Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTH8C5U5)

• DOT Name: Eukaryotic peptide chain release factor subunit 1 (ETF1)
• Synonyms: Eukaryotic release factor 1; eRF1; Protein Cl1; TB3-1
• Gene Name: ETF1
• Related Disease:
  Breast cancer
  Breast carcinoma
  Diabetic kidney disease
  Endometrial carcinoma
  Kidney failure
  Schizophrenia
  Chronic renal failure
  End-stage renal disease
  Myeloid neoplasm
• UniProt ID: ERF1_HUMAN
• PDB ID: 1DT9; 2HST; 2KTU; 2KTV; 2LGT; 2LLX; 2MQ6; 2MQ9; 3E1Y; 3J5Y; 3JAG; 3JAH; 3JAI; 4D5N; 4D61; 5A8L; 5LZT; 5LZU; 5LZV; 6D90; 6IP8; 6XA1; 6ZME
• Pfam ID: PF03463 ; PF03464 ; PF03465
• Sequence:
  MADDPSAADRNVEIWKIKKLIKSLEAARGNGTSMISLIIPPKDQISRVAKMLADEFGTAS
  NIKSRVNRLSVLGAITSVQQRLKLYNKVPPNGLVVYCGTIVTEEGKEKKVNIDFEPFKPI
  NTSLYLCDNKFHTEALTALLSDDSKFGFIVIDGSGALFGTLQGNTREVLHKFTVDLPKKH
  GRGGQSALRFARLRMEKRHNYVRKVAETAVQLFISGDKVNVAGLVLAGSADFKTELSQSD
  MFDQRLQSKVLKLVDISYGGENGFNQAIELSTEVLSNVKFIQEKKLIGRYFDEISQDTGK
  YCFGVEDTLKALEMGAVEILIVYENLDIMRYVLHCQGTEEEKILYLTPEQEKDKSHFTDK
  ETGQEHELIESMPLLEWFANNYKKFGATLEIVTDKSQEGSQFVKGFGGIGGILRYRVDFQ
  GMEYQGGDDEFFDLDDY
• Function: Component of the eRF1-eRF3-GTP ternary complex, a ternary complex that mediates translation termination in response to the termination codons. The eRF1-eRF3-GTP complex binds to a stop codon in the ribosomal A-site. ETF1/ERF1 is responsible for stop codon recognition and inducing hydrolysis of peptidyl-tRNA. Following GTP hydrolysis, eRF3 (GSPT1/ERF3A or GSPT2/ERF3B) dissociates, permitting ETF1/eRF1 to accommodate fully in the A-site and mediate hydrolysis of peptidyl-tRNA. Component of the transient SURF complex which recruits UPF1 to stalled ribosomes in the context of nonsense-mediated decay (NMD) of mRNAs containing premature stop codons. Required for SHFL-mediated translation termination which inhibits programmed ribosomal frameshifting (-1PRF) of mRNA from viruses and cellular genes.
• KEGG Pathway: mR. surveillance pathway (hsa03015)
• Reactome Pathway:
  Regulation of expression of SLITs and ROBOs (R-HSA-9010553)
  Protein hydroxylation (R-HSA-9629569)
  Nonsense Mediated Decay (NMD) independent of the Exon Junction Complex (EJC) (R-HSA-975956)
  Nonsense Mediated Decay (NMD) enhanced by the Exon Junction Complex (EJC) (R-HSA-975957)
  Eukaryotic Translation Termination (R-HSA-72764)

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Strong	Biomarker	[1]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[1]
Diabetic kidney disease	DISJMWEY	Strong	Biomarker	[2]
Endometrial carcinoma	DISXR5CY	Strong	Altered Expression	[3]
Kidney failure	DISOVQ9P	Strong	Genetic Variation	[4]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[5]
Chronic renal failure	DISGG7K6	Limited	Genetic Variation	[6]
End-stage renal disease	DISXA7GG	Limited	Genetic Variation	[6]
Myeloid neoplasm	DIS2YOWO	Limited	Biomarker	[7]

8 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 Eukaryotic peptide chain release factor subunit 1 (ETF1).	[8]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Eukaryotic peptide chain release factor subunit 1 (ETF1).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Eukaryotic peptide chain release factor subunit 1 (ETF1).	[10]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Eukaryotic peptide chain release factor subunit 1 (ETF1).	[11]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Eukaryotic peptide chain release factor subunit 1 (ETF1).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Eukaryotic peptide chain release factor subunit 1 (ETF1).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Eukaryotic peptide chain release factor subunit 1 (ETF1).	[14]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of Eukaryotic peptide chain release factor subunit 1 (ETF1).	[15]

References

• [1] Modulation of translation factor's gene expression by histone deacetylase inhibitors in breast cancer cells.Clin Chem Lab Med. 2005;43(2):151-6. doi: 10.1515/CCLM.2005.025.
• [2] Investigation of mechanisms of mesenchymal stem cells for treatment of diabetic nephropathy via construction of a miRNA-TF-mRNA network.Ren Fail. 2018 Nov;40(1):136-145. doi: 10.1080/0886022X.2017.1421556. Epub 2018 Mar 13.
• [3] Identification of ERF-1 as a member of the AP2 transcription factor family.Proc Natl Acad Sci U S A. 1997 Apr 29;94(9):4342-7. doi: 10.1073/pnas.94.9.4342.
• [4] Evaluation of markers on human chromosome 10, including the homologue of the rodent Rf-1 gene, for linkage to ESRD in black patients.Am J Kidney Dis. 1999 Feb;33(2):294-300. doi: 10.1016/s0272-6386(99)70303-3.
• [5] Genome-Wide Association Study Detected Novel Susceptibility Genes for Schizophrenia and Shared Trans-Populations/Diseases Genetic Effect.Schizophr Bull. 2019 Jun 18;45(4):824-834. doi: 10.1093/schbul/sby140.
• [6] Linkage heterogeneity of end-stage renal disease on human chromosome 10.Kidney Int. 2002 Sep;62(3):770-4. doi: 10.1046/j.1523-1755.2002.00534.x.
• [7] Evaluation of ETF1/eRF1, mapping to 5q31, as a candidate myeloid tumor suppressor gene.Cancer Genet Cytogenet. 2002 Apr 1;134(1):33-7. doi: 10.1016/s0165-4608(01)00605-7.
• [8] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [9] 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.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [12] 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.
• [13] 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.
• [14] Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model. Environ Pollut. 2023 Oct 15;335:122359. doi: 10.1016/j.envpol.2023.122359. Epub 2023 Aug 9.
• [15] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.