Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTEDM1L5)

• DOT Name: Mediator of RNA polymerase II transcription subunit 28 (MED28)
• Synonyms: Endothelial-derived protein 1; Mediator complex subunit 28; Merlin and Grb2-interacting cytoskeletal protein; Magicin; Tumor angiogenesis marker EG-1
• Gene Name: MED28
• Related Disease:
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Colorectal carcinoma
  Non-small-cell lung cancer
  Prostate cancer
  Prostate carcinoma
  Breast neoplasm
• UniProt ID: MED28_HUMAN
• PDB ID: 7EMF; 7ENA; 7ENC; 7ENJ; 7LBM; 7NVR; 8GXQ; 8GXS
• Pfam ID: PF11594
• Sequence:
  MAAPLGGMFSGQPPGPPQAPPGLPGQASLLQAAPGAPRPSSSTLVDELESSFEACFASLV
  SQDYVNGTDQEEIRTGVDQCIQKFLDIARQTECFFLQKRLQLSVQKPEQVIKEDVSELRN
  ELQRKDALVQKHLTKLRHWQQVLEDINVQHKKPADIPQGSLAYLEQASANIPAPLKPT
• 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 be part of a complex containing NF2/merlin that participates in cellular signaling to the actin cytoskeleton downstream of tyrosine kinase signaling pathways.
• Tissue Specificity: Widely expressed. Highly expressed in vascular tissues such as placenta, testis and liver.
• Reactome Pathway:
  Transcriptional regulation of white adipocyte differentiation (R-HSA-381340)
  PPARA activates gene expression (R-HSA-1989781)

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Breast cancer	DIS7DPX1	Strong	Biomarker	[2]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[2]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[3]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[4]
Prostate cancer	DISF190Y	Strong	Altered Expression	[5]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[5]
Breast neoplasm	DISNGJLM	moderate	Biomarker	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Mediator of RNA polymerase II transcription subunit 28 (MED28).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Mediator of RNA polymerase II transcription subunit 28 (MED28).	[8]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Mediator of RNA polymerase II transcription subunit 28 (MED28).	[9]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Mediator of RNA polymerase II transcription subunit 28 (MED28).	[10]
Nicotine	DMWX5CO	Approved	Nicotine increases the expression of Mediator of RNA polymerase II transcription subunit 28 (MED28).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Mediator of RNA polymerase II transcription subunit 28 (MED28).	[12]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Mediator of RNA polymerase II transcription subunit 28 (MED28).	[13]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone increases the expression of Mediator of RNA polymerase II transcription subunit 28 (MED28).	[14]
Forskolin	DM6ITNG	Investigative	Forskolin increases the expression of Mediator of RNA polymerase II transcription subunit 28 (MED28).	[14]

References

• [1] MED28 Over-Expression Shortens the Cell Cycle and Induces Genomic Instability.Int J Mol Sci. 2019 Apr 9;20(7):1746. doi: 10.3390/ijms20071746.
• [2] MED28 increases the colony-forming ability of breast cancer cells by stabilizing the ZNF224 protein upon DNA damage.Oncol Lett. 2018 Mar;15(3):3147-3154. doi: 10.3892/ol.2017.7718. Epub 2017 Dec 29.
• [3] All Trans-Retinoic Acid Mediates MED28/HMG Box-Containing Protein 1 (HBP1)/-Catenin Signaling in Human Colorectal Cancer Cells.J Cell Physiol. 2016 Aug;231(8):1796-803. doi: 10.1002/jcp.25285. Epub 2015 Dec 30.
• [4] MED28 and forkhead box M1 (FOXM1) mediate matrix metalloproteinase 2 (MMP2)-dependent cellular migration in human nonsmall cell lung cancer (NSCLC) cells.J Cell Physiol. 2019 Jul;234(7):11265-11275. doi: 10.1002/jcp.27784. Epub 2018 Nov 29.
• [5] The novel gene EG-1 stimulates cellular proliferation.Cancer Res. 2005 Jul 15;65(14):6159-66. doi: 10.1158/0008-5472.CAN-04-4016.
• [6] Resveratrol modulates MED28 (Magicin/EG-1) expression and inhibits epidermal growth factor (EGF)-induced migration in MDA-MB-231 human breast cancer cells.J Agric Food Chem. 2011 Nov 9;59(21):11853-61. doi: 10.1021/jf202426k. Epub 2011 Oct 17.
• [7] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [8] 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.
• [9] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [10] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [11] Nicotinic modulation of gene expression in SH-SY5Y neuroblastoma cells. Brain Res. 2006 Oct 20;1116(1):39-49.
• [12] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [13] Cellular reactions to long-term volatile organic compound (VOC) exposures. Sci Rep. 2016 Dec 1;6:37842. doi: 10.1038/srep37842.
• [14] Identification of genes targeted by the androgen and PKA signaling pathways in prostate cancer cells. Oncogene. 2006 Nov 23;25(55):7311-23.