Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDK1FPH)

• DOT Name: Cysteine/serine-rich nuclear protein 1 (CSRNP1)
• Synonyms: CSRNP-1; Axin-1 up-regulated gene 1 protein; Protein URAX1; TGF-beta-induced apoptosis protein 3; TAIP-3
• Gene Name: CSRNP1
• Related Disease:
  Hepatocellular carcinoma
  Carcinoma
  Colon cancer
  Neoplasm
  Small lymphocytic lymphoma
  Dilated cardiomyopathy
  Dilated cardiomyopathy 1A
• UniProt ID: CSRN1_HUMAN
• Pfam ID: PF16019
• Sequence:
  MTGLLKRKFDQLDEDNSSVSSSSSSSGCQSRSCSPSSSVSRAWDSEEEGPWDQMPLPDRD
  FCGPRSFTPLSILKRARRERPGRVAFDGITVFYFPRCQGFTSVPSRGGCTLGMALRHSAC
  RRFSLAEFAQEQARARHEKLRQRLKEEKLEMLQWKLSAAGVPQAEAGLPPVVDAIDDASV
  EEDLAVAVAGGRLEEVSFLQPYPARRRRALLRASGVRRIDREEKRELQALRQSREDCGCH
  CDRICDPETCSCSLAGIKCQMDHTAFPCGCCREGCENPMGRVEFNQARVQTHFIHTLTRL
  QLEQEAESFRELEAPAQGSPPSPGEEALVPTFPLAKPPMNNELGDNSCSSDMTDSSTASS
  SASGTSEAPDCPTHPGLPGPGFQPGVDDDSLARILSFSDSDFGGEEEEEEEGSVGNLDNL
  SCFHPADIFGTSDPGGLASWTHSYSGCSFTSGVLDENANLDASCFLNGGLEGSREGSLPG
  TSVPPSMDAGRSSSVDLSLSSCDSFELLQALPDYSLGPHYTSQKVSDSLDNIEAPHFPLP
  GLSPPGDASSCFLESLMGFSEPAAEALDPFIDSQFEDTVPASLMEPVPV
• Function: Binds to the consensus sequence 5'-AGAGTG-3' and has transcriptional activator activity. May have a tumor-suppressor function. May play a role in apoptosis.
• Tissue Specificity: Ubiquitous. Most abundantly expressed in lung, placenta, skeletal muscle, pancreas and leukocyte. Frequently down-regulated in lung, kidney, liver and colon cancers compared with their corresponding normal tissues.

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hepatocellular carcinoma	DIS0J828	Definitive	Biomarker	[1]
Carcinoma	DISH9F1N	Strong	Altered Expression	[2]
Colon cancer	DISVC52G	Strong	Altered Expression	[2]
Neoplasm	DISZKGEW	Strong	Biomarker	[2]
Small lymphocytic lymphoma	DIS30POX	Disputed	Genetic Variation	[3]
Dilated cardiomyopathy	DISX608J	Limited	Biomarker	[4]
Dilated cardiomyopathy 1A	DIS0RK9Z	Limited	Biomarker	[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 Cysteine/serine-rich nuclear protein 1 (CSRNP1).	[5]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Cysteine/serine-rich nuclear protein 1 (CSRNP1).	[21]

26 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 Cysteine/serine-rich nuclear protein 1 (CSRNP1).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Cysteine/serine-rich nuclear protein 1 (CSRNP1).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Cysteine/serine-rich nuclear protein 1 (CSRNP1).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Cysteine/serine-rich nuclear protein 1 (CSRNP1).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Cysteine/serine-rich nuclear protein 1 (CSRNP1).	[10]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Cysteine/serine-rich nuclear protein 1 (CSRNP1).	[11]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Cysteine/serine-rich nuclear protein 1 (CSRNP1).	[12]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Cysteine/serine-rich nuclear protein 1 (CSRNP1).	[12]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Cysteine/serine-rich nuclear protein 1 (CSRNP1).	[13]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Cysteine/serine-rich nuclear protein 1 (CSRNP1).	[14]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Cysteine/serine-rich nuclear protein 1 (CSRNP1).	[1]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate increases the expression of Cysteine/serine-rich nuclear protein 1 (CSRNP1).	[16]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Cysteine/serine-rich nuclear protein 1 (CSRNP1).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Cysteine/serine-rich nuclear protein 1 (CSRNP1).	[18]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Cysteine/serine-rich nuclear protein 1 (CSRNP1).	[19]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Cysteine/serine-rich nuclear protein 1 (CSRNP1).	[20]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Cysteine/serine-rich nuclear protein 1 (CSRNP1).	[22]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Cysteine/serine-rich nuclear protein 1 (CSRNP1).	[23]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Cysteine/serine-rich nuclear protein 1 (CSRNP1).	[24]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Cysteine/serine-rich nuclear protein 1 (CSRNP1).	[25]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Cysteine/serine-rich nuclear protein 1 (CSRNP1).	[26]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Cysteine/serine-rich nuclear protein 1 (CSRNP1).	[27]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Cysteine/serine-rich nuclear protein 1 (CSRNP1).	[28]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of Cysteine/serine-rich nuclear protein 1 (CSRNP1).	[29]
Paraquat	DMR8O3X	Investigative	Paraquat increases the expression of Cysteine/serine-rich nuclear protein 1 (CSRNP1).	[30]
Propanoic Acid	DM9TN2W	Investigative	Propanoic Acid increases the expression of Cysteine/serine-rich nuclear protein 1 (CSRNP1).	[31]

References

• [1] Computational discovery of niclosamide ethanolamine, a repurposed drug candidate that reduces growth of hepatocellular carcinoma cells initro and in mice by inhibiting cell division cycle 37 signaling. Gastroenterology. 2017 Jun;152(8):2022-2036.
• [2] Identification of AXUD1, a novel human gene induced by AXIN1 and its reduced expression in human carcinomas of the lung, liver, colon and kidney.Oncogene. 2001 Aug 16;20(36):5062-6. doi: 10.1038/sj.onc.1204603.
• [3] Meta-analysis of genome-wide association studies discovers multiple loci for chronic lymphocytic leukemia.Nat Commun. 2016 Mar 9;7:10933. doi: 10.1038/ncomms10933.
• [4] Transcriptional analysis of doxorubicin-induced cardiotoxicity.Am J Physiol Heart Circ Physiol. 2006 Mar;290(3):H1098-102. doi: 10.1152/ajpheart.00832.2005. Epub 2005 Oct 21.
• [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] 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.
• [7] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [8] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [9] 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.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [12] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [13] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [14] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [15] Computational discovery of niclosamide ethanolamine, a repurposed drug candidate that reduces growth of hepatocellular carcinoma cells initro and in mice by inhibiting cell division cycle 37 signaling. Gastroenterology. 2017 Jun;152(8):2022-2036.
• [16] 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.
• [17] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [18] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [19] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [20] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [21] 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.
• [22] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [23] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [24] Chemical stresses fail to mimic the unfolded protein response resulting from luminal load with unfolded polypeptides. J Biol Chem. 2018 Apr 13;293(15):5600-5612.
• [25] 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.
• [26] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [27] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [28] In vitro effects of aldehydes present in tobacco smoke on gene expression in human lung alveolar epithelial cells. Toxicol In Vitro. 2013 Apr;27(3):1072-81.
• [29] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [30] An in vitro strategy using multiple human induced pluripotent stem cell-derived models to assess the toxicity of chemicals: A case study on paraquat. Toxicol In Vitro. 2022 Jun;81:105333. doi: 10.1016/j.tiv.2022.105333. Epub 2022 Feb 16.
• [31] Propionic acid induces mitochondrial dysfunction and affects gene expression for mitochondria biogenesis and neuronal differentiation in SH-SY5Y cell line. Neurotoxicology. 2019 Dec;75:116-122. doi: 10.1016/j.neuro.2019.09.009. Epub 2019 Sep 14.