Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTY55PLY)

• DOT Name: ELAV-like protein 1 (ELAVL1)
• Synonyms: Hu-antigen R; HuR
• Gene Name: ELAVL1
• UniProt ID: ELAV1_HUMAN
• PDB ID: 3HI9; 4ED5; 4EGL; 4FXV; 5SZW; 6G2K; 6GC5; 6GD1; 6GD2; 6GD3
• Pfam ID: PF00076
• Sequence:
  MSNGYEDHMAEDCRGDIGRTNLIVNYLPQNMTQDELRSLFSSIGEVESAKLIRDKVAGHS
  LGYGFVNYVTAKDAERAINTLNGLRLQSKTIKVSYARPSSEVIKDANLYISGLPRTMTQK
  DVEDMFSRFGRIINSRVLVDQTTGLSRGVAFIRFDKRSEAEEAITSFNGHKPPGSSEPIT
  VKFAANPNQNKNVALLSQLYHSPARRFGGPVHHQAQRFRFSPMGVDHMSGLSGVNVPGNA
  SSGWCIFIYNLGQDADEGILWQMFGPFGAVTNVKVIRDFNTNKCKGFGFVTMTNYEEAAM
  AIASLNGYRLGDKILQVSFKTNKSHK
• Function: RNA-binding protein that binds to the 3'-UTR region of mRNAs and increases their stability. Involved in embryonic stem cell (ESC) differentiation: preferentially binds mRNAs that are not methylated by N6-methyladenosine (m6A), stabilizing them, promoting ESC differentiation. Has also been shown to be capable of binding to m6A-containing mRNAs and contributes to MYC stability by binding to m6A-containing MYC mRNAs. Binds to poly-U elements and AU-rich elements (AREs) in the 3'-UTR of target mRNAs. Binds avidly to the AU-rich element in FOS and IL3/interleukin-3 mRNAs. In the case of the FOS AU-rich element, binds to a core element of 27 nucleotides that contain AUUUA, AUUUUA, and AUUUUUA motifs. Binds preferentially to the 5'-UUUU[AG]UUU-3' motif in vitro. With ZNF385A, binds the 3'-UTR of p53/TP53 mRNA to control their nuclear export induced by CDKN2A. Hence, may regulate p53/TP53 expression and mediate in part the CDKN2A anti-proliferative activity. May also bind with ZNF385A the CCNB1 mRNA. Increases the stability of the leptin mRNA harboring an AU-rich element (ARE) in its 3' UTR.
• Tissue Specificity: Ubiquitous. Detected in brain, liver, thymus and muscle.
• KEGG Pathway:
  AMPK sig.ling pathway (hsa04152)
  IL-17 sig.ling pathway (hsa04657)
• Reactome Pathway: HuR (ELAVL1) binds and stabilizes mRNA (R-HSA-450520)

Molecular Interaction Atlas (MIA) of This DOT

19 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 ELAV-like protein 1 (ELAVL1).	[1]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of ELAV-like protein 1 (ELAVL1).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of ELAV-like protein 1 (ELAVL1).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of ELAV-like protein 1 (ELAVL1).	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of ELAV-like protein 1 (ELAVL1).	[5]
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the expression of ELAV-like protein 1 (ELAVL1).	[7]
Ibuprofen	DM8VCBE	Approved	Ibuprofen increases the expression of ELAV-like protein 1 (ELAVL1).	[8]
Flurbiprofen	DMGN4BY	Approved	Flurbiprofen increases the expression of ELAV-like protein 1 (ELAVL1).	[8]
Amsacrine	DMZKYIV	Approved	Amsacrine decreases the expression of ELAV-like protein 1 (ELAVL1).	[9]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of ELAV-like protein 1 (ELAVL1).	[10]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate increases the expression of ELAV-like protein 1 (ELAVL1).	[11]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of ELAV-like protein 1 (ELAVL1).	[12]
DNCB	DMDTVYC	Phase 2	DNCB increases the expression of ELAV-like protein 1 (ELAVL1).	[13]
Ym155	DM5Q1W4	Phase 2	Ym155 decreases the expression of ELAV-like protein 1 (ELAVL1).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of ELAV-like protein 1 (ELAVL1).	[16]
MG-132	DMKA2YS	Preclinical	MG-132 increases the expression of ELAV-like protein 1 (ELAVL1).	[18]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of ELAV-like protein 1 (ELAVL1).	[19]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of ELAV-like protein 1 (ELAVL1).	[20]
crotylaldehyde	DMTWRQI	Investigative	crotylaldehyde decreases the expression of ELAV-like protein 1 (ELAVL1).	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Menadione	DMSJDTY	Approved	Menadione increases the phosphorylation of ELAV-like protein 1 (ELAVL1).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of ELAV-like protein 1 (ELAVL1).	[15]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of ELAV-like protein 1 (ELAVL1).	[17]
2-Methylamino-succinic acid(NMDA)	DMKP6BM	Investigative	2-Methylamino-succinic acid(NMDA) increases the phosphorylation of ELAV-like protein 1 (ELAVL1).	[23]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Paraquat	DMR8O3X	Investigative	Paraquat affects the localization of ELAV-like protein 1 (ELAVL1).	[21]

References

• [1] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [2] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [3] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] 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.
• [6] Tyrosine phosphorylation of HuR by JAK3 triggers dissociation and degradation of HuR target mRNAs. Nucleic Acids Res. 2014 Jan;42(2):1196-208. doi: 10.1093/nar/gkt903. Epub 2013 Oct 7.
• [7] Effects of SIDT2 on the miR-25/NOX4/HuR axis and SIRT3 mRNA stability lead to ROS-mediated TNF- expression in hydroquinone-treated leukemia cells. Cell Biol Toxicol. 2023 Oct;39(5):2207-2225. doi: 10.1007/s10565-022-09705-5. Epub 2022 Mar 18.
• [8] The p38 MAPK pathway mediates aryl propionic acid induced messenger rna stability of p75 NTR in prostate cancer cells. Cancer Res. 2007 Dec 1;67(23):11402-10. doi: 10.1158/0008-5472.CAN-07-1792.
• [9] Amsacrine downregulates BCL2L1 expression and triggers apoptosis in human chronic myeloid leukemia cells through the SIDT2/NOX4/ERK/HuR pathway. Toxicol Appl Pharmacol. 2023 Sep 1;474:116625. doi: 10.1016/j.taap.2023.116625. Epub 2023 Jul 13.
• [10] Methionine adenosyltransferase 2B, HuR, and sirtuin 1 protein cross-talk impacts on the effect of resveratrol on apoptosis and growth in liver cancer cells. J Biol Chem. 2013 Aug 9;288(32):23161-70.
• [11] 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.
• [12] 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.
• [13] Isoeugenol destabilizes IL-8 mRNA expression in THP-1 cells through induction of the negative regulator of mRNA stability tristetraprolin. Arch Toxicol. 2012 Feb;86(2):239-48. doi: 10.1007/s00204-011-0758-2. Epub 2011 Oct 4.
• [14] Autophagic HuR mRNA degradation induces survivin and MCL1 downregulation in YM155-treated human leukemia cells. Toxicol Appl Pharmacol. 2020 Jan 15;387:114857. doi: 10.1016/j.taap.2019.114857. Epub 2019 Dec 16.
• [15] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [16] 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.
• [17] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [18] Autophagy activation clears ELAVL1/HuR-mediated accumulation of SQSTM1/p62 during proteasomal inhibition in human retinal pigment epithelial cells. PLoS One. 2013 Jul 29;8(7):e69563. doi: 10.1371/journal.pone.0069563. Print 2013.
• [19] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [20] 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.
• [21] Inhibition of TDP-43 accumulation by bis(thiosemicarbazonato)-copper complexes. PLoS One. 2012;7(8):e42277. doi: 10.1371/journal.pone.0042277. Epub 2012 Aug 3.
• [22] Gene expression profile and cytotoxicity of human bronchial epithelial cells exposed to crotonaldehyde. Toxicol Lett. 2010 Aug 16;197(2):113-22.
• [23] Regulation of the SIRT1 signaling pathway in NMDA-induced Excitotoxicity. Toxicol Lett. 2020 Apr 1;322:66-76. doi: 10.1016/j.toxlet.2020.01.009. Epub 2020 Jan 13.