Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5SFQA3)

• DOT Name: RNA-binding protein 4 (RBM4)
• Synonyms: Lark homolog; hLark; RNA-binding motif protein 4; RNA-binding motif protein 4a
• Gene Name: RBM4
• Related Disease:
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Carcinoma of esophagus
  Esophageal cancer
  Gastric cancer
  Neoplasm of esophagus
  Stomach cancer
  Hepatocellular carcinoma
  Lung cancer
  Lung carcinoma
  High blood pressure
  Rectal carcinoma
  Tauopathy
• UniProt ID: RBM4_HUMAN
• PDB ID: 2DNQ
• Pfam ID: PF00076 ; PF00098
• Sequence:
  MVKLFIGNLPREATEQEIRSLFEQYGKVLECDIIKNYGFVHIEDKTAAEDAIRNLHHYKL
  HGVNINVEASKNKSKTSTKLHVGNISPTCTNKELRAKFEEYGPVIECDIVKDYAFVHMER
  AEDAVEAIRGLDNTEFQGKRMHVQLSTSRLRTAPGMGDQSGCYRCGKEGHWSKECPIDRS
  GRVADLTEQYNEQYGAVRTPYTMSYGDSLYYNNAYGALDAYYKRCRAARSYEAVAAAAAS
  VYNYAEQTLSQLPQVQNTAMASHLTSTSLDPYDRHLLPTSGAAATAAAAAAAAAAVTAAS
  TSYYGRDRSPLRRATAPVPTVGEGYGYGHESELSQASAAARNSLYDMARYEREQYADRAR
  YSAF
• Function: RNA-binding factor involved in multiple aspects of cellular processes like alternative splicing of pre-mRNA and translation regulation. Modulates alternative 5'-splice site and exon selection. Acts as a muscle cell differentiation-promoting factor. Activates exon skipping of the PTB pre-mRNA during muscle cell differentiation. Antagonizes the activity of the splicing factor PTBP1 to modulate muscle cell-specific exon selection of alpha tropomyosin. Binds to intronic pyrimidine-rich sequence of the TPM1 and MAPT pre-mRNAs. Required for the translational activation of PER1 mRNA in response to circadian clock. Binds directly to the 3'-UTR of the PER1 mRNA. Exerts a suppressive activity on Cap-dependent translation via binding to CU-rich responsive elements within the 3'UTR of mRNAs, a process increased under stress conditions or during myocytes differentiation. Recruits EIF4A1 to stimulate IRES-dependent translation initiation in respons to cellular stress. Associates to internal ribosome entry segment (IRES) in target mRNA species under stress conditions. Plays a role for miRNA-guided RNA cleavage and translation suppression by promoting association of AGO2-containing miRNPs with their cognate target mRNAs. Associates with miRNAs during muscle cell differentiation. Binds preferentially to 5'-CGCGCG[GCA]-3' motif in vitro.
• Tissue Specificity: Expressed in the cerebellum. Expressed in neurons and glial cells, including layers II neurons in the frontal cortex and CA1 pyramidal neurons in the hippocampus. Expressed in heart, liver, pancreas, skeletal muscle, placenta, primary fibroblasts and peripheral blood monocytes (at protein level). Ubiquitously expressed. Highly expressed in heart, placenta and skeletal muscle. Weakly expressed in pancreas, kidney, liver, lung and brain.
• Reactome Pathway: Circadian Clock (R-HSA-400253)

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Breast cancer	DIS7DPX1	Strong	Biomarker	[2]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[2]
Carcinoma of esophagus	DISS6G4D	Strong	Biomarker	[3]
Esophageal cancer	DISGB2VN	Strong	Biomarker	[3]
Gastric cancer	DISXGOUK	Strong	Biomarker	[4]
Neoplasm of esophagus	DISOLKAQ	Strong	Biomarker	[3]
Stomach cancer	DISKIJSX	Strong	Biomarker	[4]
Hepatocellular carcinoma	DIS0J828	moderate	Biomarker	[2]
Lung cancer	DISCM4YA	moderate	Biomarker	[2]
Lung carcinoma	DISTR26C	moderate	Biomarker	[2]
High blood pressure	DISY2OHH	Limited	Biomarker	[5]
Rectal carcinoma	DIS8FRR7	Limited	Altered Expression	[1]
Tauopathy	DISY2IPA	Limited	Altered Expression	[6]

13 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 RNA-binding protein 4 (RBM4).	[7]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of RNA-binding protein 4 (RBM4).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of RNA-binding protein 4 (RBM4).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of RNA-binding protein 4 (RBM4).	[10]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of RNA-binding protein 4 (RBM4).	[11]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of RNA-binding protein 4 (RBM4).	[12]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of RNA-binding protein 4 (RBM4).	[13]
Marinol	DM70IK5	Approved	Marinol decreases the expression of RNA-binding protein 4 (RBM4).	[14]
Selenium	DM25CGV	Approved	Selenium decreases the expression of RNA-binding protein 4 (RBM4).	[15]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of RNA-binding protein 4 (RBM4).	[16]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of RNA-binding protein 4 (RBM4).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of RNA-binding protein 4 (RBM4).	[20]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of RNA-binding protein 4 (RBM4).	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of RNA-binding protein 4 (RBM4).	[17]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of RNA-binding protein 4 (RBM4).	[18]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of RNA-binding protein 4 (RBM4).	[19]

References

• [1] Transcriptome-wide targets of alternative splicing by RBM4 and possible role in cancer.Genomics. 2016 Apr;107(4):138-44. doi: 10.1016/j.ygeno.2016.02.003. Epub 2016 Feb 17.
• [2] Decrease of RBM4 indicates poor prognosis in patients with hepatocellular carcinoma after hepatectomy.Onco Targets Ther. 2017 Jan 11;10:339-345. doi: 10.2147/OTT.S125250. eCollection 2017.
• [3] Natural antisense transcript TPM1-AS regulates the alternative splicing of tropomyosin I through an interaction with RNA-binding motif protein 4.Int J Biochem Cell Biol. 2017 Sep;90:59-67. doi: 10.1016/j.biocel.2017.07.017. Epub 2017 Jul 25.
• [4] RNA-Binding Motif 4 (RBM4) Suppresses Tumor Growth and Metastasis in Human Gastric Cancer.Med Sci Monit. 2019 May 30;25:4025-4034. doi: 10.12659/MSM.914513.
• [5] Community Health Workers Improve Linkage to Hypertension Care in WesternKenya.J Am Coll Cardiol. 2019 Oct 15;74(15):1897-1906. doi: 10.1016/j.jacc.2019.08.003. Epub 2019 Sep 2.
• [6] RBM4 interacts with an intronic element and stimulates tau exon 10 inclusion.J Biol Chem. 2006 Aug 25;281(34):24479-88. doi: 10.1074/jbc.M603971200. Epub 2006 Jun 15.
• [7] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [8] Proteomics investigations of drug-induced hepatotoxicity in HepG2 cells. Toxicol Sci. 2011 Mar;120(1):109-22.
• [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] 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.
• [12] Protein expression profiling identifies molecular targets of quercetin as a major dietary flavonoid in human colon cancer cells. Proteomics. 2004 Jul;4(7):2160-74.
• [13] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [14] JunD is involved in the antiproliferative effect of Delta9-tetrahydrocannabinol on human breast cancer cells. Oncogene. 2008 Aug 28;27(37):5033-44.
• [15] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [16] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [17] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [18] 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.
• [19] 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.
• [20] Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model. Environ Pollut. 2023 Oct 15;335:122359. doi: 10.1016/j.envpol.2023.122359. Epub 2023 Aug 9.
• [21] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.