Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTP1GQCH)

• DOT Name: Cytoplasmic polyadenylation element-binding protein 3 (CPEB3)
• Synonyms: CPE-BP3; CPE-binding protein 3; hCPEB-3
• Gene Name: CPEB3
• Related Disease:
  Advanced cancer
  Glioma
  Hepatocellular carcinoma
  Non-insulin dependent diabetes
  Ovarian serous adenocarcinoma
  Colorectal carcinoma
  Cervical cancer
  Neoplasm
  Tourette syndrome
• UniProt ID: CPEB3_HUMAN
• PDB ID: 2DNL; 2RUG; 7N2E; 7N2F; 7N2G
• Pfam ID: PF16366 ; PF16367
• Sequence:
  MQDDLLMDKSKTQPQPQQQQRQQQQPQPESSVSEAPSTPLSSETPKPEENSAVPALSPAA
  APPAPNGPDKMQMESPLLPGLSFHQPPQQPPPPQEPAAPGASLSPSFGSTWSTGTTNAVE
  DSFFQGITPVNGTMLFQNFPHHVNPVFGGTFSPQIGLAQTQHHQQPPPPAPAPQPAQPAQ
  PPQAQPPQQRRSPASPSQAPYAQRSAAAAYGHQPIMTSKPSSSSAVAAAAAAAAASSASS
  SWNTHQSVNAAWSAPSNPWGGLQAGRDPRRAVGVGVGVGVGVPSPLNPISPLKKPFSSNV
  IAPPKFPRAAPLTSKSWMEDNAFRTDNGNNLLPFQDRSRPYDTFNLHSLENSLMDMIRTD
  HEPLKGKHYPPSGPPMSFADIMWRNHFAGRMGINFHHPGTDNIMALNNAFLDDSHGDQAL
  SSGLSSPTRCQNGERVERYSRKVFVGGLPPDIDEDEITASFRRFGPLVVDWPHKAESKSY
  FPPKGYAFLLFQEESSVQALIDACLEEDGKLYLCVSSPTIKDKPVQIRPWNLSDSDFVMD
  GSQPLDPRKTIFVGGVPRPLRAVELAMIMDRLYGGVCYAGIDTDPELKYPKGAGRVAFSN
  QQSYIAAISARFVQLQHNDIDKRVEVKPYVLDDQMCDECQGTRCGGKFAPFFCANVTCLQ
  YYCEYCWASIHSRAGREFHKPLVKEGGDRPRHVPFRWS
• Function: Sequence-specific RNA-binding protein which acts as a translational repressor in the basal unstimulated state but, following neuronal stimulation, acts as a translational activator. In contrast to CPEB1, does not bind to the cytoplasmic polyadenylation element (CPE), a uridine-rich sequence element within the mRNA 3'-UTR, but binds to a U-rich loop within a stem-loop structure. Required for the consolidation and maintenance of hippocampal-based long term memory. In the basal state, binds to the mRNA 3'-UTR of the glutamate receptors GRIA2/GLUR2 mRNA and negatively regulates their translation. Also represses the translation of DLG4, GRIN1, GRIN2A and GRIN2B. When activated, acts as a translational activator of GRIA1 and GRIA2. In the basal state, suppresses SUMO2 translation but activates it following neuronal stimulation. Binds to the 3'-UTR of TRPV1 mRNA and represses TRPV1 translation which is required to maintain normal thermoception. Binds actin mRNA, leading to actin translational repression in the basal state and to translational activation following neuronal stimulation. Negatively regulates target mRNA levels by binding to TOB1 which recruits CNOT7/CAF1 to a ternary complex and this leads to target mRNA deadenylation and decay. In addition to its role in translation, binds to and inhibits the transcriptional activation activity of STAT5B without affecting its dimerization or DNA-binding activity. This, in turn, represses transcription of the STAT5B target gene EGFR which has been shown to play a role in enhancing learning and memory performance. In contrast to CPEB1, CPEB2 and CPEB4, not required for cell cycle progression.
• KEGG Pathway:
  Oocyte meiosis (hsa04114)
  Progesterone-mediated oocyte maturation (hsa04914)

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[1]
Glioma	DIS5RPEH	Strong	Biomarker	[2]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[1]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[3]
Ovarian serous adenocarcinoma	DISSU72Z	Strong	Altered Expression	[4]
Colorectal carcinoma	DIS5PYL0	moderate	Altered Expression	[5]
Cervical cancer	DISFSHPF	Disputed	Altered Expression	[6]
Neoplasm	DISZKGEW	Limited	Biomarker	[5]
Tourette syndrome	DISX9D54	No Known	Unknown	[7]

14 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 Cytoplasmic polyadenylation element-binding protein 3 (CPEB3).	[8]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Cytoplasmic polyadenylation element-binding protein 3 (CPEB3).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Cytoplasmic polyadenylation element-binding protein 3 (CPEB3).	[10]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Cytoplasmic polyadenylation element-binding protein 3 (CPEB3).	[11]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Cytoplasmic polyadenylation element-binding protein 3 (CPEB3).	[12]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Cytoplasmic polyadenylation element-binding protein 3 (CPEB3).	[14]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Cytoplasmic polyadenylation element-binding protein 3 (CPEB3).	[15]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Cytoplasmic polyadenylation element-binding protein 3 (CPEB3).	[15]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Cytoplasmic polyadenylation element-binding protein 3 (CPEB3).	[16]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Cytoplasmic polyadenylation element-binding protein 3 (CPEB3).	[17]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Cytoplasmic polyadenylation element-binding protein 3 (CPEB3).	[18]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Cytoplasmic polyadenylation element-binding protein 3 (CPEB3).	[19]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Cytoplasmic polyadenylation element-binding protein 3 (CPEB3).	[21]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Cytoplasmic polyadenylation element-binding protein 3 (CPEB3).	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Cytoplasmic polyadenylation element-binding protein 3 (CPEB3).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Cytoplasmic polyadenylation element-binding protein 3 (CPEB3).	[20]

References

• [1] Effects of Lidocaine-Mediated CPEB3 Upregulation in Human Hepatocellular Carcinoma Cell Proliferation In Vitro.Biomed Res Int. 2018 Apr 17;2018:8403157. doi: 10.1155/2018/8403157. eCollection 2018.
• [2] Long non-coding RNA HCG11 modulates glioma progression through cooperating with miR-496/CPEB3 axis.Cell Prolif. 2019 Sep;52(5):e12615. doi: 10.1111/cpr.12615. Epub 2019 Jul 16.
• [3] Genome-wide association study identifies three novel loci for type 2 diabetes.Hum Mol Genet. 2014 Jan 1;23(1):239-46. doi: 10.1093/hmg/ddt399. Epub 2013 Aug 14.
• [4] miRNA-301b-3p accelerates migration and invasion of high-grade ovarian serous tumor via targeting CPEB3/EGFR axis.J Cell Biochem. 2019 Aug;120(8):12618-12627. doi: 10.1002/jcb.28528. Epub 2019 Mar 4.
• [5] LncRNA SUMO1P3 promotes proliferation and inhibits apoptosis in colorectal cancer by epigenetically silencing CPEB3.Biochem Biophys Res Commun. 2019 Apr 2;511(2):239-245. doi: 10.1016/j.bbrc.2019.02.006. Epub 2019 Feb 22.
• [6] Expression of CPEB, GAPDH and U6snRNA in cervical and ovarian tissue during cancer development.APMIS. 2009 Jan;117(1):53-9. doi: 10.1111/j.1600-0463.2008.00015.x.
• [7] De Novo Coding Variants Are Strongly Associated with Tourette Disorder. Neuron. 2017 May 3;94(3):486-499.e9. doi: 10.1016/j.neuron.2017.04.024.
• [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] 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.
• [11] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [12] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [13] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [14] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [15] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [16] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [17] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [18] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [19] 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.
• [20] 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.
• [21] 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.
• [22] In vitro effects of aldehydes present in tobacco smoke on gene expression in human lung alveolar epithelial cells. Toxicol In Vitro. 2013 Apr;27(3):1072-81.