Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTG4TEGR)

• DOT Name: Protein Largen (PRR16)
• Synonyms: Mesenchymal stem cell protein DSC54; Proline-rich protein 16
• Gene Name: PRR16
• Related Disease:
  Major depressive disorder
  Mood disorder
• UniProt ID: LARGN_HUMAN
• Pfam ID: PF15252
• Sequence:
  MSAKSKGNPSSSCPAEGPPAASKTKVKEQIKIIVEDLELVLGDLKDVAKELKEVVDQIDT
  LTSDLQLEDEMTDSSKTDTLNSSSSGTTASSLEKIKVQANAPLIKPPAHPSAILTVLRKP
  NPPPPPPRLTPVKCEDPKRVVPTANPVKTNGTLLRNGGLPGGPNKIPNGDICCIPNSNLD
  KAPVQLLMHRPEKDRCPQAGPRERVRFNEKVQYHGYCPDCDTRYNIKNREVHLHSEPVHP
  PGKIPHQGPPLPPTPHLPPFPLENGGMGISHSNSFPPIRPATVPPPTAPKPQKTILRKST
  TTTV
• Function: Regulator of cell size that promotes cell size increase independently of mTOR and Hippo signaling pathways. Acts by stimulating the translation of specific mRNAs, including those encoding proteins affecting mitochondrial functions. Increases mitochondrial mass and respiration.

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[1]
Mood disorder	DISLVMWO	Strong	Genetic Variation	[1]

16 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 Protein Largen (PRR16).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Protein Largen (PRR16).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Protein Largen (PRR16).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Protein Largen (PRR16).	[5]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Protein Largen (PRR16).	[6]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Protein Largen (PRR16).	[8]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Protein Largen (PRR16).	[9]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Protein Largen (PRR16).	[9]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Protein Largen (PRR16).	[10]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Protein Largen (PRR16).	[11]
Folic acid	DMEMBJC	Approved	Folic acid affects the expression of Protein Largen (PRR16).	[12]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Protein Largen (PRR16).	[10]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Protein Largen (PRR16).	[14]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Protein Largen (PRR16).	[15]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Protein Largen (PRR16).	[16]
Lithium chloride	DMHYLQ2	Investigative	Lithium chloride decreases the expression of Protein Largen (PRR16).	[17]

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 Protein Largen (PRR16).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Protein Largen (PRR16).	[13]

References

• [1] Meta-analysis of genome-wide association studies for neuroticism in 449,484 individuals identifies novel genetic loci and pathways.Nat Genet. 2018 Jul;50(7):920-927. doi: 10.1038/s41588-018-0151-7. Epub 2018 Jun 25.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] 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.
• [4] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [5] 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.
• [6] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
• [7] 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.
• [8] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [9] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [10] 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.
• [11] Genistein disrupts glucocorticoid receptor signaling in human uterine endometrial Ishikawa cells. Environ Health Perspect. 2015 Jan;123(1):80-7. doi: 10.1289/ehp.1408437. Epub 2014 Aug 19.
• [12] Folate deficiency in normal human fibroblasts leads to altered expression of genes primarily linked to cell signaling, the cytoskeleton and extracellular matrix. J Nutr Biochem. 2007 Aug;18(8):541-52. doi: 10.1016/j.jnutbio.2006.11.002. Epub 2007 Feb 22.
• [13] 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.
• [14] 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.
• [15] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [16] 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.
• [17] Early gene response in lithium chloride induced apoptosis. Apoptosis. 2005 Jan;10(1):75-90. doi: 10.1007/s10495-005-6063-x.