Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2T2YOK)

• DOT Name: Muscleblind-like protein 3 (MBNL3)
• Synonyms: Cys3His CCG1-required protein; Muscleblind-like X-linked protein; Protein HCHCR
• Gene Name: MBNL3
• Related Disease:
  Blast phase chronic myelogenous leukemia, BCR-ABL1 positive
  Hepatocellular carcinoma
  Pathologic nystagmus
• UniProt ID: MBNL3_HUMAN
• Pfam ID: PF14608 ; PF18044
• Sequence:
  MTAVNVALIRDTKWLTLEVCREFQRGTCSRADADCKFAHPPRVCHVENGRVVACFDSLKG
  RCTRENCKYLHPPPHLKTQLEINGRNNLIQQKTAAAMFAQQMQLMLQNAQMSSLGSFPMT
  PSIPANPPMAFNPYIPHPGMGLVPAELVPNTPVLIPGNPPLAMPGAVGPKLMRSDKLEVC
  REFQRGNCTRGENDCRYAHPTDASMIEASDNTVTICMDYIKGRCSREKCKYFHPPAHLQA
  RLKAAHHQMNHSAASAMALQPGTLQLIPKRSALEKPNGATPVFNPTVFHCQQALTNLQLP
  QPAFIPAGPILCMAPASNIVPMMHGATPTTVSAATTPATSVPFAAPTTGNQLKF
• Function: Mediates pre-mRNA alternative splicing regulation. Acts either as activator or repressor of splicing on specific pre-mRNA targets. Inhibits cardiac troponin-T (TNNT2) pre-mRNA exon inclusion but induces insulin receptor (IR) pre-mRNA exon inclusion in muscle. Antagonizes the alternative splicing activity pattern of CELF proteins. May play a role in myotonic dystrophy pathophysiology (DM). Could inhibit terminal muscle differentiation, acting at approximately the time of myogenin induction.
• Tissue Specificity: Highly expressed in the placenta.

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Blast phase chronic myelogenous leukemia, BCR-ABL1 positive	DIS3KLUX	Strong	Biomarker	[1]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[2]
Pathologic nystagmus	DIS1QSPO	Strong	Biomarker	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Muscleblind-like protein 3 (MBNL3).	[4]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Muscleblind-like protein 3 (MBNL3).	[19]

20 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Muscleblind-like protein 3 (MBNL3).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Muscleblind-like protein 3 (MBNL3).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Muscleblind-like protein 3 (MBNL3).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Muscleblind-like protein 3 (MBNL3).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Muscleblind-like protein 3 (MBNL3).	[9]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Muscleblind-like protein 3 (MBNL3).	[10]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Muscleblind-like protein 3 (MBNL3).	[11]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Muscleblind-like protein 3 (MBNL3).	[12]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Muscleblind-like protein 3 (MBNL3).	[13]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Muscleblind-like protein 3 (MBNL3).	[14]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Muscleblind-like protein 3 (MBNL3).	[15]
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the expression of Muscleblind-like protein 3 (MBNL3).	[16]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of Muscleblind-like protein 3 (MBNL3).	[17]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Muscleblind-like protein 3 (MBNL3).	[18]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Muscleblind-like protein 3 (MBNL3).	[15]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of Muscleblind-like protein 3 (MBNL3).	[15]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Muscleblind-like protein 3 (MBNL3).	[20]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Muscleblind-like protein 3 (MBNL3).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Muscleblind-like protein 3 (MBNL3).	[22]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Muscleblind-like protein 3 (MBNL3).	[23]

References

• [1] Reversion to an embryonic alternative splicing program enhances leukemia stem cell self-renewal.Proc Natl Acad Sci U S A. 2015 Dec 15;112(50):15444-9. doi: 10.1073/pnas.1506943112. Epub 2015 Nov 30.
• [2] The MBNL3 splicing factor promotes hepatocellular carcinoma by increasing PXN expression through the alternative splicing of lncRNA-PXN-AS1.Nat Cell Biol. 2017 Jul;19(7):820-832. doi: 10.1038/ncb3538. Epub 2017 May 29.
• [3] Fine mapping of the X-linked recessive congenital idiopathic nystagmus locus at Xq24-q26.3.Mol Vis. 2006 Oct 18;12:1211-6.
• [4] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [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] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [7] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [8] 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.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [11] Persistent and non-persistent changes in gene expression result from long-term estrogen exposure of MCF-7 breast cancer cells. J Steroid Biochem Mol Biol. 2011 Feb;123(3-5):140-50.
• [12] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [13] Gene microarray analysis of human renal cell carcinoma: the effects of HDAC inhibition and retinoid treatment. Cancer Biol Ther. 2008 Oct;7(10):1607-18.
• [14] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [15] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [16] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [17] Chronic ethanol exposure increases goosecoid (GSC) expression in human embryonic carcinoma cell differentiation. J Appl Toxicol. 2014 Jan;34(1):66-75.
• [18] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [19] 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.
• [20] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [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] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [23] 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.