Details of Drug Off-Target (DOT)

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

• DOT Name: Cold-inducible RNA-binding protein (CIRBP)
• Synonyms: A18 hnRNP; Glycine-rich RNA-binding protein CIRP
• Gene Name: CIRBP
• Related Disease:
  Acute monocytic leukemia
  Adenoma
  Adult acute monocytic leukemia
  Adult respiratory distress syndrome
  Advanced cancer
  Autism spectrum disorder
  Bladder cancer
  Breast cancer
  Breast carcinoma
  Carcinoma of liver and intrahepatic biliary tract
  Cardiac failure
  Colon cancer
  Colon carcinoma
  Congestive heart failure
  Cushing disease
  Endometrial cancer
  Endometrial carcinoma
  Hepatitis C virus infection
  Hepatocellular carcinoma
  Knee osteoarthritis
  Liver cancer
  Neonatal sepsis
  Osteoarthritis
  Pituitary gland disorder
  Pneumonia
  Pneumonitis
  Prostate cancer
  Prostate carcinoma
  Skin cancer
  Urinary bladder cancer
  Urinary bladder neoplasm
  Chronic obstructive pulmonary disease
  Clear cell renal carcinoma
  Coronary atherosclerosis
  High blood pressure
  Renal cell carcinoma
  Rheumatoid arthritis
  Myocardial ischemia
  Nasopharyngeal carcinoma
  Neoplasm
  Undifferentiated carcinoma
• UniProt ID: CIRBP_HUMAN
• PDB ID: 1X5S; 5TBX
• Pfam ID: PF00076
• Sequence:
  MASDEGKLFVGGLSFDTNEQSLEQVFSKYGQISEVVVVKDRETQRSRGFGFVTFENIDDA
  KDAMMAMNGKSVDGRQIRVDQAGKSSDNRSRGYRGGSAGGRGFFRGGRGRGRGFSRGGGD
  RGYGGNRFESRSGGYGGSRDYYSSRSQSGGYSDRSSGGSYRDSYDSYATHNE
• Function: Cold-inducible mRNA binding protein that plays a protective role in the genotoxic stress response by stabilizing transcripts of genes involved in cell survival. Acts as a translational activator. Seems to play an essential role in cold-induced suppression of cell proliferation. Binds specifically to the 3'-untranslated regions (3'-UTRs) of stress-responsive transcripts RPA2 and TXN. Acts as a translational repressor. Promotes assembly of stress granules (SGs), when overexpressed.
• Tissue Specificity: Ubiquitous.

Molecular Interaction Atlas (MIA) of This DOT

41 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute monocytic leukemia	DIS28NEL	Strong	Altered Expression	[1]
Adenoma	DIS78ZEV	Strong	Altered Expression	[2]
Adult acute monocytic leukemia	DISG6BLX	Strong	Altered Expression	[1]
Adult respiratory distress syndrome	DISIJV47	Strong	Biomarker	[3]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[4]
Autism spectrum disorder	DISXK8NV	Strong	Biomarker	[5]
Bladder cancer	DISUHNM0	Strong	Biomarker	[6]
Breast cancer	DIS7DPX1	Strong	Biomarker	[7]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[7]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Strong	Biomarker	[8]
Cardiac failure	DISDC067	Strong	Altered Expression	[9]
Colon cancer	DISVC52G	Strong	Biomarker	[10]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[10]
Congestive heart failure	DIS32MEA	Strong	Altered Expression	[9]
Cushing disease	DISOG6P2	Strong	Biomarker	[11]
Endometrial cancer	DISW0LMR	Strong	Biomarker	[7]
Endometrial carcinoma	DISXR5CY	Strong	Biomarker	[7]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[12]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[8]
Knee osteoarthritis	DISLSNBJ	Strong	Biomarker	[13]
Liver cancer	DISDE4BI	Strong	Biomarker	[8]
Neonatal sepsis	DIS8Q3VE	Strong	Biomarker	[14]
Osteoarthritis	DIS05URM	Strong	Biomarker	[15]
Pituitary gland disorder	DIS7XB48	Strong	Altered Expression	[11]
Pneumonia	DIS8EF3M	Strong	Biomarker	[16]
Pneumonitis	DIS88E0K	Strong	Biomarker	[16]
Prostate cancer	DISF190Y	Strong	Biomarker	[17]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[17]
Skin cancer	DISTM18U	Strong	Biomarker	[18]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[6]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[6]
Chronic obstructive pulmonary disease	DISQCIRF	moderate	Altered Expression	[19]
Clear cell renal carcinoma	DISBXRFJ	moderate	Altered Expression	[20]
Coronary atherosclerosis	DISKNDYU	moderate	Biomarker	[21]
High blood pressure	DISY2OHH	moderate	Biomarker	[22]
Renal cell carcinoma	DISQZ2X8	moderate	Altered Expression	[20]
Rheumatoid arthritis	DISTSB4J	moderate	Biomarker	[15]
Myocardial ischemia	DISFTVXF	Limited	Biomarker	[21]
Nasopharyngeal carcinoma	DISAOTQ0	Limited	Altered Expression	[4]
Neoplasm	DISZKGEW	Limited	Altered Expression	[4]
Undifferentiated carcinoma	DISIAZST	Limited	Altered Expression	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Cold-inducible RNA-binding protein (CIRBP).	[23]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Cold-inducible RNA-binding protein (CIRBP).	[35]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Cold-inducible RNA-binding protein (CIRBP).	[24]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Cold-inducible RNA-binding protein (CIRBP).	[25]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Cold-inducible RNA-binding protein (CIRBP).	[26]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Cold-inducible RNA-binding protein (CIRBP).	[27]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Cold-inducible RNA-binding protein (CIRBP).	[28]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Cold-inducible RNA-binding protein (CIRBP).	[29]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Cold-inducible RNA-binding protein (CIRBP).	[30]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Cold-inducible RNA-binding protein (CIRBP).	[31]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Cold-inducible RNA-binding protein (CIRBP).	[32]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of Cold-inducible RNA-binding protein (CIRBP).	[33]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Cold-inducible RNA-binding protein (CIRBP).	[34]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Cold-inducible RNA-binding protein (CIRBP).	[36]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Cold-inducible RNA-binding protein (CIRBP).	[37]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Cold-inducible RNA-binding protein (CIRBP).	[38]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Cold-inducible RNA-binding protein (CIRBP).	[39]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Cold-inducible RNA-binding protein (CIRBP).	[40]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Cold-inducible RNA-binding protein (CIRBP).	[41]
GALLICACID	DM6Y3A0	Investigative	GALLICACID increases the expression of Cold-inducible RNA-binding protein (CIRBP).	[42]

References

• [1] Effect of moderate hypothermia on gene expression by THP-1 cells: a DNA microarray study.Physiol Genomics. 2006 Jun 16;26(1):91-8. doi: 10.1152/physiolgenomics.00296.2005. Epub 2006 Apr 4.
• [2] Expression of cold-inducible RNA-binding protein (CIRP) in pituitary adenoma and its relationships with tumor recurrence.Med Sci Monit. 2015 May 2;21:1256-60. doi: 10.12659/MSM.893128.
• [3] Deficiency in cold-inducible RNA-binding protein attenuates acute respiratory distress syndrome induced by intestinal ischemia-reperfusion.Surgery. 2017 Oct;162(4):917-927. doi: 10.1016/j.surg.2017.06.004. Epub 2017 Jul 11.
• [4] Loss of Cirbp expression is correlated with the malignant progression and poor prognosis in nasopharyngeal carcinoma.Cancer Manag Res. 2019 Jul 24;11:6959-6969. doi: 10.2147/CMAR.S211389. eCollection 2019.
• [5] Disrupted brain thyroid hormone homeostasis and altered thyroid hormone-dependent brain gene expression in autism spectrum disorders.J Physiol Pharmacol. 2014 Apr;65(2):257-72.
• [6] CIRBP is a novel oncogene in human bladder cancer inducing expression of HIF-1.Cell Death Dis. 2018 Oct 12;9(10):1046. doi: 10.1038/s41419-018-1109-5.
• [7] Cold-inducible RNA-binding protein contributes to human antigen R and cyclin E1 deregulation in breast cancer.Mol Carcinog. 2010 Feb;49(2):130-40. doi: 10.1002/mc.20582.
• [8] Cold-inducible RNA-binding protein promotes the development of liver cancer.Cancer Sci. 2015 Apr;106(4):352-8. doi: 10.1111/cas.12611. Epub 2015 Mar 3.
• [9] CIRP downregulation renders cardiac cells prone to apoptosis in heart failure.Biochem Biophys Res Commun. 2019 Oct 1;517(4):545-550. doi: 10.1016/j.bbrc.2019.05.012. Epub 2019 Aug 9.
• [10] Expression of RNA-binding Motif Protein 3 (RBM3) and Cold-inducible RNA-binding protein (CIRP) Is Associated with Improved Clinical Outcome in Patients with Colon Cancer.Anticancer Res. 2017 Apr;37(4):1779-1785. doi: 10.21873/anticanres.11511.
• [11] Cold inducible RNA binding protein upregulation in pituitary corticotroph adenoma induces corticotroph cell proliferation via Erk signaling pathway.Oncotarget. 2016 Feb 23;7(8):9175-87. doi: 10.18632/oncotarget.7037.
• [12] Altered m(6)A Modification of Specific Cellular Transcripts Affects Flaviviridae Infection.Mol Cell. 2020 Feb 6;77(3):542-555.e8. doi: 10.1016/j.molcel.2019.11.007. Epub 2019 Dec 3.
• [13] Synovial fluid concentrations of cold-inducible RNA-binding protein are associated with severity in knee osteoarthritis.Clin Chim Acta. 2017 Jan;464:44-49. doi: 10.1016/j.cca.2016.11.016. Epub 2016 Nov 10.
• [14] C23, an oligopeptide derived from cold-inducible RNA-binding protein, suppresses inflammation and reduces lung injury in neonatal sepsis.J Pediatr Surg. 2019 Oct;54(10):2053-2060. doi: 10.1016/j.jpedsurg.2018.12.020. Epub 2019 Jan 4.
• [15] Serum and synovial fluid concentrations of cold-inducible RNA-binding protein in patients with rheumatoid arthritis.Int J Rheum Dis. 2018 Jan;21(1):148-154. doi: 10.1111/1756-185X.12892. Epub 2016 Jun 17.
• [16] Attenuation of hemorrhage-associated lung injury by adjuvant treatment with C23, an oligopeptide derived from cold-inducible RNA-binding protein.J Trauma Acute Care Surg. 2017 Oct;83(4):690-697. doi: 10.1097/TA.0000000000001566.
• [17] Down-regulating cold shock protein genes impairs cancer cell survival and enhances chemosensitivity.J Cell Biochem. 2009 May 1;107(1):179-88. doi: 10.1002/jcb.22114.
• [18] The mechanism of CIRP in inhibition of keratinocytes growth arrest and apoptosis following low dose UVB radiation.Mol Carcinog. 2017 Jun;56(6):1554-1569. doi: 10.1002/mc.22597. Epub 2017 Jan 5.
• [19] Cold-inducible RNA-binding protein mediates airway inflammation and mucus hypersecretion through a post-transcriptional regulatory mechanism under cold stress.Int J Biochem Cell Biol. 2016 Sep;78:335-348. doi: 10.1016/j.biocel.2016.07.029. Epub 2016 Jul 28.
• [20] Expression of cold-inducible RNA-binding protein (CIRP) in renal cell carcinoma and the effect of CIRP downregulation cell proliferation and chemosensitivity to gemcitabine.Oncol Lett. 2018 May;15(5):7611-7616. doi: 10.3892/ol.2018.8338. Epub 2018 Mar 23.
• [21] CIRBP protects H9C2 cells against myocardial ischemia through inhibition of NF-B pathway.Braz J Med Biol Res. 2017 Mar 23;50(4):e5861. doi: 10.1590/1414-431X20175861.
• [22] Cross Talk Between Mitochondrial Reactive Oxygen Species and Sarcoplasmic Reticulum Calcium in Pulmonary Arterial Smooth Muscle Cells.Adv Exp Med Biol. 2017;967:289-298. doi: 10.1007/978-3-319-63245-2_17.
• [23] 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.
• [24] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [25] 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.
• [26] 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.
• [27] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [28] 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.
• [29] 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.
• [30] 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.
• [31] 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.
• [32] 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.
• [33] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [34] 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.
• [35] 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.
• [36] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [37] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [38] 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.
• [39] 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.
• [40] Gene expression profiling in Ishikawa cells: a fingerprint for estrogen active compounds. Toxicol Appl Pharmacol. 2009 Apr 1;236(1):85-96.
• [41] Transcriptomic alterations induced by Ochratoxin A in rat and human renal proximal tubular in vitro models and comparison to a rat in vivo model. Arch Toxicol. 2012 Apr;86(4):571-89.
• [42] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.