Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5OY8BO)

• DOT Name: Immediate early response gene 2 protein (IER2)
• Synonyms: Protein ETR101
• Gene Name: IER2
• Related Disease:
  Advanced cancer
  Lung cancer
  Lung neoplasm
  Neoplasm
  Systemic lupus erythematosus
  Venous thromboembolism
• UniProt ID: IER2_HUMAN
• Pfam ID: PF05760
• Sequence:
  MEVQKEAQRIMTLSVWKMYHSRMQRGGLRLHRSLQLSLVMRSARELYLSAKVEALEPEVS
  LPAALPSDPRLHPPREAESTAETATPDGEHPFPEPMDTQEAPTAEETSACCAPRPAKVSR
  KRRSSSLSDGGDAGLVPSKKARLEEKEEEEGASSEVADRLQPPPAQAEGAFPNLARVLQR
  RFSGLLNCSPAAPPTAPPACEAKPACRPADSMLNVLVRAVVAF
• Function: DNA-binding protein that seems to act as a transcription factor. Involved in the regulation of neuronal differentiation, acts upon JNK-signaling pathway activation and plays a role in neurite outgrowth in hippocampal cells. May mediate with FIBP FGF-signaling in the establishment of laterality in the embryo. Promotes cell motility, seems to stimulate tumor metastasis.
• Tissue Specificity: Expressed in activated T-cells (at protein level) . Expression increases in metastatic tumor cells (at protein level) .

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Lung cancer	DISCM4YA	Strong	Biomarker	[2]
Lung neoplasm	DISVARNB	Strong	Biomarker	[2]
Neoplasm	DISZKGEW	Strong	Biomarker	[1]
Systemic lupus erythematosus	DISI1SZ7	Strong	Altered Expression	[3]
Venous thromboembolism	DISUR7CR	Strong	Genetic Variation	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Immediate early response gene 2 protein (IER2).	[5]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Immediate early response gene 2 protein (IER2).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Immediate early response gene 2 protein (IER2).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Immediate early response gene 2 protein (IER2).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Immediate early response gene 2 protein (IER2).	[9]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Immediate early response gene 2 protein (IER2).	[10]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Immediate early response gene 2 protein (IER2).	[11]
Arsenic	DMTL2Y1	Approved	Arsenic increases the expression of Immediate early response gene 2 protein (IER2).	[12]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Immediate early response gene 2 protein (IER2).	[13]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide affects the expression of Immediate early response gene 2 protein (IER2).	[14]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Immediate early response gene 2 protein (IER2).	[15]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Immediate early response gene 2 protein (IER2).	[5]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Immediate early response gene 2 protein (IER2).	[16]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Immediate early response gene 2 protein (IER2).	[17]
Azathioprine	DMMZSXQ	Approved	Azathioprine increases the expression of Immediate early response gene 2 protein (IER2).	[18]
Bexarotene	DMOBIKY	Approved	Bexarotene decreases the expression of Immediate early response gene 2 protein (IER2).	[19]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Immediate early response gene 2 protein (IER2).	[20]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Immediate early response gene 2 protein (IER2).	[21]
Afimoxifene	DMFORDT	Phase 2	Afimoxifene increases the expression of Immediate early response gene 2 protein (IER2).	[11]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate increases the expression of Immediate early response gene 2 protein (IER2).	[22]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Immediate early response gene 2 protein (IER2).	[24]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Immediate early response gene 2 protein (IER2).	[25]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Immediate early response gene 2 protein (IER2).	[26]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride increases the expression of Immediate early response gene 2 protein (IER2).	[27]
ELLAGIC ACID	DMX8BS5	Investigative	ELLAGIC ACID increases the expression of Immediate early response gene 2 protein (IER2).	[21]

1 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 Immediate early response gene 2 protein (IER2).	[23]

References

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• [2] Bronchial airway gene expression signatures in mouse lung squamous cell carcinoma and their modulation by cancer chemopreventive agents.Oncotarget. 2017 Mar 21;8(12):18885-18900. doi: 10.18632/oncotarget.13806.
• [3] Gene profiling involved in immature CD4+ T lymphocyte responsible for systemic lupus erythematosus.Mol Immunol. 2006 Mar;43(9):1497-507. doi: 10.1016/j.molimm.2005.07.039. Epub 2005 Sep 6.
• [4] Genomic and transcriptomic association studies identify 16 novel susceptibility loci for venous thromboembolism.Blood. 2019 Nov 7;134(19):1645-1657. doi: 10.1182/blood.2019000435.
• [5] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [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] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [11] Estrogenic GPR30 signalling induces proliferation and migration of breast cancer cells through CTGF. EMBO J. 2009 Mar 4;28(5):523-32.
• [12] Activation of inflammation/NF-kappaB signaling in infants born to arsenic-exposed mothers. PLoS Genet. 2007 Nov;3(11):e207.
• [13] 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.
• [14] Patterns of gene expressions induced by arsenic trioxide in cultured human fibroblasts. Toxicol Lett. 2003 Jul 20;143(2):155-62. doi: 10.1016/s0378-4274(03)00171-1.
• [15] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [16] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [17] Single-cell Transcriptome Mapping Identifies Common and Cell-type Specific Genes Affected by Acute Delta9-tetrahydrocannabinol in Humans. Sci Rep. 2020 Feb 26;10(1):3450. doi: 10.1038/s41598-020-59827-1.
• [18] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [19] Identification of biomarkers modulated by the rexinoid LGD1069 (bexarotene) in human breast cells using oligonucleotide arrays. Cancer Res. 2006 Dec 15;66(24):12009-18.
• [20] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [21] Interactive gene expression pattern in prostate cancer cells exposed to phenolic antioxidants. Life Sci. 2002 Mar 1;70(15):1821-39.
• [22] Expression of endogenous retroviruses reflects increased usage of atypical enhancers in T cells. EMBO J. 2019 Jun 17;38(12):e101107. doi: 10.15252/embj.2018101107. Epub 2019 May 8.
• [23] 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.
• [24] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [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] Regulation of chromatin assembly and cell transformation by formaldehyde exposure in human cells. Environ Health Perspect. 2017 Sep 21;125(9):097019.
• [27] Classification of heavy-metal toxicity by human DNA microarray analysis. Environ Sci Technol. 2007 May 15;41(10):3769-74.