Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZ3F6D2)

• DOT Name: Protein phosphatase 1 regulatory subunit 14C (PPP1R14C)
• Synonyms: Kinase-enhanced PP1 inhibitor; PKC-potentiated PP1 inhibitory protein; Serologically defined breast cancer antigen NY-BR-81
• Gene Name: PPP1R14C
• Related Disease:
  Breast cancer
  Breast carcinoma
  Metastatic malignant neoplasm
  Myopathy
  Neoplasm
  Acute myelogenous leukaemia
  Endometrial carcinoma
• UniProt ID: PP14C_HUMAN
• Pfam ID: PF05361
• Sequence:
  MSVATGSSETAGGASGGGARVFFQSPRGGAGGSPGSSSGSGSSREDSAPVATAAAAGQVQ
  QQQQRRHQQGKVTVKYDRKELRKRLVLEEWIVEQLGQLYGCEEEEMPEVEIDIDDLLDAD
  SDEERASKLQEALVDCYKPTEEFIKELLSRIRGMRKLSPPQKKSV
• Function: Inhibitor of the PP1 regulatory subunit PPP1CA.
• Tissue Specificity: Detected in breast cancer.

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Strong	Altered Expression	[1]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[1]
Metastatic malignant neoplasm	DIS86UK6	Strong	Altered Expression	[1]
Myopathy	DISOWG27	Strong	Genetic Variation	[2]
Neoplasm	DISZKGEW	Strong	Biomarker	[1]
Acute myelogenous leukaemia	DISCSPTN	Limited	Genetic Variation	[3]
Endometrial carcinoma	DISXR5CY	Limited	Genetic Variation	[4]

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 Protein phosphatase 1 regulatory subunit 14C (PPP1R14C).	[5]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Protein phosphatase 1 regulatory subunit 14C (PPP1R14C).	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Protein phosphatase 1 regulatory subunit 14C (PPP1R14C).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Protein phosphatase 1 regulatory subunit 14C (PPP1R14C).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Protein phosphatase 1 regulatory subunit 14C (PPP1R14C).	[8]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Protein phosphatase 1 regulatory subunit 14C (PPP1R14C).	[10]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Protein phosphatase 1 regulatory subunit 14C (PPP1R14C).	[11]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Protein phosphatase 1 regulatory subunit 14C (PPP1R14C).	[11]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Protein phosphatase 1 regulatory subunit 14C (PPP1R14C).	[12]
Phenobarbital	DMXZOCG	Approved	Phenobarbital decreases the expression of Protein phosphatase 1 regulatory subunit 14C (PPP1R14C).	[13]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Protein phosphatase 1 regulatory subunit 14C (PPP1R14C).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Protein phosphatase 1 regulatory subunit 14C (PPP1R14C).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Protein phosphatase 1 regulatory subunit 14C (PPP1R14C).	[16]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Protein phosphatase 1 regulatory subunit 14C (PPP1R14C).	[17]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Protein phosphatase 1 regulatory subunit 14C (PPP1R14C).	[18]
Lithium chloride	DMHYLQ2	Investigative	Lithium chloride decreases the expression of Protein phosphatase 1 regulatory subunit 14C (PPP1R14C).	[19]

References

• [1] Expression of the protein phosphatase 1 inhibitor KEPI is downregulated in breast cancer cell lines and tissues and involved in the regulation of the tumor suppressor EGR1 via the MEK-ERK pathway.Biol Chem. 2007 May;388(5):489-95. doi: 10.1515/BC.2007.062.
• [2] Genomewide Association Study of Statin-Induced Myopathy in Patients Recruited Using the UK Clinical Practice Research Datalink.Clin Pharmacol Ther. 2019 Dec;106(6):1353-1361. doi: 10.1002/cpt.1557. Epub 2019 Jul 31.
• [3] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [4] Identification of nine new susceptibility loci for endometrial cancer.Nat Commun. 2018 Aug 9;9(1):3166. doi: 10.1038/s41467-018-05427-7.
• [5] 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.
• [6] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [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] 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.
• [10] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [11] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [12] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [13] Dose- and time-dependent effects of phenobarbital on gene expression profiling in human hepatoma HepaRG cells. Toxicol Appl Pharmacol. 2009 Feb 1;234(3):345-60.
• [14] The molecular basis of genistein-induced mitotic arrest and exit of self-renewal in embryonal carcinoma and primary cancer cell lines. BMC Med Genomics. 2008 Oct 10;1:49.
• [15] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [16] Low dose of bisphenol a modulates ovarian cancer gene expression profile and promotes epithelial to mesenchymal transition via canonical Wnt pathway. Toxicol Sci. 2018 Aug 1;164(2):527-538.
• [17] 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.
• [18] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [19] Effects of lithium and valproic acid on gene expression and phenotypic markers in an NT2 neurosphere model of neural development. PLoS One. 2013;8(3):e58822.