Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2SZQI7)

• DOT Name: Transmembrane gamma-carboxyglutamic acid protein 4 (PRRG4)
• Synonyms: Proline-rich gamma-carboxyglutamic acid protein 4; Proline-rich Gla protein 4
• Gene Name: PRRG4
• Related Disease:
  Lung cancer
  Lung carcinoma
  Intellectual disability
• UniProt ID: TMG4_HUMAN
• Pfam ID: PF00594
• Sequence:
  MFTLLVLLSQLPTVTLGFPHCARGPKASKHAGEEVFTSKEEANFFIHRRLLYNRFDLELF
  TPGNLERECNEELCNYEEAREIFVDEDKTIAFWQEYSAKGPTTKSDGNREKIDVMGLLTG
  LIAAGVFLVIFGLLGYYLCITKCNRLQHPCSSAVYERGRHTPSIIFRRPEEAALSPLPPS
  VEDAGLPSYEQAVALTRKHSVSPPPPYPGHTKGFRVFKKSMSLPSH
• Function: May control axon guidance across the CNS. Prevents the delivery of ROBO1 at the cell surface and down-regulates its expression.
• Tissue Specificity: Widely expressed with highest levels in kidney.

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Lung cancer	DISCM4YA	Definitive	Biomarker	[1]
Lung carcinoma	DISTR26C	Definitive	Biomarker	[1]
Intellectual disability	DISMBNXP	Limited	Biomarker	[2]

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 Transmembrane gamma-carboxyglutamic acid protein 4 (PRRG4).	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Transmembrane gamma-carboxyglutamic acid protein 4 (PRRG4).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Transmembrane gamma-carboxyglutamic acid protein 4 (PRRG4).	[4]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Transmembrane gamma-carboxyglutamic acid protein 4 (PRRG4).	[5]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Transmembrane gamma-carboxyglutamic acid protein 4 (PRRG4).	[6]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of Transmembrane gamma-carboxyglutamic acid protein 4 (PRRG4).	[7]
Paclitaxel	DMLB81S	Approved	Paclitaxel decreases the expression of Transmembrane gamma-carboxyglutamic acid protein 4 (PRRG4).	[8]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate decreases the expression of Transmembrane gamma-carboxyglutamic acid protein 4 (PRRG4).	[9]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Transmembrane gamma-carboxyglutamic acid protein 4 (PRRG4).	[10]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Transmembrane gamma-carboxyglutamic acid protein 4 (PRRG4).	[11]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Transmembrane gamma-carboxyglutamic acid protein 4 (PRRG4).	[12]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Transmembrane gamma-carboxyglutamic acid protein 4 (PRRG4).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Transmembrane gamma-carboxyglutamic acid protein 4 (PRRG4).	[15]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Transmembrane gamma-carboxyglutamic acid protein 4 (PRRG4).	[16]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Transmembrane gamma-carboxyglutamic acid protein 4 (PRRG4).	[17]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Transmembrane gamma-carboxyglutamic acid protein 4 (PRRG4).	[18]

References

• [1] Long Noncoding RNA PRRG4-4 Promotes Viability, Cell Cycle, Migration, and Invasion in Lung Cancer Cells.DNA Cell Biol. 2018 Dec;37(12):953-966. doi: 10.1089/dna.2018.4220. Epub 2018 Oct 26.
• [2] Characterization of 11p14-p12 deletion in WAGR syndrome by array CGH for identifying genes contributing to mental retardation and autism.Cytogenet Genome Res. 2008;122(2):181-7. doi: 10.1159/000172086. Epub 2008 Dec 18.
• [3] 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.
• [4] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [5] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [6] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [7] Gene expression signatures after ethanol exposure in differentiating embryoid bodies. Toxicol In Vitro. 2018 Feb;46:66-76.
• [8] Identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell. 2009 Aug 21;138(4):645-659. doi: 10.1016/j.cell.2009.06.034. Epub 2009 Aug 13.
• [9] 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.
• [10] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [11] 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.
• [12] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [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] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [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] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [18] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.