Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTH5KB2P)

• DOT Name: Nuclear inhibitor of protein phosphatase 1 (PPP1R8)
• Synonyms: NIPP-1; Protein phosphatase 1 regulatory inhibitor subunit 8
• Gene Name: PPP1R8
• Related Disease:
  Ablepharon macrostomia syndrome
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Colon cancer
  Colon carcinoma
  Diabetic kidney disease
  Hepatocellular carcinoma
  Lung adenocarcinoma
  Prostate cancer
  Prostate carcinoma
  Breast disorder
  Colitis
  Colorectal carcinoma
  Neoplasm
• UniProt ID: PP1R8_HUMAN
• PDB ID: 3V4Y
• EC Number: 3.1.4.-
• Pfam ID: PF00498
• Sequence:
  MAAAANSGSSLPLFDCPTWAGKPPPGLHLDVVKGDKLIEKLIIDEKKYYLFGRNPDLCDF
  TIDHQSCSRVHAALVYHKHLKRVFLIDLNSTHGTFLGHIRLEPHKPQQIPIDSTVSFGAS
  TRAYTLREKPQTLPSAVKGDEKMGGEDDELKGLLGLPEEETELDNLTEFNTAHNKRISTL
  TIEEGNLDIQRPKRKRKNSRVTFSEDDEIINPEDVDPSVGRFRNMVQTAVVPVKKKRVEG
  PGSLGLEESGSRRMQNFAFSGGLYGGLPPTHSEAGSQPHGIHGTALIGGLPMPYPNLAPD
  VDLTPVVPSAVNMNPAPNPAVYNPEAVNEPKKKKYAKEAWPGKKPTPSLLI
• Function: Inhibitor subunit of the major nuclear protein phosphatase-1 (PP-1). It has RNA-binding activity but does not cleave RNA and may target PP-1 to RNA-associated substrates. May also be involved in pre-mRNA splicing. Binds DNA and might act as a transcriptional repressor. Seems to be required for cell proliferation.; Isoform Gamma is a site-specific single-strand endoribonuclease that cleaves single strand RNA 3' to purines and pyrimidines in A+U-rich regions. It generates 5'-phosphate termini at the site of cleavage. This isoform does not inhibit PP-1. May be implicated in mRNA splicing.
• Tissue Specificity: Ubiquitously expressed, with highest levels in heart and skeletal muscle, followed by brain, placenta, lung, liver and pancreas. Less abundant in kidney. The concentration and ratio between isoforms is cell-type dependent. Isoform Alpha (>90%) and isoform Beta were found in brain, heart and kidney. Isoform Gamma is mainly found in B-cells and T-lymphocytes, and has been found in 293 embryonic kidney cells.
• Reactome Pathway: mRNA Splicing - Major Pathway (R-HSA-72163)

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Ablepharon macrostomia syndrome	DIS1P3YX	Strong	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[3]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[3]
Colon cancer	DISVC52G	Strong	Altered Expression	[2]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[2]
Diabetic kidney disease	DISJMWEY	Strong	Altered Expression	[4]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[5]
Lung adenocarcinoma	DISD51WR	Strong	Altered Expression	[6]
Prostate cancer	DISF190Y	Strong	Biomarker	[7]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[7]
Breast disorder	DISJTGMA	Limited	Biomarker	[8]
Colitis	DISAF7DD	Limited	Altered Expression	[9]
Colorectal carcinoma	DIS5PYL0	Limited	Altered Expression	[9]
Neoplasm	DISZKGEW	Limited	Altered Expression	[10]

7 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 Nuclear inhibitor of protein phosphatase 1 (PPP1R8).	[11]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Nuclear inhibitor of protein phosphatase 1 (PPP1R8).	[12]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Nuclear inhibitor of protein phosphatase 1 (PPP1R8).	[13]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Nuclear inhibitor of protein phosphatase 1 (PPP1R8).	[14]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Nuclear inhibitor of protein phosphatase 1 (PPP1R8).	[15]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Nuclear inhibitor of protein phosphatase 1 (PPP1R8).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Nuclear inhibitor of protein phosphatase 1 (PPP1R8).	[18]

1 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 Nuclear inhibitor of protein phosphatase 1 (PPP1R8).	[17]

References

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• [2] Diverse roles of arrest defective 1 in cancer development.Arch Pharm Res. 2019 Dec;42(12):1040-1051. doi: 10.1007/s12272-019-01195-0. Epub 2019 Dec 7.
• [3] ARD1 contributes to IKK-mediated breast cancer tumorigenesis.Cell Death Dis. 2018 Aug 28;9(9):860. doi: 10.1038/s41419-018-0921-2.
• [4] Activation of the receptor for advanced glycation end products induces nuclear inhibitor of protein phosphatase-1 suppression.Kidney Int. 2014 Jul;86(1):103-17. doi: 10.1038/ki.2014.3. Epub 2014 Jan 29.
• [5] ARD1/NAA10 in hepatocellular carcinoma: pathways and clinical implications.Exp Mol Med. 2018 Jul 27;50(7):1-12. doi: 10.1038/s12276-018-0106-1.
• [6] Down-regulation of the expression of the FIH-1 and ARD-1 genes at the transcriptional level by nickel and cobalt in the human lung adenocarcinoma A549 cell line. Int J Environ Res Public Health. 2005 Apr;2(1):10-3. doi: 10.3390/ijerph2005010010.
• [7] ARD1/NAA10 acetylation in prostate cancer.Exp Mol Med. 2018 Jul 27;50(7):1-8. doi: 10.1038/s12276-018-0107-0.
• [8] Up-regulation of human arrest-defective 1 protein is correlated with metastatic phenotype and poor prognosis in breast cancer.Asian Pac J Cancer Prev. 2011;12(8):1973-7.
• [9] Generation of novel monoclonal antibodies and their application for detecting ARD1 expression in colorectal cancer.Cancer Lett. 2008 Jun 8;264(1):83-92. doi: 10.1016/j.canlet.2008.01.028. Epub 2008 Mar 5.
• [10] The selective inhibition of protein phosphatase-1 results in mitotic catastrophe and impaired tumor growth.J Cell Sci. 2015 Dec 15;128(24):4526-37. doi: 10.1242/jcs.175588. Epub 2015 Nov 5.
• [11] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [12] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [13] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [14] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [15] Microarray analysis of H2O2-, HNE-, or tBH-treated ARPE-19 cells. Free Radic Biol Med. 2002 Nov 15;33(10):1419-32.
• [16] A genomic approach to predict synergistic combinations for breast cancer treatment. Pharmacogenomics J. 2013 Feb;13(1):94-104. doi: 10.1038/tpj.2011.48. Epub 2011 Nov 15.
• [17] 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.
• [18] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.