Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT111JZ3)

• DOT Name: CUGBP Elav-like family member 6 (CELF6)
• Synonyms: CELF-6; Bruno-like protein 6; CUG-BP- and ETR-3-like factor 6; RNA-binding protein BRUNOL-6
• Gene Name: CELF6
• Related Disease:
  Autism
  Cervical cancer
  Cervical carcinoma
  Myotonic dystrophy
  Neoplasm
• UniProt ID: CELF6_HUMAN
• PDB ID: 2DGQ
• Pfam ID: PF00076
• Sequence:
  MAAAPGGSAQPAGPGPRLGFSTADSGVGMSGLNPGPAVPMKDHDAIKLFVGQIPRGLDEQ
  DLKPLFEEFGRIYELTVLKDRLTGLHKGCAFLTYCARDSALKAQSALHEQKTLPGMNRPI
  QVKPAASEGRGEDRKLFVGMLGKQQGEEDVRRLFQPFGHIEECTVLRSPDGTSKGCAFVK
  FGSQGEAQAAIRGLHGSRTMAGASSSLVVKLADTDRERALRRMQQMAGHLGAFHPAPLPL
  GACGAYTTAILQHQAALLAAAQGPGLGPVAAVAAQMQHVAAFSLVAAPLLPAAAANSPPG
  SGPGTLPGLPAPIGVNGFGPLTPQTNGQPGSDTLYNNGLSPYPAQSPGVADPLQQAYAGM
  HHYAAAYPSAYAPVSTAFPQQPSALPQQQREGPEGCNLFIYHLPQEFGDAELIQTFLPFG
  AVVSAKVFVDRATNQSKCFGFVSFDNPTSAQTAIQAMNGFQIGMKRLKVQLKRPKDANRP
  Y
• Function: RNA-binding protein implicated in the regulation of pre-mRNA alternative splicing. Mediates exon inclusion and/or exclusion in pre-mRNA that are subject to tissue-specific and developmentally regulated alternative splicing. Specifically activates exon 5 inclusion of TNNT2 in a muscle-specific splicing enhancer (MSE)-dependent manner. Promotes also exon exclusion of INSR pre-mRNA.
• Tissue Specificity: Expressed mainly in kidney, brain and testis and present in other tissues albeit at lower levels. Also expressed in fetal kidney.

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autism	DISV4V1Z	Strong	Genetic Variation	[1]
Cervical cancer	DISFSHPF	Strong	Genetic Variation	[2]
Cervical carcinoma	DIST4S00	Strong	Genetic Variation	[2]
Myotonic dystrophy	DISNBEMX	Strong	Biomarker	[3]
Neoplasm	DISZKGEW	Strong	Biomarker	[3]

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 CUGBP Elav-like family member 6 (CELF6).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of CUGBP Elav-like family member 6 (CELF6).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of CUGBP Elav-like family member 6 (CELF6).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of CUGBP Elav-like family member 6 (CELF6).	[7]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of CUGBP Elav-like family member 6 (CELF6).	[8]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of CUGBP Elav-like family member 6 (CELF6).	[9]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate increases the expression of CUGBP Elav-like family member 6 (CELF6).	[10]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of CUGBP Elav-like family member 6 (CELF6).	[11]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of CUGBP Elav-like family member 6 (CELF6).	[13]

2 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 CUGBP Elav-like family member 6 (CELF6).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of CUGBP Elav-like family member 6 (CELF6).	[14]

References

• [1] Loss of CELF6 RNA binding protein impairs cocaine conditioned place preference and contextual fear conditioning.Genes Brain Behav. 2019 Sep;18(7):e12593. doi: 10.1111/gbb.12593. Epub 2019 Jun 19.
• [2] Correlation between polymorphisms in microRNA-regulated genes and cervical cancer susceptibility in a Xinjiang Uygur population.Oncotarget. 2017 May 9;8(19):31758-31764. doi: 10.18632/oncotarget.15970.
• [3] RNA-binding protein CELF6 is cell cycle regulated and controls cancer cell proliferation by stabilizing p21.Cell Death Dis. 2019 Sep 18;10(10):688. doi: 10.1038/s41419-019-1927-0.
• [4] Effects of lithium and valproic acid on gene expression and phenotypic markers in an NT2 neurosphere model of neural development. PLoS One. 2013;8(3):e58822.
• [5] 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.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [8] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [9] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [10] CXCL14 downregulation in human keratinocytes is a potential biomarker for a novel in vitro skin sensitization test. Toxicol Appl Pharmacol. 2020 Jan 1;386:114828. doi: 10.1016/j.taap.2019.114828. Epub 2019 Nov 14.
• [11] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [12] 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.
• [13] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [14] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.