Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0HXICH)

• DOT Name: Pinin (PNN)
• Synonyms: 140 kDa nuclear and cell adhesion-related phosphoprotein; Desmosome-associated protein; Domain-rich serine protein; DRS protein; DRSP; Melanoma metastasis clone A protein; Nuclear protein SDK3; SR-like protein
• Gene Name: PNN
• Related Disease:
  Anca-associated vasculitis
  Autoimmune disease
  Colorectal neoplasm
  Crohn disease
  Delirium
  Dementia
  Depression
  Endometrial cancer
  Endometrial carcinoma
  Hepatocellular carcinoma
  Mental disorder
  Muscular dystrophy
  Neoplasm
  Sleep disorder
  Ulcerative colitis
  Vasculitis
  Advanced cancer
  Neuroendocrine neoplasm
  Polycystic ovarian syndrome
  Small-cell lung cancer
  Tuberculosis
  Acute lymphocytic leukaemia
  Acute myelogenous leukaemia
  Anxiety
  Anxiety disorder
  Asthma
  Congenital heart disease
  Pachyonychia congenita 3
  Post-traumatic stress disorder
• UniProt ID: PININ_HUMAN
• Pfam ID: PF04696 ; PF04697
• Sequence:
  MAVAVRTLQEQLEKAKESLKNVDENIRKLTGRDPNDVRPIQARLLALSGPGGGRGRGSLL
  LRRGFSDSGGGPPAKQRDLEGAVSRLGGERRTRRESRQESDPEDDDVKKPALQSSVVATS
  KERTRRDLIQDQNMDEKGKQRNRRIFGLLMGTLQKFKQESTVATERQKRRQEIEQKLEVQ
  AEEERKQVENERRELFEERRAKQTELRLLEQKVELAQLQEEWNEHNAKIIKYIRTKTKPH
  LFYIPGRMCPATQKLIEESQRKMNALFEGRRIEFAEQINKMEARPRRQSMKEKEHQVVRN
  EEQKAEQEEGKVAQREEELEETGNQHNDVEIEEAGEEEEKEIAIVHSDAEKEQEEEEQKQ
  EMEVKMEEETEVRESEKQQDSQPEEVMDVLEMVENVKHVIADQEVMETNRVESVEPSENE
  ASKELEPEMEFEIEPDKECKTLSPGKENVSALDMEKESEEKEEKESEPQPEPVAQPQPQS
  QPQLQLQSQSQPVLQSQPPSQPEDLSLAVLQPTPQVTQEQGHLLPERKDFPVESVKLTEV
  PVEPVLTVHPESKSKTKTRSRSRGRARNKTSKSRSRSSSSSSSSSSSTSSSSGSSSSSGS
  SSSRSSSSSSSSTSGSSSRDSSSSTSSSSESRSRSRGRGHNRDRKHRRSVDRKRRDTSGL
  ERSHKSSKGGSSRDTKGSKDKNSRSDRKRSISESSRSGKRSSRSERDRKSDRKDKRR
• Function: Transcriptional activator binding to the E-box 1 core sequence of the E-cadherin promoter gene; the core-binding sequence is 5'CAGGTG-3'. Capable of reversing CTBP1-mediated transcription repression. Auxiliary component of the splicing-dependent multiprotein exon junction complex (EJC) deposited at splice junction on mRNAs. The EJC is a dynamic structure consisting of core proteins and several peripheral nuclear and cytoplasmic associated factors that join the complex only transiently either during EJC assembly or during subsequent mRNA metabolism. Participates in the regulation of alternative pre-mRNA splicing. Associates to spliced mRNA within 60 nt upstream of the 5'-splice sites. Component of the PSAP complex which binds RNA in a sequence-independent manner and is proposed to be recruited to the EJC prior to or during the splicing process and to regulate specific excision of introns in specific transcription subsets. Involved in the establishment and maintenance of epithelia cell-cell adhesion. Potential tumor suppressor for renal cell carcinoma.
• Tissue Specificity: Expressed in placenta, lung, liver, kidney, pancreas, spleen, thymus, prostate, testis, ovary, small intestine, colon, heart, epidermis, esophagus, brain and smooth and skeletal muscle. Expressed strongly in melanoma metastasis lesions and advanced primary tumors.
• KEGG Pathway:
  Nucleocytoplasmic transport (hsa03013)
  mR. surveillance pathway (hsa03015)
• Reactome Pathway: mRNA Splicing - Major Pathway (R-HSA-72163)

Molecular Interaction Atlas (MIA) of This DOT

29 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Anca-associated vasculitis	DISU3CNU	Strong	Genetic Variation	[1]
Autoimmune disease	DISORMTM	Strong	Biomarker	[1]
Colorectal neoplasm	DISR1UCN	Strong	Altered Expression	[2]
Crohn disease	DIS2C5Q8	Strong	Biomarker	[3]
Delirium	DIS2OKP1	Strong	Genetic Variation	[4]
Dementia	DISXL1WY	Strong	Genetic Variation	[5]
Depression	DIS3XJ69	Strong	Biomarker	[6]
Endometrial cancer	DISW0LMR	Strong	Biomarker	[7]
Endometrial carcinoma	DISXR5CY	Strong	Biomarker	[7]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[8]
Mental disorder	DIS3J5R8	Strong	Genetic Variation	[9]
Muscular dystrophy	DISJD6P7	Strong	Genetic Variation	[10]
Neoplasm	DISZKGEW	Strong	Biomarker	[11]
Sleep disorder	DIS3JP1U	Strong	Biomarker	[12]
Ulcerative colitis	DIS8K27O	Strong	Biomarker	[3]
Vasculitis	DISQRKDX	Strong	Biomarker	[1]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[13]
Neuroendocrine neoplasm	DISNPLOO	moderate	Altered Expression	[14]
Polycystic ovarian syndrome	DISZ2BNG	moderate	Biomarker	[15]
Small-cell lung cancer	DISK3LZD	moderate	Altered Expression	[16]
Tuberculosis	DIS2YIMD	Disputed	Biomarker	[17]
Acute lymphocytic leukaemia	DISPX75S	Limited	Biomarker	[18]
Acute myelogenous leukaemia	DISCSPTN	Limited	Biomarker	[18]
Anxiety	DISIJDBA	Limited	Genetic Variation	[19]
Anxiety disorder	DISBI2BT	Limited	Genetic Variation	[19]
Asthma	DISW9QNS	Limited	Altered Expression	[20]
Congenital heart disease	DISQBA23	Limited	Biomarker	[21]
Pachyonychia congenita 3	DISZLC6C	Limited	Biomarker	[22]
Post-traumatic stress disorder	DISHL1EY	Limited	Genetic Variation	[23]

18 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 Pinin (PNN).	[24]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Pinin (PNN).	[25]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Pinin (PNN).	[26]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Pinin (PNN).	[27]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Pinin (PNN).	[28]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Pinin (PNN).	[29]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Pinin (PNN).	[30]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Pinin (PNN).	[31]
Propofol	DMB4OLE	Approved	Propofol decreases the expression of Pinin (PNN).	[32]
Sevoflurane	DMC9O43	Approved	Sevoflurane increases the expression of Pinin (PNN).	[32]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene decreases the expression of Pinin (PNN).	[25]
Phenol	DM1QSM3	Phase 2/3	Phenol decreases the expression of Pinin (PNN).	[33]
Tanespimycin	DMNLQHK	Phase 2	Tanespimycin increases the expression of Pinin (PNN).	[34]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Pinin (PNN).	[35]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Pinin (PNN).	[36]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Pinin (PNN).	[39]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride decreases the expression of Pinin (PNN).	[40]
Resorcinol	DMM37C0	Investigative	Resorcinol increases the expression of Pinin (PNN).	[41]

3 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Pinin (PNN).	[37]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Pinin (PNN).	[38]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Pinin (PNN).	[38]

References

• [1] Proteinase 3: the odd one out that became an autoantigen.J Leukoc Biol. 2017 Sep;102(3):689-698. doi: 10.1189/jlb.3MR0217-069R. Epub 2017 May 25.
• [2] Down-regulation of drs mRNA in colorectal neoplasms.Jpn J Cancer Res. 2002 Aug;93(8):888-93. doi: 10.1111/j.1349-7006.2002.tb01334.x.
• [3] The use of selected neutrophil protein plasma concentrations in the diagnosis of Crohn's disease and ulcerative colitis - a preliminary report.Postepy Hig Med Dosw (Online). 2017 Apr 6;71(0):243-253. doi: 10.5604/01.3001.0010.3810.
• [4] Accuracy of the Delirium Observational Screening Scale (DOS) as a screening tool for delirium in patients with advanced cancer.BMC Cancer. 2019 Feb 19;19(1):160. doi: 10.1186/s12885-019-5351-8.
• [5] Subsyndromal delirium compared with delirium, dementia, and subjects without delirium or dementia in elderly general hospital admissions and nursing home residents.Alzheimers Dement (Amst). 2016 Dec 1;7:1-10. doi: 10.1016/j.dadm.2016.11.002. eCollection 2017.
• [6] Screening for Executive Dysfunction in Late-Life Depression: Utility of Trail Making Test and Self-Report Measures.Am J Geriatr Psychiatry. 2018 Oct;26(10):1091-1094. doi: 10.1016/j.jagp.2018.06.006. Epub 2018 Jun 25.
• [7] The influence of hormone therapy with drospirenone-estradiol on endometrioid type endometrial cancer patients.J Gynecol Oncol. 2018 Sep;29(5):e72. doi: 10.3802/jgo.2018.29.e72. Epub 2018 May 4.
• [8] Pinin associates with prognosis of hepatocellular carcinoma through promoting cell proliferation and suppressing glucose deprivation-induced apoptosis.Oncotarget. 2016 Jun 28;7(26):39694-39704. doi: 10.18632/oncotarget.9233.
• [9] Subsyndromal delirium in the intensive care setting: Phenomenological characteristics and discrimination of subsyndromal delirium versus no and full-syndromal delirium.Palliat Support Care. 2018 Feb;16(1):3-13. doi: 10.1017/S1478951517000104. Epub 2017 Mar 6.
• [10] Transgenic mice expressing mutant Pinin exhibit muscular dystrophy, nebulin deficiency and elevated expression of slow-type muscle fiber genes.Biochem Biophys Res Commun. 2014 Jan 3;443(1):313-20. doi: 10.1016/j.bbrc.2013.11.108. Epub 2013 Dec 2.
• [11] Proteomics and metabolomics identify molecular mechanisms of aging potentially predisposing for chronic lymphocytic leukemia.Mol Cell Proteomics. 2018 Feb;17(2):290-303. doi: 10.1074/mcp.RA117.000425. Epub 2017 Dec 1.
• [12] Sleep-wake cycle disturbances in elderly acute general medical inpatients: Longitudinal relationship to delirium and dementia.Alzheimers Dement (Amst). 2017 Jan 21;7:61-68. doi: 10.1016/j.dadm.2016.12.013. eCollection 2017.
• [13] Pinin interacts with C-terminal binding proteins for RNA alternative splicing and epithelial cell identity of human ovarian cancer cells.Oncotarget. 2016 Mar 8;7(10):11397-411. doi: 10.18632/oncotarget.7242.
• [14] Downregulation of drs tumor suppressor gene in highly malignant human pulmonary neuroendocrine tumors.Oncol Rep. 2009 Jun;21(6):1367-72. doi: 10.3892/or_00000362.
• [15] Effect of chlormadinone acetate versus drospirenone-containing oral contraceptives on the endocrinal features of women with polycystic ovary syndrome: Systematic review and meta-analysis of randomized clinical trials.J Gynecol Obstet Hum Reprod. 2019 Nov;48(9):763-770. doi: 10.1016/j.jogoh.2019.03.025. Epub 2019 Mar 30.
• [16] Identification of deregulation of apoptosis and cell cycle in neuroendocrine tumors of the lung via NanoString nCounter expression analysis.Oncotarget. 2015 Sep 22;6(28):24690-8. doi: 10.18632/oncotarget.3992.
• [17] Rapid identification of mycobacteria and drug-resistant Mycobacterium tuberculosis by use of a single multiplex PCR and DNA sequencing.J Clin Microbiol. 2012 Feb;50(2):326-36. doi: 10.1128/JCM.05570-11. Epub 2011 Dec 7.
• [18] cDNA cloning of human myeloperoxidase: decrease in myeloperoxidase mRNA upon induction of HL-60 cells.Proc Natl Acad Sci U S A. 1987 Apr;84(7):2057-61. doi: 10.1073/pnas.84.7.2057.
• [19] Interaction of the neuropeptide S receptor gene AsnIle variant and environment: contribution to affective and anxiety disorders, and suicidal behaviour.Int J Neuropsychopharmacol. 2014 Apr;17(4):541-52. doi: 10.1017/S1461145713001478. Epub 2013 Dec 16.
• [20] Differential gene expression and cytokine production from neutrophils in asthma phenotypes.Eur Respir J. 2010 Mar;35(3):522-31. doi: 10.1183/09031936.00027409. Epub 2009 Sep 24.
• [21] Association of aminoacyl-tRNA synthetases gene polymorphisms with the risk of congenital heart disease in the Chinese Han population.PLoS One. 2014 Oct 13;9(10):e110072. doi: 10.1371/journal.pone.0110072. eCollection 2014.
• [22] Studies of the antitumor mechanism of action of dermaseptin B2, a multifunctional cationic antimicrobial peptide, reveal a partial implication of cell surface glycosaminoglycans.PLoS One. 2017 Aug 10;12(8):e0182926. doi: 10.1371/journal.pone.0182926. eCollection 2017.
• [23] Post-traumatic stress disorder (PTSD) related symptoms following an experience of delirium.J Psychosom Res. 2019 Aug;123:109725. doi: 10.1016/j.jpsychores.2019.05.003. Epub 2019 May 24.
• [24] 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.
• [25] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [26] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [27] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [28] 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.
• [29] 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.
• [30] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [31] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [32] The differential cancer growth associated with anaesthetics in a cancer xenograft model of mice: mechanisms and implications of postoperative cancer recurrence. Cell Biol Toxicol. 2023 Aug;39(4):1561-1575. doi: 10.1007/s10565-022-09747-9. Epub 2022 Aug 12.
• [33] Classification of heavy-metal toxicity by human DNA microarray analysis. Environ Sci Technol. 2007 May 15;41(10):3769-74.
• [34] Candidate therapeutic agents for hepatocellular cancer can be identified from phenotype-associated gene expression signatures. Cancer. 2009 Aug 15;115(16):3738-48. doi: 10.1002/cncr.24417.
• [35] 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.
• [36] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [37] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [38] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [39] 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.
• [40] The contact allergen nickel triggers a unique inflammatory and proangiogenic gene expression pattern via activation of NF-kappaB and hypoxia-inducible factor-1alpha. J Immunol. 2007 Mar 1;178(5):3198-207.
• [41] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.