Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3WQXNA)

• DOT Name: 14-3-3 protein epsilon
• Synonyms: 14-3-3E
• Gene Name: YWHAE
• UniProt ID: 1433E_HUMAN
• PDB ID: 2BR9; 3UAL; 3UBW; 6EIH; 7C8E; 7V9B; 8DGM; 8DGN; 8DGP; 8DP5
• Pfam ID: PF00244
• Sequence:
  MDDREDLVYQAKLAEQAERYDEMVESMKKVAGMDVELTVEERNLLSVAYKNVIGARRASW
  RIISSIEQKEENKGGEDKLKMIREYRQMVETELKLICCDILDVLDKHLIPAANTGESKVF
  YYKMKGDYHRYLAEFATGNDRKEAAENSLVAYKAASDIAMTELPPTHPIRLGLALNFSVF
  YYEILNSPDRACRLAKAAFDDAIAELDTLSEESYKDSTLIMQLLRDNLTLWTSDMQGDGE
  EQNKEALQDVEDENQ
• Function: Adapter protein implicated in the regulation of a large spectrum of both general and specialized signaling pathways. Binds to a large number of partners, usually by recognition of a phosphoserine or phosphothreonine motif. Binding generally results in the modulation of the activity of the binding partner. Positively regulates phosphorylated protein HSF1 nuclear export to the cytoplasm. Plays a positive role in the antiviral signaling pathway upstream of TBK1 via interaction with RIGI. Mechanistically, directs RIGI redistribution from the cytosol to mitochondrial associated membranes where it mediates MAVS-dependent innate immune signaling during viral infection. Plays a role in proliferation inhibition and cell cycle arrest by exporting HNRNPC from the nucleus to the cytoplasm to be degraded by ubiquitination.
• KEGG Pathway:
  Cell cycle (hsa04110)
  Oocyte meiosis (hsa04114)
  PI3K-Akt sig.ling pathway (hsa04151)
  Hippo sig.ling pathway (hsa04390)
  NOD-like receptor sig.ling pathway (hsa04621)
  Neurotrophin sig.ling pathway (hsa04722)
  Hepatitis C (hsa05160)
  Viral carcinogenesis (hsa05203)
• Reactome Pathway:
  Translocation of SLC2A4 (GLUT4) to the plasma membrane (R-HSA-1445148)
  Signaling by Hippo (R-HSA-2028269)
  NADE modulates death signalling (R-HSA-205025)
  Regulation of PLK1 Activity at G2/M Transition (R-HSA-2565942)
  Regulation of HSF1-mediated heat shock response (R-HSA-3371453)
  HSF1 activation (R-HSA-3371511)
  Loss of Nlp from mitotic centrosomes (R-HSA-380259)
  Recruitment of mitotic centrosome proteins and complexes (R-HSA-380270)
  Loss of proteins required for interphase microtubule organization from the centrosome (R-HSA-380284)
  Recruitment of NuMA to mitotic centrosomes (R-HSA-380320)
  Anchoring of the basal body to the plasma membrane (R-HSA-5620912)
  RHO GTPases activate PKNs (R-HSA-5625740)
  TP53 Regulates Metabolic Genes (R-HSA-5628897)
  Chk1/Chk2(Cds1) mediated inactivation of Cyclin B (R-HSA-75035)
  AURKA Activation by TPX2 (R-HSA-8854518)
  Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models (R-HSA-8862803)
  RAB GEFs exchange GTP for GDP on RABs (R-HSA-8876198)
  SARS-CoV-1 targets host intracellular signalling and regulatory pathways (R-HSA-9735871)
  SARS-CoV-2 targets host intracellular signalling and regulatory pathways (R-HSA-9755779)
  Activation of BAD and translocation to mitochondria (R-HSA-111447)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
PEITC	DMOMN31	Phase 2	14-3-3 protein epsilon affects the binding of PEITC.	[23]
Sulforaphane	DMQY3L0	Investigative	14-3-3 protein epsilon affects the binding of Sulforaphane.	[23]

25 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 14-3-3 protein epsilon.	[1]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of 14-3-3 protein epsilon.	[2]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of 14-3-3 protein epsilon.	[3]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of 14-3-3 protein epsilon.	[4]
Arsenic	DMTL2Y1	Approved	Arsenic decreases the expression of 14-3-3 protein epsilon.	[5]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of 14-3-3 protein epsilon.	[6]
Marinol	DM70IK5	Approved	Marinol increases the expression of 14-3-3 protein epsilon.	[7]
Selenium	DM25CGV	Approved	Selenium decreases the expression of 14-3-3 protein epsilon.	[8]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of 14-3-3 protein epsilon.	[9]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of 14-3-3 protein epsilon.	[10]
Aspirin	DM672AH	Approved	Aspirin decreases the expression of 14-3-3 protein epsilon.	[11]
Indomethacin	DMSC4A7	Approved	Indomethacin decreases the expression of 14-3-3 protein epsilon.	[12]
Menthol	DMG2KW7	Approved	Menthol affects the expression of 14-3-3 protein epsilon.	[13]
Cocaine	DMSOX7I	Approved	Cocaine increases the expression of 14-3-3 protein epsilon.	[14]
Etretinate	DM2CZFA	Approved	Etretinate increases the expression of 14-3-3 protein epsilon.	[15]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of 14-3-3 protein epsilon.	[16]
Curcumin	DMQPH29	Phase 3	Curcumin decreases the expression of 14-3-3 protein epsilon.	[17]
EXISULIND	DMBY56U	Phase 3	EXISULIND decreases the expression of 14-3-3 protein epsilon.	[12]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of 14-3-3 protein epsilon.	[18]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of 14-3-3 protein epsilon.	[8]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the expression of 14-3-3 protein epsilon.	[19]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of 14-3-3 protein epsilon.	[20]
SC-236	DMO1URE	Terminated	SC-236 decreases the expression of 14-3-3 protein epsilon.	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of 14-3-3 protein epsilon.	[21]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of 14-3-3 protein epsilon.	[22]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [2] 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.
• [3] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [4] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [5] Nucleophosmin in the pathogenesis of arsenic-related bladder carcinogenesis revealed by quantitative proteomics. Toxicol Appl Pharmacol. 2010 Jan 15;242(2):126-35. doi: 10.1016/j.taap.2009.09.016. Epub 2009 Oct 7.
• [6] Proteomic analysis revealed association of aberrant ROS signaling with suberoylanilide hydroxamic acid-induced autophagy in Jurkat T-leukemia cells. Autophagy. 2010 Aug;6(6):711-24. doi: 10.4161/auto.6.6.12397. Epub 2010 Aug 17.
• [7] Inhibiting Heat Shock Proteins Can Potentiate the Cytotoxic Effect of Cannabidiol in Human Glioma Cells. Anticancer Res. 2015 Nov;35(11):5827-37.
• [8] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [9] Cellular response to 5-fluorouracil (5-FU) in 5-FU-resistant colon cancer cell lines during treatment and recovery. Mol Cancer. 2006 May 18;5:20. doi: 10.1186/1476-4598-5-20.
• [10] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [11] Nonsteroidal anti-inflammatory drugs induced endothelial apoptosis by perturbing peroxisome proliferator-activated receptor-delta transcriptional pathway. Mol Pharmacol. 2008 Nov;74(5):1399-406. doi: 10.1124/mol.108.049569. Epub 2008 Aug 4.
• [12] Nonsteroidal anti-inflammatory drugs induce colorectal cancer cell apoptosis by suppressing 14-3-3epsilon. Cancer Res. 2007 Apr 1;67(7):3185-91. doi: 10.1158/0008-5472.CAN-06-3431.
• [13] Repurposing L-menthol for systems medicine and cancer therapeutics? L-menthol induces apoptosis through caspase 10 and by suppressing HSP90. OMICS. 2016 Jan;20(1):53-64.
• [14] Gene expression profiling reveals distinct cocaine-responsive genes in human fetal CNS cell types. J Addict Med. 2009 Dec;3(4):218-26. doi: 10.1097/ADM.0b013e318199d863.
• [15] Consequences of the natural retinoid/retinoid X receptor ligands action in human breast cancer MDA-MB-231 cell line: Focus on functional proteomics. Toxicol Lett. 2017 Nov 5;281:26-34. doi: 10.1016/j.toxlet.2017.09.001. Epub 2017 Sep 5.
• [16] Differential expression of genes induced by resveratrol in LNCaP cells: P53-mediated molecular targets. Int J Cancer. 2003 Mar 20;104(2):204-12.
• [17] Curcumin suppresses PPARdelta expression and related genes in HT-29 cells. World J Gastroenterol. 2009 Mar 21;15(11):1346-52. doi: 10.3748/wjg.15.1346.
• [18] A high concentration of genistein down-regulates activin A, Smad3 and other TGF-beta pathway genes in human uterine leiomyoma cells. Exp Mol Med. 2012 Apr 30;44(4):281-92.
• [19] Comparative proteomics reveals concordant and discordant biochemical effects of caffeine versus epigallocatechin-3-gallate in human endothelial cells. Toxicol Appl Pharmacol. 2019 Sep 1;378:114621. doi: 10.1016/j.taap.2019.114621. Epub 2019 Jun 10.
• [20] Proteomic signatures in thapsigargin-treated hepatoma cells. Chem Res Toxicol. 2011 Aug 15;24(8):1215-22. doi: 10.1021/tx200109y. Epub 2011 Jul 1.
• [21] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [22] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [23] Identification of potential protein targets of isothiocyanates by proteomics. Chem Res Toxicol. 2011 Oct 17;24(10):1735-43. doi: 10.1021/tx2002806. Epub 2011 Aug 26.