Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTA5SZLC)

• DOT Name: Ribonuclease 4 (RNASE4)
• Synonyms: RNase 4; EC 3.1.27.-
• Gene Name: RNASE4
• Related Disease:
  Cervical cancer
  Cervical carcinoma
  Congenital disorder of glycosylation
  Hepatitis C virus infection
  Huntington disease
  Melanoma
  Parkinson disease
  Prostate cancer
  Prostate neoplasm
  Skin neoplasm
  Spinal muscular atrophy
  Hepatocellular carcinoma
  Advanced cancer
  Cardiomyopathy
• UniProt ID: RNAS4_HUMAN
• PDB ID: 1RNF; 2RNF
• EC Number: 3.1.27.-
• Pfam ID: PF00074
• Sequence:
  MALQRTHSLLLLLLLTLLGLGLVQPSYGQDGMYQRFLRQHVHPEETGGSDRYCNLMMQRR
  KMTLYHCKRFNTFIHEDIWNIRSICSTTNIQCKNGKMNCHEGVVKVTDCRDTGSSRAPNC
  RYRAIASTRRVVIACEGNPQVPVHFDG
• Function: Cleaves preferentially after uridine bases. Has antimicrobial activity against uropathogenic E.coli (UPEC). Probably contributes to urinary tract sterility.
• Tissue Specificity: Expressed in the cortical and medullary tubules of the kidney, and in the transitional epithelium of the urinary bladder (at protein level).

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cervical cancer	DISFSHPF	Strong	Genetic Variation	[1]
Cervical carcinoma	DIST4S00	Strong	Genetic Variation	[1]
Congenital disorder of glycosylation	DIS400QP	Strong	Altered Expression	[2]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[3]
Huntington disease	DISQPLA4	Strong	Biomarker	[4]
Melanoma	DIS1RRCY	Strong	Biomarker	[5]
Parkinson disease	DISQVHKL	Strong	Altered Expression	[6]
Prostate cancer	DISF190Y	Strong	Biomarker	[7]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[7]
Skin neoplasm	DIS16DDV	Strong	Altered Expression	[5]
Spinal muscular atrophy	DISTLKOB	Strong	Biomarker	[8]
Hepatocellular carcinoma	DIS0J828	moderate	Biomarker	[9]
Advanced cancer	DISAT1Z9	Limited	Altered Expression	[6]
Cardiomyopathy	DISUPZRG	Limited	Altered Expression	[6]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Fluorouracil	DMUM7HZ	Approved	Ribonuclease 4 (RNASE4) affects the response to substance of Fluorouracil.	[33]

1 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 Ribonuclease 4 (RNASE4).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Ribonuclease 4 (RNASE4).	[11]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Ribonuclease 4 (RNASE4).	[12]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Ribonuclease 4 (RNASE4).	[13]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Ribonuclease 4 (RNASE4).	[14]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Ribonuclease 4 (RNASE4).	[15]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Ribonuclease 4 (RNASE4).	[16]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Ribonuclease 4 (RNASE4).	[17]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Ribonuclease 4 (RNASE4).	[18]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Ribonuclease 4 (RNASE4).	[19]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Ribonuclease 4 (RNASE4).	[20]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Ribonuclease 4 (RNASE4).	[21]
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the expression of Ribonuclease 4 (RNASE4).	[22]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Ribonuclease 4 (RNASE4).	[23]
DTI-015	DMXZRW0	Approved	DTI-015 increases the expression of Ribonuclease 4 (RNASE4).	[24]
Amphotericin B	DMTAJQE	Approved	Amphotericin B decreases the expression of Ribonuclease 4 (RNASE4).	[25]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Ribonuclease 4 (RNASE4).	[26]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Ribonuclease 4 (RNASE4).	[27]
OTX-015	DMI8RG1	Phase 1/2	OTX-015 decreases the expression of Ribonuclease 4 (RNASE4).	[28]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Ribonuclease 4 (RNASE4).	[29]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Ribonuclease 4 (RNASE4).	[30]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde decreases the expression of Ribonuclease 4 (RNASE4).	[31]
Bilirubin	DMI0V4O	Investigative	Bilirubin decreases the expression of Ribonuclease 4 (RNASE4).	[32]

References

• [1] Correlation between polymorphisms in microRNA-regulated genes and cervical cancer susceptibility in a Xinjiang Uygur population.Oncotarget. 2017 May 9;8(19):31758-31764. doi: 10.18632/oncotarget.15970.
• [2] COG7 deficiency in Drosophila generates multifaceted developmental, behavioral and protein glycosylation phenotypes.J Cell Sci. 2017 Nov 1;130(21):3637-3649. doi: 10.1242/jcs.209049. Epub 2017 Sep 7.
• [3] Role for TBC1D20 and Rab1 in hepatitis C virus replication via interaction with lipid droplet-bound nonstructural protein 5A.J Virol. 2012 Jun;86(12):6491-502. doi: 10.1128/JVI.00496-12. Epub 2012 Apr 4.
• [4] Identification of differentially expressed genes and regulatory relationships in Huntington's disease by bioinformatics analysis.Mol Med Rep. 2018 Mar;17(3):4317-4326. doi: 10.3892/mmr.2018.8410. Epub 2018 Jan 9.
• [5] Weighted correlation network and differential expression analyses identify candidate genes associated with BRAF gene in melanoma.BMC Med Genet. 2019 Mar 29;20(1):54. doi: 10.1186/s12881-019-0791-1.
• [6] Rab1 in cell signaling, cancer and other diseases.Oncogene. 2016 Nov 3;35(44):5699-5704. doi: 10.1038/onc.2016.81. Epub 2016 Apr 4.
• [7] Identification of genes potentially involved in the acquisition of androgen-independent and metastatic tumor growth in an autochthonous genetically engineered mouse prostate cancer model.Prostate. 2007 Jan 1;67(1):83-106. doi: 10.1002/pros.20505.
• [8] YAC contigs of the Rab1 and wobbler (wr) spinal muscular atrophy gene region on proximal mouse chromosome 11 and of the homologous region on human chromosome 2p.Genomics. 1996 Mar 15;32(3):447-54. doi: 10.1006/geno.1996.0140.
• [9] MiR-223 modulates hepatocellular carcinoma cell proliferation through promoting apoptosis via the Rab1-mediated mTOR activation.Biochem Biophys Res Commun. 2017 Jan 29;483(1):630-637. doi: 10.1016/j.bbrc.2016.12.091. Epub 2016 Dec 18.
• [10] 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.
• [11] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [12] Retinoic acid receptor alpha amplifications and retinoic acid sensitivity in breast cancers. Clin Breast Cancer. 2013 Oct;13(5):401-8.
• [13] 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.
• [14] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [15] 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.
• [16] 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.
• [17] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [18] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [19] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [20] Effects of progesterone treatment on expression of genes involved in uterine quiescence. Reprod Sci. 2011 Aug;18(8):781-97.
• [21] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [22] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [23] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [24] Gene expression profile induced by BCNU in human glioma cell lines with differential MGMT expression. J Neurooncol. 2005 Jul;73(3):189-98.
• [25] Differential expression of microRNAs and their predicted targets in renal cells exposed to amphotericin B and its complex with copper (II) ions. Toxicol Mech Methods. 2017 Sep;27(7):537-543. doi: 10.1080/15376516.2017.1333554. Epub 2017 Jun 8.
• [26] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [27] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [28] Comprehensive transcriptome profiling of BET inhibitor-treated HepG2 cells. PLoS One. 2022 Apr 29;17(4):e0266966. doi: 10.1371/journal.pone.0266966. eCollection 2022.
• [29] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [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] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.
• [32] Global changes in gene regulation demonstrate that unconjugated bilirubin is able to upregulate and activate select components of the endoplasmic reticulum stress response pathway. J Biochem Mol Toxicol. 2010 Mar-Apr;24(2):73-88.
• [33] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.