Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTALFN4S)

• DOT Name: Mediator of RNA polymerase II transcription subunit 4 (MED4)
• Synonyms: Activator-recruited cofactor 36 kDa component; ARC36; Mediator complex subunit 4; TRAP/SMCC/PC2 subunit p36 subunit; Vitamin D3 receptor-interacting protein complex 36 kDa component; DRIP36
• Gene Name: MED4
• Related Disease:
  Advanced cancer
  Endometriosis
  Retinoblastoma
• UniProt ID: MED4_HUMAN
• PDB ID: 7EMF; 7ENA; 7ENC; 7ENJ; 7LBM; 7NVR; 8GXQ; 8GXS
• Pfam ID: PF10018
• Sequence:
  MAASSSGEKEKERLGGGLGVAGGNSTRERLLSALEDLEVLSRELIEMLAISRNQKLLQAG
  EENQVLELLIHRDGEFQELMKLALNQGKIHHEMQVLEKEVEKRDSDIQQLQKQLKEAEQI
  LATAVYQAKEKLKSIEKARKGAISSEEIIKYAHRISASNAVCAPLTWVPGDPRRPYPTDL
  EMRSGLLGQMNNPSTNGVNGHLPGDALAAGRLPDVLAPQYPWQSNDMSMNMLPPNHSSDF
  LLEPPGHNKENEDDVEIMSTDSSSSSSESD
• 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.
• 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

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[1]
Endometriosis	DISX1AG8	Strong	Biomarker	[2]
Retinoblastoma	DISVPNPB	Strong	Biomarker	[3]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Paclitaxel	DMLB81S	Approved	Mediator of RNA polymerase II transcription subunit 4 (MED4) affects the response to substance of Paclitaxel.	[9]

4 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 4 (MED4).	[4]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Mediator of RNA polymerase II transcription subunit 4 (MED4).	[5]
Aspirin	DM672AH	Approved	Aspirin increases the expression of Mediator of RNA polymerase II transcription subunit 4 (MED4).	[6]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Mediator of RNA polymerase II transcription subunit 4 (MED4).	[8]

1 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 increases the methylation of Mediator of RNA polymerase II transcription subunit 4 (MED4).	[7]

References

• [1] Linked CD4 T Cell Help: Broadening Immune Attack Against Cancer by Vaccination.Curr Top Microbiol Immunol. 2017;405:123-143. doi: 10.1007/82_2016_500.
• [2] Nuclear receptor, coregulator signaling, and chromatin remodeling pathways suggest involvement of the epigenome in the steroid hormone response of endometrium and abnormalities in endometriosis.Reprod Sci. 2012 Feb;19(2):152-62. doi: 10.1177/1933719111415546. Epub 2011 Dec 2.
• [3] The survival gene MED4 explains low penetrance retinoblastoma in patients with large RB1 deletion.Hum Mol Genet. 2014 Oct 1;23(19):5243-50. doi: 10.1093/hmg/ddu245. Epub 2014 May 23.
• [4] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [5] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [6] Expression profile analysis of human peripheral blood mononuclear cells in response to aspirin. Arch Immunol Ther Exp (Warsz). 2005 Mar-Apr;53(2):151-8.
• [7] 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.
• [8] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [9] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.