Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTP0YL53)

• DOT Name: p53 apoptosis effector related to PMP-22 (PERP)
• Synonyms: Keratinocyte-associated protein 1; KCP-1; P53-induced protein PIGPC1; Transmembrane protein THW
• Gene Name: PERP
• Related Disease:
  Uveal Melanoma
  Advanced cancer
  Arrhythmogenic right ventricular cardiomyopathy
  Breast cancer
  Breast carcinoma
  Ectodermal dysplasia
  Erythrokeratodermia variabilis et progressiva 7
  Gastroesophageal reflux disease
  Lung adenocarcinoma
  Lung cancer
  Lung carcinoma
  Male infertility
  Melanoma
  Metastatic malignant neoplasm
  Neoplasm
  Oligospermia
  Olmsted syndrome 2
  Salmonella infection
  Squamous cell carcinoma
  Obsolete mutilating palmoplantar keratoderma with periorificial keratotic plaques
• UniProt ID: PERP_HUMAN
• Pfam ID: PF00822
• Sequence:
  MIRCGLACERCRWILPLLLLSAIAFDIIALAGRGWLQSSDHGQTSSLWWKCSQEGGGSGS
  YEEGCQSLMEYAWGRAAAAMLFCGFIILVICFILSFFALCGPQMLVFLRVIGGLLALAAV
  FQIISLVIYPVKYTQTFTLHANPAVTYIYNWAYGFGWAATIILIGCAFFFCCLPNYEDDL
  LGNAKPRYFYTSA
• Function: Component of intercellular desmosome junctions. Plays a role in stratified epithelial integrity and cell-cell adhesion by promoting desmosome assembly; Plays a role as an effector in the TP53-dependent apoptotic pathway.
• Tissue Specificity: Expressed in skin, heart, placental, liver, pancreas, keratinocytes and dermal fibroblasts.
• KEGG Pathway: p53 sig.ling pathway (hsa04115)
• Reactome Pathway:
  Formation of the cornified envelope (R-HSA-6809371)
  TP53 regulates transcription of several additional cell death genes whose specific roles in p53-dependent apoptosis remain uncertain (R-HSA-6803205)

Molecular Interaction Atlas (MIA) of This DOT

20 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Uveal Melanoma	DISA7ZGL	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[2]
Arrhythmogenic right ventricular cardiomyopathy	DIS3V2BE	Strong	Biomarker	[3]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[4]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[4]
Ectodermal dysplasia	DISLRS4M	Strong	Biomarker	[5]
Erythrokeratodermia variabilis et progressiva 7	DISXFSMM	Strong	Autosomal recessive	[6]
Gastroesophageal reflux disease	DISQ8G5S	Strong	Genetic Variation	[7]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[8]
Lung cancer	DISCM4YA	Strong	Biomarker	[8]
Lung carcinoma	DISTR26C	Strong	Biomarker	[8]
Male infertility	DISY3YZZ	Strong	Altered Expression	[9]
Melanoma	DIS1RRCY	Strong	Altered Expression	[10]
Metastatic malignant neoplasm	DIS86UK6	Strong	Biomarker	[11]
Neoplasm	DISZKGEW	Strong	Biomarker	[4]
Oligospermia	DIS6YJF3	Strong	Altered Expression	[9]
Olmsted syndrome 2	DIS521VO	Strong	Autosomal dominant	[12]
Salmonella infection	DISTJ434	Strong	Biomarker	[13]
Squamous cell carcinoma	DISQVIFL	moderate	Altered Expression	[14]
Obsolete mutilating palmoplantar keratoderma with periorificial keratotic plaques	DIST2Y4B	Supportive	Autosomal dominant	[6]

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 p53 apoptosis effector related to PMP-22 (PERP).	[15]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the methylation of p53 apoptosis effector related to PMP-22 (PERP).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of p53 apoptosis effector related to PMP-22 (PERP).	[17]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of p53 apoptosis effector related to PMP-22 (PERP).	[18]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of p53 apoptosis effector related to PMP-22 (PERP).	[19]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of p53 apoptosis effector related to PMP-22 (PERP).	[20]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of p53 apoptosis effector related to PMP-22 (PERP).	[21]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of p53 apoptosis effector related to PMP-22 (PERP).	[22]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of p53 apoptosis effector related to PMP-22 (PERP).	[23]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of p53 apoptosis effector related to PMP-22 (PERP).	[24]
Paclitaxel	DMLB81S	Approved	Paclitaxel increases the expression of p53 apoptosis effector related to PMP-22 (PERP).	[25]
Enzalutamide	DMGL19D	Approved	Enzalutamide affects the expression of p53 apoptosis effector related to PMP-22 (PERP).	[26]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of p53 apoptosis effector related to PMP-22 (PERP).	[27]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of p53 apoptosis effector related to PMP-22 (PERP).	[28]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of p53 apoptosis effector related to PMP-22 (PERP).	[29]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of p53 apoptosis effector related to PMP-22 (PERP).	[30]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of p53 apoptosis effector related to PMP-22 (PERP).	[31]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of p53 apoptosis effector related to PMP-22 (PERP).	[32]

References

• [1] p63 is required beside p53 for PERP-mediated apoptosis in uveal melanoma.Br J Cancer. 2016 Oct 11;115(8):983-992. doi: 10.1038/bjc.2016.269. Epub 2016 Sep 1.
• [2] Single-nucleotide polymorphisms in the p53 pathway genes modify cancer risk in BRCA1 and BRCA2 carriers of Jewish-Ashkenazi descent.Mol Carcinog. 2010 Jun;49(6):545-55. doi: 10.1002/mc.20618.
• [3] Screening of three novel candidate genes in arrhythmogenic right ventricular cardiomyopathy. Genet Test Mol Biomarkers. 2011 Apr;15(4):267-71. doi: 10.1089/gtmb.2010.0151. Epub 2011 Jan 22.
• [4] Coactosin-like protein CLP/Cotl1 suppresses breast cancer growth through activation of IL-24/PERP and inhibition of non-canonical TGF signaling.Oncogene. 2018 Jan 18;37(3):323-331. doi: 10.1038/onc.2017.342. Epub 2017 Sep 18.
• [5] Differential PERP regulation by TP63 mutants provides insight into AEC pathogenesis.Am J Med Genet A. 2009 Sep;149A(9):1952-7. doi: 10.1002/ajmg.a.32760.
• [6] Mutations in PERP Cause Dominant and Recessive Keratoderma. J Invest Dermatol. 2019 Feb;139(2):380-390. doi: 10.1016/j.jid.2018.08.026. Epub 2018 Oct 12.
• [7] Interactions between genetic polymorphisms in the apoptotic pathway and environmental factors on esophageal adenocarcinoma risk.Carcinogenesis. 2011 Apr;32(4):502-6. doi: 10.1093/carcin/bgq287. Epub 2011 Jan 6.
• [8] PERP gene therapy attenuates lung cancer xenograft via inducing apoptosis and suppressing VEGF.Cancer Biol Ther. 2011 Dec 15;12(12):1114-9. doi: 10.4161/cbt.12.12.18435. Epub 2011 Dec 15.
• [9] Mkrn2 deficiency induces teratozoospermia and male infertility through p53/PERP-mediated apoptosis in testis.Asian J Androl. 2020 Jul-Aug;22(4):414-421. doi: 10.4103/aja.aja_76_19.
• [10] Expression of p53-induced apoptosis effector PERP in primary uveal melanomas: downregulation is associated with aggressive type.Exp Eye Res. 2006 Oct;83(4):911-9. doi: 10.1016/j.exer.2006.04.016. Epub 2006 Jun 19.
• [11] Loss of heterozygosity of gene THW is frequently found in melanoma metastases.Anticancer Res. 2001 Mar-Apr;21(2A):1071-80.
• [12] Perp is a p63-regulated gene essential for epithelial integrity. Cell. 2005 Mar 25;120(6):843-56. doi: 10.1016/j.cell.2005.01.008.
• [13] The type three secreted effector SipC regulates the trafficking of PERP during Salmonella infection.Gut Microbes. 2016;7(2):136-45. doi: 10.1080/19490976.2015.1128626.
• [14] Loss of the p53/p63 regulated desmosomal protein Perp promotes tumorigenesis.PLoS Genet. 2010 Oct 21;6(10):e1001168. doi: 10.1371/journal.pgen.1001168.
• [15] 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.
• [16] 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.
• [17] Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. Toxicol Lett. 2015 Apr 16;234(2):139-50.
• [18] 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.
• [19] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [20] Characterisation of cisplatin-induced transcriptomics responses in primary mouse hepatocytes, HepG2 cells and mouse embryonic stem cells shows conservation of regulating transcription factor networks. Mutagenesis. 2014 Jan;29(1):17-26.
• [21] 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.
• [22] 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.
• [23] 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.
• [24] Functional gene expression profile underlying methotrexate-induced senescence in human colon cancer cells. Tumour Biol. 2011 Oct;32(5):965-76.
• [25] Marked regression of liver metastasis by combined therapy of ultrasound-mediated NF kappaB-decoy transfer and transportal injection of paclitaxel, in mouse. Int J Cancer. 2008 Apr 1;122(7):1645-56. doi: 10.1002/ijc.23280.
• [26] NOTCH signaling is activated in and contributes to resistance in enzalutamide-resistant prostate cancer cells. J Biol Chem. 2019 May 24;294(21):8543-8554. doi: 10.1074/jbc.RA118.006983. Epub 2019 Apr 2.
• [27] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [28] Resveratrol-induced gene expression profiles in human prostate cancer cells. Cancer Epidemiol Biomarkers Prev. 2005 Mar;14(3):596-604. doi: 10.1158/1055-9965.EPI-04-0398.
• [29] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [30] 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.
• [31] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [32] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.