)

• DOT Name: Mediator of RNA polymerase II transcription subunit 8 (MED8)
• Synonyms: Activator-recruited cofactor 32 kDa component; ARC32; Mediator complex subunit 8
• Gene Name: MED8
• Related Disease:
  Clear cell renal carcinoma
  Leiomyoma
  Lung cancer
  Lung carcinoma
  Renal cell carcinoma
  Uterine fibroids
• UniProt ID: MED8_HUMAN
• PDB ID: 7EMF; 7ENA; 7ENC; 7ENJ; 7LBM; 7NVR; 8GXQ; 8GXS
• Pfam ID: PF10232
• Sequence:
  MQREEKQLEASLDALLSQVADLKNSLGSFICKLENEYGRLTWPSVLDSFALLSGQLNTLN
  KVLKHEKTPLFRNQVIIPLVLSPDRDEDLMRQTEGRVPVFSHEVVPDHLRTKPDPEVEEQ
  EKQLTTDAARIGADAAQKQIQSLNKMCSNLLEKISKEERESESGGLRPNKQTFNPTDTNA
  LVAAVAFGKGLSNWRPSGSSGPGQAGQPGAGTILAGTSGLQQVQMAGAPSQQQPMLSGVQ
  MAQAGQPGKMPSGIKTNIKSASMHPYQR
• 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. May play a role as a target recruitment subunit in E3 ubiquitin-protein ligase complexes and thus in ubiquitination and subsequent proteasomal degradation of target proteins.
• 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

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Clear cell renal carcinoma	DISBXRFJ	Strong	Altered Expression	[1]
Leiomyoma	DISLDDFN	Strong	Genetic Variation	[2]
Lung cancer	DISCM4YA	Strong	Altered Expression	[1]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[1]
Renal cell carcinoma	DISQZ2X8	Strong	Altered Expression	[1]
Uterine fibroids	DISBZRMJ	Strong	Genetic Variation	[2]

9 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 Mediator of RNA polymerase II transcription subunit 8 (MED8).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Mediator of RNA polymerase II transcription subunit 8 (MED8).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Mediator of RNA polymerase II transcription subunit 8 (MED8).	[5]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Mediator of RNA polymerase II transcription subunit 8 (MED8).	[6]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Mediator of RNA polymerase II transcription subunit 8 (MED8).	[7]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Mediator of RNA polymerase II transcription subunit 8 (MED8).	[8]
Ethinyl estradiol	DMODJ40	Approved	Ethinyl estradiol affects the expression of Mediator of RNA polymerase II transcription subunit 8 (MED8).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Mediator of RNA polymerase II transcription subunit 8 (MED8).	[9]
CH-223191	DMMJZYC	Investigative	CH-223191 increases the expression of Mediator of RNA polymerase II transcription subunit 8 (MED8).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Mediator of RNA polymerase II transcription subunit 8 (MED8).	[10]

References

• [1] Comprehensive analysis of the transcriptional profile of the Mediator complex across human cancer types.Oncotarget. 2016 Apr 26;7(17):23043-23055. doi: 10.18632/oncotarget.8469.
• [2] Highly heterogeneous genomic landscape of uterine leiomyomas bywhole exome sequencing and genome-wide arrays.Fertil Steril. 2017 Feb;107(2):457-466.e9. doi: 10.1016/j.fertnstert.2016.10.035. Epub 2016 Nov 23.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [5] 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.
• [6] 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.
• [7] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [8] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [9] The genomic response of Ishikawa cells to bisphenol A exposure is dose- and time-dependent. Toxicology. 2010 Apr 11;270(2-3):137-49. doi: 10.1016/j.tox.2010.02.008. Epub 2010 Feb 17.
• [10] 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.
• [11] Adaptive changes in global gene expression profile of lung carcinoma A549 cells acutely exposed to distinct types of AhR ligands. Toxicol Lett. 2018 Aug;292:162-174.