Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT747D24)

• DOT Name: Iron-responsive element-binding protein 2 (IREB2)
• Synonyms: IRE-BP 2; Iron regulatory protein 2; IRP2
• Gene Name: IREB2
• Related Disease:
  Advanced cancer
  Alpha-1 antitrypsin deficiency
  Alzheimer disease
  Anemia
  Cerebellar ataxia
  Hepatocellular carcinoma
  Hereditary hyperferritinemia with congenital cataracts
  Hyperinsulinemia
  Inflammatory bowel disease
  IRIDA syndrome
  Iron metabolism disease
  Iron-deficiency anemia
  Lung adenocarcinoma
  Lung carcinoma
  Movement disorder
  Myopathy
  Neuroblastoma
  Neurodegeneration, early-onset, with choreoathetoid movements and microcytic anemia
  Non-small-cell lung cancer
  Osteoporosis
  Parkinson disease
  Prostate cancer
  Prostate carcinoma
  Pulmonary disease
  Colorectal carcinoma
  Vitamin A deficiency
  Cystitis
  Gastritis
  Hereditary hemochromatosis
  Lung cancer
  Urinary tract infection
• UniProt ID: IREB2_HUMAN
• PDB ID: 6VCD
• Pfam ID: PF00330 ; PF00694
• Sequence:
  MDAPKAGYAFEYLIETLNDSSHKKFFDVSKLGTKYDVLPYSIRVLLEAAVRNCDGFLMKK
  EDVMNILDWKTKQSNVEVPFFPARVLLQDFTGIPAMVDFAAMREAVKTLGGDPEKVHPAC
  PTDLTVDHSLQIDFSKCAIQNAPNPGGGDLQKAGKLSPLKVQPKKLPCRGQTTCRGSCDS
  GELGRNSGTFSSQIENTPILCPFHLQPVPEPETVLKNQEVEFGRNRERLQFFKWSSRVFK
  NVAVIPPGTGMAHQINLEYLSRVVFEEKDLLFPDSVVGTDSHITMVNGLGILGWGVGGIE
  TEAVMLGLPVSLTLPEVVGCELTGSSNPFVTSIDVVLGITKHLRQVGVAGKFVEFFGSGV
  SQLSIVDRTTIANMCPEYGAILSFFPVDNVTLKHLEHTGFSKAKLESMETYLKAVKLFRN
  DQNSSGEPEYSQVIQINLNSIVPSVSGPKRPQDRVAVTDMKSDFQACLNEKVGFKGFQIA
  AEKQKDIVSIHYEGSEYKLSHGSVVIAAVISCTNNCNPSVMLAAGLLAKKAVEAGLRVKP
  YIRTSLSPGSGMVTHYLSSSGVLPYLSKLGFEIVGYGCSICVGNTAPLSDAVLNAVKQGD
  LVTCGILSGNKNFEGRLCDCVRANYLASPPLVVAYAIAGTVNIDFQTEPLGTDPTGKNIY
  LHDIWPSREEVHRVEEEHVILSMFKALKDKIEMGNKRWNSLEAPDSVLFPWDLKSTYIRC
  PSFFDKLTKEPIALQAIENAHVLLYLGDSVTTDHISPAGSIARNSAAAKYLTNRGLTPRE
  FNSYGARRGNDAVMTRGTFANIKLFNKFIGKPAPKTIHFPSGQTLDVFEAAELYQKEGIP
  LIILAGKKYGSGNSRDWAAKGPYLLGVKAVLAESYEKIHKDHLIGIGIAPLQFLPGENAD
  SLGLSGRETFSLTFPEELSPGITLNIQTSTGKVFSVIASFEDDVEITLYKHGGLLNFVAR
  KFS
• Function: RNA-binding protein that binds to iron-responsive elements (IRES), which are stem-loop structures found in the 5'-UTR of ferritin, and delta aminolevulinic acid synthase mRNAs, and in the 3'-UTR of transferrin receptor mRNA. Binding to the IRE element in ferritin results in the repression of its mRNA translation. Binding of the protein to the transferrin receptor mRNA inhibits the degradation of this otherwise rapidly degraded mRNA.
• Reactome Pathway: Iron uptake and transport (R-HSA-917937)

Molecular Interaction Atlas (MIA) of This DOT

31 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[1]
Alpha-1 antitrypsin deficiency	DISQKEHW	Strong	Biomarker	[2]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[3]
Anemia	DISTVL0C	Strong	Biomarker	[4]
Cerebellar ataxia	DIS9IRAV	Strong	Biomarker	[5]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[6]
Hereditary hyperferritinemia with congenital cataracts	DISGL689	Strong	Genetic Variation	[7]
Hyperinsulinemia	DISIDWT6	Strong	Biomarker	[8]
Inflammatory bowel disease	DISGN23E	Strong	Biomarker	[9]
IRIDA syndrome	DISPN8YW	Strong	Biomarker	[10]
Iron metabolism disease	DISWDM9J	Strong	Biomarker	[11]
Iron-deficiency anemia	DIS0VQYF	Strong	Genetic Variation	[12]
Lung adenocarcinoma	DISD51WR	Strong	Altered Expression	[13]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[14]
Movement disorder	DISOJJ2D	Strong	Biomarker	[15]
Myopathy	DISOWG27	Strong	Biomarker	[16]
Neuroblastoma	DISVZBI4	Strong	Biomarker	[15]
Neurodegeneration, early-onset, with choreoathetoid movements and microcytic anemia	DISE0WDX	Strong	Autosomal recessive	[17]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[18]
Osteoporosis	DISF2JE0	Strong	Biomarker	[11]
Parkinson disease	DISQVHKL	Strong	Biomarker	[19]
Prostate cancer	DISF190Y	Strong	Biomarker	[20]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[20]
Pulmonary disease	DIS6060I	Strong	Biomarker	[21]
Colorectal carcinoma	DIS5PYL0	moderate	Altered Expression	[1]
Vitamin A deficiency	DISBEPZO	moderate	Biomarker	[22]
Cystitis	DIS2D4B9	Limited	Genetic Variation	[23]
Gastritis	DIS8G07K	Limited	Altered Expression	[24]
Hereditary hemochromatosis	DISVG5MT	Limited	Altered Expression	[25]
Lung cancer	DISCM4YA	Limited	Altered Expression	[14]
Urinary tract infection	DISMT6UV	Limited	Biomarker	[23]

3 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 Iron-responsive element-binding protein 2 (IREB2).	[26]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Iron-responsive element-binding protein 2 (IREB2).	[34]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Iron-responsive element-binding protein 2 (IREB2).	[35]

10 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 Iron-responsive element-binding protein 2 (IREB2).	[27]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Iron-responsive element-binding protein 2 (IREB2).	[28]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Iron-responsive element-binding protein 2 (IREB2).	[29]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Iron-responsive element-binding protein 2 (IREB2).	[30]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of Iron-responsive element-binding protein 2 (IREB2).	[31]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Iron-responsive element-binding protein 2 (IREB2).	[32]
Etoposide	DMNH3PG	Approved	Etoposide decreases the expression of Iron-responsive element-binding protein 2 (IREB2).	[29]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Iron-responsive element-binding protein 2 (IREB2).	[33]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Iron-responsive element-binding protein 2 (IREB2).	[36]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Iron-responsive element-binding protein 2 (IREB2).	[37]

References

• [1] BRAF mutations are associated with increased iron regulatory protein-2 expression in colorectal tumorigenesis.Cancer Sci. 2017 Jun;108(6):1135-1143. doi: 10.1111/cas.13234. Epub 2017 Jun 2.
• [2] Association of IREB2 and CHRNA3 polymorphisms with airflow obstruction in severe alpha-1 antitrypsin deficiency.Respir Res. 2012 Feb 22;13(1):16. doi: 10.1186/1465-9921-13-16.
• [3] Preliminary demonstration of an allelic association of the IREB2 gene with Alzheimer's disease.J Alzheimers Dis. 2006 Aug;9(3):225-33. doi: 10.3233/jad-2006-9301.
• [4] Iron-regulatory proteins secure iron availability in cardiomyocytes to prevent heart failure.Eur Heart J. 2017 Feb 1;38(5):362-372. doi: 10.1093/eurheartj/ehw333.
• [5] Hereditary causes of disturbed iron homeostasis in the central nervous system.Ann N Y Acad Sci. 2004 Mar;1012:267-81. doi: 10.1196/annals.1306.022.
• [6] Effect of hypoxia on the binding and subcellular distribution of iron regulatory proteins.Mol Cell Biochem. 2007 Jul;301(1-2):21-32. doi: 10.1007/s11010-006-9393-2. Epub 2007 Jan 3.
• [7] A case report of spontaneous mutation (C33>U) in the iron-responsive element of L-ferritin causing hyperferritinemia-cataract syndrome.Blood Cells Mol Dis. 2010 Jan 15;44(1):22-7. doi: 10.1016/j.bcmd.2009.09.003. Epub 2009 Oct 2.
• [8] Hyperinsulinemia induces hepatic iron overload by increasing liver TFR1 via the PI3K/IRP2 pathway.J Mol Endocrinol. 2014 Dec;53(3):381-92. doi: 10.1530/JME-14-0122.
• [9] Comparative genomics of a subset of Adherent/Invasive Escherichia coli strains isolated from individuals without inflammatory bowel disease.Genomics. 2020 Mar;112(2):1813-1820. doi: 10.1016/j.ygeno.2019.10.013. Epub 2019 Nov 2.
• [10] Methods for Studying Iron Regulatory Protein 1: An Important Protein in Human Iron Metabolism.Methods Enzymol. 2018;599:139-155. doi: 10.1016/bs.mie.2017.09.006. Epub 2017 Dec 6.
• [11] Irp2 Knockout Causes Osteoporosis by Inhibition of Bone Remodeling.Calcif Tissue Int. 2019 Jan;104(1):70-78. doi: 10.1007/s00223-018-0469-2. Epub 2018 Sep 6.
• [12] Absence of iron-responsive element-binding protein 2 causes a novel neurodegenerative syndrome.Brain. 2019 May 1;142(5):1195-1202. doi: 10.1093/brain/awz072.
• [13] Transcription deregulation at the 15q25 locus in association with lung adenocarcinoma risk.Clin Cancer Res. 2009 Mar 1;15(5):1837-42. doi: 10.1158/1078-0432.CCR-08-2107. Epub 2009 Feb 17.
• [14] Transcriptome-wide association study reveals candidate causal genes for lung cancer.Int J Cancer. 2020 Apr 1;146(7):1862-1878. doi: 10.1002/ijc.32771. Epub 2019 Dec 9.
• [15] Oxidative Stress Regulated Iron Regulatory Protein IRP2 Through FBXL5-Mediated Ubiquitination-Proteasome Way in SH-SY5Y Cells.Front Neurosci. 2019 Jan 29;13:20. doi: 10.3389/fnins.2019.00020. eCollection 2019.
• [16] Posttranslational stability of the heme biosynthetic enzyme ferrochelatase is dependent on iron availability and intact iron-sulfur cluster assembly machinery.Blood. 2010 Jan 28;115(4):860-9. doi: 10.1182/blood-2009-09-243105. Epub 2009 Nov 25.
• [17] Targeted deletion of the gene encoding iron regulatory protein-2 causes misregulation of iron metabolism and neurodegenerative disease in mice. Nat Genet. 2001 Feb;27(2):209-14. doi: 10.1038/84859.
• [18] IRP2 as a potential modulator of cell proliferation, apoptosis and prognosis in nonsmall cell lung cancer.Eur Respir J. 2017 Apr 12;49(4):1600711. doi: 10.1183/13993003.00711-2016. Print 2017 Apr.
• [19] Possible involvement of iron-induced oxidative insults in neurodegeneration.Neurosci Lett. 2015 Feb 19;588:29-35. doi: 10.1016/j.neulet.2014.12.052. Epub 2014 Dec 27.
• [20] Iron-responsive element-binding protein 2 plays an essential role in regulating prostate cancer cell growth.Oncotarget. 2017 Jul 17;8(47):82231-82243. doi: 10.18632/oncotarget.19288. eCollection 2017 Oct 10.
• [21] Susceptibility loci in lung cancer and COPD: association of IREB2 and FAM13A with pulmonary diseases.Sci Rep. 2015 Aug 27;5:13502. doi: 10.1038/srep13502.
• [22] Vitamin A deficiency aggravates iron deficiency by upregulating the expression of iron regulatory protein-2.Nutrition. 2012 Mar;28(3):281-7. doi: 10.1016/j.nut.2011.08.015. Epub 2011 Dec 9.
• [23] Contribution of yersiniabactin to the virulence of an Escherichia coli sequence type 69 ("clonal group A") cystitis isolate in murine models of urinary tract infection and sepsis.Microb Pathog. 2018 Jul;120:128-131. doi: 10.1016/j.micpath.2018.04.048. Epub 2018 Apr 24.
• [24] The role of transferrin receptor in the Helicobacter pylori pathogenesis; L-ferritin as a novel marker for intestinal metaplasia.Microb Pathog. 2019 Jan;126:157-164. doi: 10.1016/j.micpath.2018.10.039. Epub 2018 Oct 31.
• [25] Iron regulatory proteins 1 and 2 in human monocytes, macrophages and duodenum: expression and regulation in hereditary hemochromatosis and iron deficiency.Haematologica. 2006 Mar;91(3):303-10. Epub 2006 Feb 17.
• [26] 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.
• [27] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [28] 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.
• [29] Lysosome Fe(2+) release is responsible for etoposide- and cisplatin-induced stemness of small cell lung cancer cells. Environ Toxicol. 2021 Aug;36(8):1654-1663. doi: 10.1002/tox.23161. Epub 2021 May 10.
• [30] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [31] Multi-level gene expression profiles affected by thymidylate synthase and 5-fluorouracil in colon cancer. BMC Genomics. 2006 Apr 3;7:68. doi: 10.1186/1471-2164-7-68.
• [32] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [33] 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.
• [34] 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.
• [35] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [36] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [37] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.