Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTB3JFH4)

DOT Name Transcription factor E2F4 (E2F4)
Synonyms E2F-4
Gene Name E2F4
Related Disease
Myocardial infarction ( )
Abdominal aortic aneurysm ( )
Acute erythroid leukemia ( )
Acute myelogenous leukaemia ( )
Adenoma ( )
Adult T-cell leukemia/lymphoma ( )
Astrocytoma ( )
Bladder cancer ( )
Breast cancer ( )
Breast carcinoma ( )
Breast neoplasm ( )
Burkitt lymphoma ( )
Carcinoma ( )
Childhood acute lymphoblastic leukemia ( )
Ciliopathy ( )
Colon cancer ( )
Colon carcinoma ( )
Colonic neoplasm ( )
Colorectal neoplasm ( )
Epithelial ovarian cancer ( )
Ewing sarcoma ( )
Hepatocellular carcinoma ( )
Intervertebral disc degeneration ( )
Lung adenocarcinoma ( )
Lung neoplasm ( )
Neoplasm ( )
Oropharyngeal carcinoma ( )
Otitis media ( )
Prostate cancer ( )
Pulmonary fibrosis ( )
Squamous cell carcinoma ( )
T-cell leukaemia ( )
Urinary bladder cancer ( )
Urinary bladder neoplasm ( )
Liposarcoma ( )
Adenocarcinoma ( )
Advanced cancer ( )
Colorectal adenocarcinoma ( )
Colorectal adenoma ( )
Colorectal carcinoma ( )
Digestive system neoplasm ( )
Gastric neoplasm ( )
Microphthalmia ( )
Neuroblastoma ( )
Prostate carcinoma ( )
Retinoblastoma ( )
Thyroid gland papillary carcinoma ( )
UniProt ID
E2F4_HUMAN
3D Structure
Download
2D Sequence (FASTA)
Download
3D Structure (PDB)
Download
PDB ID
1CF7; 5TUU
Pfam ID
PF16421 ; PF02319
Sequence
MAEAGPQAPPPPGTPSRHEKSLGLLTTKFVSLLQEAKDGVLDLKLAADTLAVRQKRRIYD
ITNVLEGIGLIEKKSKNSIQWKGVGPGCNTREIADKLIELKAEIEELQQREQELDQHKVW
VQQSIRNVTEDVQNSCLAYVTHEDICRCFAGDTLLAIRAPSGTSLEVPIPEGLNGQKKYQ
IHLKSVSGPIEVLLVNKEAWSSPPVAVPVPPPEDLLQSPSAVSTPPPLPKPALAQSQEAS
RPNSPQLTPTAVPGSAEVQGMAGPAAEITVSGGPGTDSKDSGELSSLPLGPTTLDTRPLQ
SSALLDSSSSSSSSSSSSSNSNSSSSSGPNPSTSFEPIKADPTGVLELPKELSEIFDPTR
ECMSSELLEELMSSEVFAPLLRLSPPPGDHDYIYNLDESEGVCDLFDVPVLNL
Function
Transcription activator that binds DNA cooperatively with DP proteins through the E2 recognition site, 5'-TTTC[CG]CGC-3' found in the promoter region of a number of genes whose products are involved in cell cycle regulation or in DNA replication. The DRTF1/E2F complex functions in the control of cell-cycle progression from G1 to S phase. E2F4 binds with high affinity to RBL1 and RBL2. In some instances can also bind RB1. Specifically required for multiciliate cell differentiation: together with MCIDAS and E2F5, binds and activate genes required for centriole biogenesis.
Tissue Specificity Found in all tissue examined including heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas.
KEGG Pathway
Cell cycle (hsa04110 )
Cellular senescence (hsa04218 )
TGF-beta sig.ling pathway (hsa04350 )
Reactome Pathway
Transcription of E2F targets under negative control by p107 (RBL1) and p130 (RBL2) in complex with HDAC1 (R-HSA-1362300 )
G0 and Early G1 (R-HSA-1538133 )
SMAD2/SMAD3 (R-HSA-2173796 )
TP53 Regulates Transcription of Genes Involved in G2 Cell Cycle Arrest (R-HSA-6804114 )
Cyclin E associated events during G1/S transition (R-HSA-69202 )
G1/S-Specific Transcription (R-HSA-69205 )
Cyclin D associated events in G1 (R-HSA-69231 )
Cyclin A (R-HSA-69656 )
Transcription of E2F targets under negative control by DREAM complex (R-HSA-1362277 )

Molecular Interaction Atlas (MIA) of This DOT

47 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
Myocardial infarction DIS655KI Definitive Genetic Variation [1]
Abdominal aortic aneurysm DISD06OF Strong Altered Expression [2]
Acute erythroid leukemia DISZFC1O Strong Biomarker [3]
Acute myelogenous leukaemia DISCSPTN Strong Genetic Variation [4]
Adenoma DIS78ZEV Strong Biomarker [5]
Adult T-cell leukemia/lymphoma DIS882XU Strong Genetic Variation [4]
Astrocytoma DISL3V18 Strong Biomarker [6]
Bladder cancer DISUHNM0 Strong Biomarker [7]
Breast cancer DIS7DPX1 Strong Biomarker [8]
Breast carcinoma DIS2UE88 Strong Biomarker [8]
Breast neoplasm DISNGJLM Strong Altered Expression [9]
Burkitt lymphoma DIS9D5XU Strong Biomarker [10]
Carcinoma DISH9F1N Strong Genetic Variation [11]
Childhood acute lymphoblastic leukemia DISJ5D6U Strong Genetic Variation [4]
Ciliopathy DIS10G4I Strong Biomarker [12]
Colon cancer DISVC52G Strong Biomarker [13]
Colon carcinoma DISJYKUO Strong Biomarker [13]
Colonic neoplasm DISSZ04P Strong Genetic Variation [14]
Colorectal neoplasm DISR1UCN Strong Genetic Variation [15]
Epithelial ovarian cancer DIS56MH2 Strong Biomarker [16]
Ewing sarcoma DISQYLV3 Strong Altered Expression [17]
Hepatocellular carcinoma DIS0J828 Strong Biomarker [18]
Intervertebral disc degeneration DISG3AIM Strong Altered Expression [19]
Lung adenocarcinoma DISD51WR Strong Altered Expression [20]
Lung neoplasm DISVARNB Strong Genetic Variation [21]
Neoplasm DISZKGEW Strong Genetic Variation [22]
Oropharyngeal carcinoma DIS7K3AI Strong Altered Expression [23]
Otitis media DISGZDUO Strong Biomarker [24]
Prostate cancer DISF190Y Strong Biomarker [25]
Pulmonary fibrosis DISQKVLA Strong Biomarker [26]
Squamous cell carcinoma DISQVIFL Strong Biomarker [27]
T-cell leukaemia DISJ6YIF Strong Genetic Variation [4]
Urinary bladder cancer DISDV4T7 Strong Biomarker [7]
Urinary bladder neoplasm DIS7HACE Strong Biomarker [7]
Liposarcoma DIS8IZVM moderate Altered Expression [28]
Adenocarcinoma DIS3IHTY Limited Biomarker [27]
Advanced cancer DISAT1Z9 Limited Biomarker [29]
Colorectal adenocarcinoma DISPQOUB Limited Altered Expression [30]
Colorectal adenoma DISTSVHM Limited Altered Expression [31]
Colorectal carcinoma DIS5PYL0 Limited Genetic Variation [15]
Digestive system neoplasm DISPOJCT Limited Genetic Variation [32]
Gastric neoplasm DISOKN4Y Limited Genetic Variation [32]
Microphthalmia DISGEBES Limited Altered Expression [33]
Neuroblastoma DISVZBI4 Limited Biomarker [34]
Prostate carcinoma DISMJPLE Limited Biomarker [35]
Retinoblastoma DISVPNPB Limited Biomarker [36]
Thyroid gland papillary carcinoma DIS48YMM Limited Biomarker [37]
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⏷ Show the Full List of 47 Disease(s)
Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
3 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 Transcription factor E2F4 (E2F4). [38]
Benzo(a)pyrene DMN7J43 Phase 1 Benzo(a)pyrene increases the methylation of Transcription factor E2F4 (E2F4). [48]
PMID28870136-Compound-52 DMFDERP Patented PMID28870136-Compound-52 increases the phosphorylation of Transcription factor E2F4 (E2F4). [50]
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14 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 Transcription factor E2F4 (E2F4). [39]
Doxorubicin DMVP5YE Approved Doxorubicin decreases the expression of Transcription factor E2F4 (E2F4). [40]
Estradiol DMUNTE3 Approved Estradiol increases the expression of Transcription factor E2F4 (E2F4). [41]
Arsenic trioxide DM61TA4 Approved Arsenic trioxide increases the expression of Transcription factor E2F4 (E2F4). [42]
Selenium DM25CGV Approved Selenium increases the expression of Transcription factor E2F4 (E2F4). [43]
Fluorouracil DMUM7HZ Approved Fluorouracil decreases the expression of Transcription factor E2F4 (E2F4). [44]
Rosiglitazone DMILWZR Approved Rosiglitazone decreases the expression of Transcription factor E2F4 (E2F4). [45]
Genistein DM0JETC Phase 2/3 Genistein decreases the expression of Transcription factor E2F4 (E2F4). [46]
phorbol 12-myristate 13-acetate DMJWD62 Phase 2 phorbol 12-myristate 13-acetate increases the expression of Transcription factor E2F4 (E2F4). [47]
PMID28460551-Compound-2 DM4DOUB Patented PMID28460551-Compound-2 increases the expression of Transcription factor E2F4 (E2F4). [49]
Eugenol DM7US1H Patented Eugenol decreases the expression of Transcription factor E2F4 (E2F4). [51]
Bisphenol A DM2ZLD7 Investigative Bisphenol A affects the expression of Transcription factor E2F4 (E2F4). [52]
Glyphosate DM0AFY7 Investigative Glyphosate decreases the expression of Transcription factor E2F4 (E2F4). [53]
Dibutyl phthalate DMEDGKO Investigative Dibutyl phthalate increases the expression of Transcription factor E2F4 (E2F4). [54]
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⏷ Show the Full List of 14 Drug(s)

References

1 Close correlation between mutations of E2F4 and hMSH3 genes in colorectal cancers with microsatellite instability.Cancer Res. 1998 Feb 15;58(4):594-8.
2 Identification of key genes associated with the human abdominal aortic aneurysm based on the gene expression profile.Mol Med Rep. 2015 Dec;12(6):7891-8. doi: 10.3892/mmr.2015.4448. Epub 2015 Oct 15.
3 Functional interrelationship between TFII-I and E2F transcription factors at specific cell cycle gene loci.J Cell Biochem. 2018 Jan;119(1):712-722. doi: 10.1002/jcb.26235. Epub 2017 Jul 31.
4 Mutations of the E2F4 gene in hematological malignancies having microsatellite instability.Blood. 2000 Feb 15;95(4):1509-10.
5 Molecular mechanisms underlying the tumorigenesis of colorectal adenomas: correlation to activated K-ras oncogene.Oncol Rep. 2006 Dec;16(6):1245-52.
6 The E2F-family proteins induce distinct cell cycle regulatory factors in p16-arrested, U343 astrocytoma cells.Oncogene. 1998 Aug 20;17(7):867-76. doi: 10.1038/sj.onc.1202008.
7 E2F4 Program Is Predictive of Progression and Intravesical Immunotherapy Efficacy in Bladder Cancer.Mol Cancer Res. 2015 Sep;13(9):1316-24. doi: 10.1158/1541-7786.MCR-15-0120. Epub 2015 Jun 1.
8 RETRACTED: Comprehensive Analysis of the Expression and Prognosis for E2Fs in Human Breast Cancer.Mol Ther. 2019 Jun 5;27(6):1153-1165. doi: 10.1016/j.ymthe.2019.03.019. Epub 2019 Apr 6.
9 Aberrant promoter methylation status is associated with upregulation of the E2F4 gene in breast cancer.Oncol Lett. 2018 Jun;15(6):8461-8469. doi: 10.3892/ol.2018.8382. Epub 2018 Mar 29.
10 Burkitt lymphoma-associated network construction and important network motif analysis.Oncol Lett. 2018 Sep;16(3):3054-3062. doi: 10.3892/ol.2018.9010. Epub 2018 Jun 21.
11 Accumulated frameshift mutations at coding nucleotide repeats during the progression of gastric carcinoma with microsatellite instability.Lab Invest. 1999 Sep;79(9):1113-20.
12 Cytoplasmic E2f4 forms organizing centres for initiation of centriole amplification during multiciliogenesis.Nat Commun. 2017 Jul 4;8:15857. doi: 10.1038/ncomms15857.
13 E2F4 expression is required for cell cycle progression of normal intestinal crypt cells and colorectal cancer cells.J Cell Physiol. 2009 Nov;221(2):350-8. doi: 10.1002/jcp.21859.
14 The effect of mismatch repair deficiency on tumourigenesis; microsatellite instability affecting genes containing short repeated sequences.Int J Oncol. 2000 Jan;16(1):133-9. doi: 10.3892/ijo.16.1.133.
15 Functional impact of colorectal cancer-associated mutations in the transcription factor E2F4.Int J Oncol. 2013 Dec;43(6):2015-22. doi: 10.3892/ijo.2013.2131. Epub 2013 Oct 8.
16 Mining Featured Biomarkers Linked with Epithelial Ovarian CancerBased on Bioinformatics.Diagnostics (Basel). 2019 Apr 9;9(2):39. doi: 10.3390/diagnostics9020039.
17 EWS-FLI1 employs an E2F switch to drive target gene expression.Nucleic Acids Res. 2015 Mar 11;43(5):2780-9. doi: 10.1093/nar/gkv123. Epub 2015 Feb 20.
18 Key signaling pathways, genes and transcription factors associated with hepatocellular carcinoma.Mol Med Rep. 2018 Jun;17(6):8153-8160. doi: 10.3892/mmr.2018.8871. Epub 2018 Apr 12.
19 Identification of genes associated with disc degeneration using bioinformatics.Biotech Histochem. 2015 Jul;90(5):353-60. doi: 10.3109/10520295.2015.1007481. Epub 2015 Mar 24.
20 Transcriptional E2F1/2/5/8 as potential targets and transcriptional E2F3/6/7 as new biomarkers for the prognosis of human lung carcinoma.Aging (Albany NY). 2018 May 11;10(5):973-987. doi: 10.18632/aging.101441.
21 Genomic structure and mutation screening of the E2F4 gene in human tumors.Int J Cancer. 2000 Jun 1;86(5):672-7. doi: 10.1002/(sici)1097-0215(20000601)86:5<672::aid-ijc11>3.0.co;2-x.
22 ER(+) Breast Cancers Resistant to Prolonged Neoadjuvant Letrozole Exhibit an E2F4 Transcriptional Program Sensitive to CDK4/6 Inhibitors.Clin Cancer Res. 2018 Jun 1;24(11):2517-2529. doi: 10.1158/1078-0432.CCR-17-2904. Epub 2018 Mar 26.
23 Proteomic analysis of oropharyngeal carcinomas reveals novel HPV-associated biological pathways.Int J Cancer. 2013 Feb 1;132(3):568-79. doi: 10.1002/ijc.27699. Epub 2012 Jul 20.
24 E2F4 is essential for normal erythrocyte maturation and neonatal viability.Mol Cell. 2000 Aug;6(2):281-91. doi: 10.1016/s1097-2765(00)00029-0.
25 Identification of differentially expressed genes by serial analysis of gene expression in human prostate cancer.Cancer Res. 2001 May 15;61(10):4283-6.
26 Overexpressing p130/E2F4 in mesenchymal stem cells facilitates the repair of injured alveolar epithelial cells in LPS-induced ARDS mice.Stem Cell Res Ther. 2019 Mar 6;10(1):74. doi: 10.1186/s13287-019-1169-1.
27 Microsatellite instability and alteration of E2F-4 gene in adenosquamous and squamous cell carcinomas of the stomach.Pathol Int. 2000 Sep;50(9):690-5. doi: 10.1046/j.1440-1827.2000.01105.x.
28 Integrative Genomic Analyses Yield Cell-Cycle Regulatory Programs with Prognostic Value.Mol Cancer Res. 2016 Apr;14(4):332-43. doi: 10.1158/1541-7786.MCR-15-0368. Epub 2016 Feb 8.
29 Interplay between NRF1, E2F4 and MYC transcription factors regulating common target genes contributes to cancer development and progression.Cell Oncol (Dordr). 2018 Oct;41(5):465-484. doi: 10.1007/s13402-018-0395-3. Epub 2018 Jul 25.
30 Expression of E2F-4 gene in colorectal adenocarcinoma and corresponding covering mucosa: an immunohistochemistry, image analysis, and immunoblot study.Appl Immunohistochem Mol Morphol. 2002 Sep;10(3):225-30. doi: 10.1097/00129039-200209000-00007.
31 ERK-associated changes in E2F4 phosphorylation, localization and transcriptional activity during mitogenic stimulation in human intestinal epithelial crypt cells.BMC Cell Biol. 2013 Aug 6;14:33. doi: 10.1186/1471-2121-14-33.
32 Frequent mutation of the E2F-4 cell cycle gene in primary human gastrointestinal tumors.Cancer Res. 1997 Jun 15;57(12):2350-3.
33 Activation of a cAMP pathway and induction of melanogenesis correlate with association of p16(INK4) and p27(KIP1) to CDKs, loss of E2F-binding activity, and premature senescence of human melanocytes.Exp Cell Res. 1999 Dec 15;253(2):561-72. doi: 10.1006/excr.1999.4688.
34 Weighted gene co-expression network analysis in identification of endometrial cancer prognosis markers.Asian Pac J Cancer Prev. 2012;13(9):4607-11. doi: 10.7314/apjcp.2012.13.9.4607.
35 E2F4 regulates a stable G2 arrest response to genotoxic stress in prostate carcinoma.Oncogene. 2007 Mar 22;26(13):1897-909. doi: 10.1038/sj.onc.1209998. Epub 2006 Oct 9.
36 Heat shock protein 27 promotes cell cycle progression by down-regulating E2F transcription factor 4 and retinoblastoma family protein p130.J Biol Chem. 2018 Oct 12;293(41):15815-15826. doi: 10.1074/jbc.RA118.003310. Epub 2018 Aug 30.
37 Up-regulation of transcriptional factor E2F1 in papillary and anaplastic thyroid cancers.J Hum Genet. 2004;49(6):312-318. doi: 10.1007/s10038-004-0146-3. Epub 2004 Apr 29.
38 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.
39 Pharmacogenomic analysis of acute promyelocytic leukemia cells highlights CYP26 cytochrome metabolism in differential all-trans retinoic acid sensitivity. Blood. 2007 May 15;109(10):4450-60.
40 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.
41 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
42 Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
43 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.
44 New insights into the mechanisms underlying 5-fluorouracil-induced intestinal toxicity based on transcriptomic and metabolomic responses in human intestinal organoids. Arch Toxicol. 2021 Aug;95(8):2691-2718. doi: 10.1007/s00204-021-03092-2. Epub 2021 Jun 20.
45 Necdin and E2F4 are modulated by rosiglitazone therapy in diabetic human adipose and muscle tissue. Diabetes. 2006 Mar;55(3):640-50. doi: 10.2337/diabetes.55.03.06.db05-1015.
46 A high concentration of genistein down-regulates activin A, Smad3 and other TGF-beta pathway genes in human uterine leiomyoma cells. Exp Mol Med. 2012 Apr 30;44(4):281-92.
47 The prolyl isomerase Pin1 induces LC-3 expression and mediates tamoxifen resistance in breast cancer. J Biol Chem. 2010 Jul 30;285(31):23829-41. doi: 10.1074/jbc.M109.092874. Epub 2010 May 17.
48 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.
49 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.
50 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.
51 Eugenol causes melanoma growth suppression through inhibition of E2F1 transcriptional activity. J Biol Chem. 2005 Feb 18;280(7):5812-9. doi: 10.1074/jbc.M411429200. Epub 2004 Dec 1.
52 Gene alterations of ovarian cancer cells expressing estrogen receptors by estrogen and bisphenol a using microarray analysis. Lab Anim Res. 2011 Jun;27(2):99-107. doi: 10.5625/lar.2011.27.2.99. Epub 2011 Jun 22.
53 Glyphosate-based herbicides at low doses affect canonical pathways in estrogen positive and negative breast cancer cell lines. PLoS One. 2019 Jul 11;14(7):e0219610. doi: 10.1371/journal.pone.0219610. eCollection 2019.
54 In silico, in vitro and in vivo studies: Dibutyl phthalate promotes prostate cancer cell proliferation by activating Forkhead Box M1 and remission after Natura- pretreatment. Toxicology. 2023 Apr;488:153465. doi: 10.1016/j.tox.2023.153465. Epub 2023 Feb 23.