Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT62460U)

• DOT Name: Ras-responsive element-binding protein 1 (RREB1)
• Synonyms: RREB-1; Finger protein in nuclear bodies; Raf-responsive zinc finger protein LZ321; Zinc finger motif enhancer-binding protein 1; Zep-1
• Gene Name: RREB1
• Related Disease:
  Multiple sclerosis
  Pancreatic cancer
  Small lymphocytic lymphoma
  Xeroderma pigmentosum group C
  Acute monocytic leukemia
  Acute myelogenous leukaemia
  Advanced cancer
  Age-related macular degeneration
  Alzheimer disease
  Amyotrophic lateral sclerosis
  B-cell lymphoma
  Blast phase chronic myelogenous leukemia, BCR-ABL1 positive
  Chromosomal disorder
  Chronic obstructive pulmonary disease
  Chronic renal failure
  DiGeorge syndrome
  End-stage renal disease
  Gout
  Intervertebral disc degeneration
  Lung adenocarcinoma
  Malignant soft tissue neoplasm
  Medullary thyroid gland carcinoma
  Melanocytic nevus
  Melanoma
  Neoplasm
  Non-insulin dependent diabetes
  Pancreatic adenocarcinoma
  Prostate cancer
  Prostate carcinoma
  Sarcoidosis
  Sarcoma
  Thyroid gland carcinoma
  Velocardiofacial syndrome
  Frontotemporal dementia
  Adenocarcinoma
  Enterovirus infection
  Kaposi sarcoma
  Parkinson disease
  Rett syndrome
  Type-1/2 diabetes
• UniProt ID: RREB1_HUMAN
• Pfam ID: PF00096 ; PF13894 ; PF13912
• Sequence:
  MTSSSPAGLEGSDLSSINTMMSAVMSVGKVTENGGSPQGIKSPSKPPGPNRIGRRNQETK
  EEKSSYNCPLCEKICTTQHQLTMHIRQHNTDTGGADHSCSICGKSLSSASSLDRHMLVHS
  GERPYKCTVCGQSFTTNGNMHRHMKIHEKDPNSATATAPPSPLKRRRLSSKRKLSHDAES
  EREDPAPAKKMVEDGQSGDLEKKADEVFHCPVCFKEFVCKYGLETHMETHSDNPLRCDIC
  CVTFRTHRGLLRHNALVHKQLPRDAMGRPFIQNNPSIPAGFHDLGFTDFSCRKFPRISQA
  WCETNLRRCISEQHRFVCDTCDKAFPMLCSLALHKQTHVAADQGQEKPQATPLPGDALDQ
  KGFLALLGLQHTKDVRPAPAEEPLPDDNQAIQLQTLKCQLPQDPGCTNLLSLSPFEAASL
  GGSLTVLPATKDSIKHLSLQPFQKGFIIQPDSSIVVKPISGESAIELADIQQILKMAASA
  PPQISLPPFSKAPAAPLQAIFKHMPPLKPKPLVTPRTVVATSTPPPLINAQQASPGCISP
  SLPPPPLKLLKGSVEAASNAHLLQSKSGTQPHAATRLSLQQPRAELPGQPEMKTQLEQDS
  IIEALLPLSMEAKIKQEITEGELKAFMTAPGGKKTPAMRKVLYPCRFCNQVFAFSGVLRA
  HVRSHLGISPYQCNICDYIAADKAALIRHLRTHSGERPYICKICHYPFTVKANCERHLRK
  KHLKATRKDIEKNIEYVSSSAAELVDAFCAPDTVCRLCGEDLKHYRALRIHMRTHCGRGL
  GGGHKGRKPFECKECSAAFAAKRNCIHHILKQHLHVPEQDIESYVLAADGLGPAEAPAAE
  ASGRGEDSGCAALGDCKPLTAFLEPQNGFLHRGPTQPPPPHVSIKLEPASSFAVDFNEPL
  DFSQKGLALVQVKQENISFLSPSSLVPYDCSMEPIDLSIPKNFRKGDKDLATPSEAKKPE
  EEAGSSEQPSPCPAPGPSLPVTLGPSGILESPMAPAPAATPEPPAQPLQGPVQLAVPIYS
  SALVSSPPLVGSSALLSGTALLRPLRPKPPLLLPKPPVTEELPPLASIAQIISSVSSAPT
  LLKTKVADPGPASTGSNTTASDSLGGSVPKAATTATPAATTSPKESSEPPAPASSPEAAS
  PTEQGPAGTSKKRGRKRGMRSRPRANSGGVDLDSSGEFASIEKMLATTDTNKFSPFLQTA
  EDNTQDEVAGAPADHHGPSDEEQGSPPEDKLLRAKRNSYTNCLQKITCPHCPRVFPWASS
  LQRHMLTHTDSQSDAETAAAAGEVLDLTSRDREQPSEGATELRQVAGDAPVEQATAETAS
  PVHREEHGRGESHEPEEEHGTEESTGDADGAEEDASSNQSLDLDFATKLMDFKLAEGDGE
  AGAGGAASQEQKLACDTCGKSFKFLGTLSRHRKAHGRQEPKDEKGDGASTAEEGPQPAPE
  QEEKPPETPAEVVESAPGAGEAPAEKLAEETEGPSDGESAAEKRSSEKSDDDKKPKTDSP
  KSVASKADKRKKVCSVCNKRFWSLQDLTRHMRSHTGERPYKCQTCERTFTLKHSLVRHQR
  IHQKARHAKHHGKDSDKEERGEEDSENESTHSGNNAVSENEAELAPNASNHMAVTRSRKE
  GLASATKDCSHREEKVTAGWPSEPGQGDLNPESPAALGQDLLEPRSKRPAHPILATADGA
  SQLVGME
• Function: Transcription factor that binds specifically to the RAS-responsive elements (RRE) of gene promoters. Represses the angiotensinogen gene. Negatively regulates the transcriptional activity of AR. Potentiates the transcriptional activity of NEUROD1. Promotes brown adipocyte differentiation. May be involved in Ras/Raf-mediated cell differentiation by enhancing calcitonin expression.
• Tissue Specificity: Expressed in heart, placenta, lung, liver, skeletal muscle, kidney and pancreas. Not found in the brain.

Molecular Interaction Atlas (MIA) of This DOT

40 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Multiple sclerosis	DISB2WZI	Definitive	Genetic Variation	[1]
Pancreatic cancer	DISJC981	Definitive	Altered Expression	[2]
Small lymphocytic lymphoma	DIS30POX	Definitive	Genetic Variation	[1]
Xeroderma pigmentosum group C	DIS8DQXS	Definitive	Biomarker	[3]
Acute monocytic leukemia	DIS28NEL	Strong	Altered Expression	[4]
Acute myelogenous leukaemia	DISCSPTN	Strong	Altered Expression	[4]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[5]
Age-related macular degeneration	DIS0XS2C	Strong	Genetic Variation	[6]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[7]
Amyotrophic lateral sclerosis	DISF7HVM	Strong	Biomarker	[8]
B-cell lymphoma	DISIH1YQ	Strong	Altered Expression	[9]
Blast phase chronic myelogenous leukemia, BCR-ABL1 positive	DIS3KLUX	Strong	Genetic Variation	[10]
Chromosomal disorder	DISM5BB5	Strong	Biomarker	[11]
Chronic obstructive pulmonary disease	DISQCIRF	Strong	Genetic Variation	[12]
Chronic renal failure	DISGG7K6	Strong	Genetic Variation	[13]
DiGeorge syndrome	DIST1RKO	Strong	GermlineModifyingMutation	[14]
End-stage renal disease	DISXA7GG	Strong	Altered Expression	[15]
Gout	DISHC0U7	Strong	Genetic Variation	[16]
Intervertebral disc degeneration	DISG3AIM	Strong	Altered Expression	[17]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[18]
Malignant soft tissue neoplasm	DISTC6NO	Strong	Biomarker	[19]
Medullary thyroid gland carcinoma	DISHBL3K	Strong	Biomarker	[20]
Melanocytic nevus	DISYS32D	Strong	Biomarker	[21]
Melanoma	DIS1RRCY	Strong	Biomarker	[22]
Neoplasm	DISZKGEW	Strong	Biomarker	[23]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[24]
Pancreatic adenocarcinoma	DISKHX7S	Strong	Altered Expression	[25]
Prostate cancer	DISF190Y	Strong	Altered Expression	[26]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[26]
Sarcoidosis	DISE5B8Z	Strong	Biomarker	[27]
Sarcoma	DISZDG3U	Strong	Biomarker	[19]
Thyroid gland carcinoma	DISMNGZ0	Strong	Biomarker	[20]
Velocardiofacial syndrome	DISOSBTY	Strong	GermlineModifyingMutation	[14]
Frontotemporal dementia	DISKYHXL	Disputed	Biomarker	[8]
Adenocarcinoma	DIS3IHTY	Limited	Biomarker	[28]
Enterovirus infection	DISH2UDP	Limited	Biomarker	[29]
Kaposi sarcoma	DISC1H1Z	Limited	Biomarker	[30]
Parkinson disease	DISQVHKL	Limited	Biomarker	[31]
Rett syndrome	DISGG5UV	Limited	Genetic Variation	[32]
Type-1/2 diabetes	DISIUHAP	Limited	Biomarker	[33]

6 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 Ras-responsive element-binding protein 1 (RREB1).	[34]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Ras-responsive element-binding protein 1 (RREB1).	[38]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Ras-responsive element-binding protein 1 (RREB1).	[44]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Ras-responsive element-binding protein 1 (RREB1).	[45]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Ras-responsive element-binding protein 1 (RREB1).	[46]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Ras-responsive element-binding protein 1 (RREB1).	[45]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Ras-responsive element-binding protein 1 (RREB1).	[35]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Ras-responsive element-binding protein 1 (RREB1).	[36]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Ras-responsive element-binding protein 1 (RREB1).	[37]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Ras-responsive element-binding protein 1 (RREB1).	[39]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Ras-responsive element-binding protein 1 (RREB1).	[40]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of Ras-responsive element-binding protein 1 (RREB1).	[41]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of Ras-responsive element-binding protein 1 (RREB1).	[42]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Ras-responsive element-binding protein 1 (RREB1).	[43]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Ras-responsive element-binding protein 1 (RREB1).	[39]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Ras-responsive element-binding protein 1 (RREB1).	[47]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Ras-responsive element-binding protein 1 (RREB1).	[48]

References

• [1] Genetic overlap between autoimmune diseases and non-Hodgkin lymphoma subtypes.Genet Epidemiol. 2019 Oct;43(7):844-863. doi: 10.1002/gepi.22242. Epub 2019 Aug 13.
• [2] RREB1-induced upregulation of the lncRNA AGAP2-AS1 regulates the proliferation and migration of pancreatic cancer partly through suppressing ANKRD1 and ANGPTL4.Cell Death Dis. 2019 Feb 27;10(3):207. doi: 10.1038/s41419-019-1384-9.
• [3] The xeroderma pigmentosum group C protein complex and ultraviolet-damaged DNA-binding protein: functional assays for damage recognition factors involved in global genome repair.Methods Enzymol. 2006;408:171-88. doi: 10.1016/S0076-6879(06)08011-6.
• [4] RAS-Responsive Element-Binding Protein 1 Blocks the Granulocytic Differentiation of Myeloid Leukemia Cells.Oncol Res. 2019 Jul 12;27(7):809-818. doi: 10.3727/096504018X15451301487729. Epub 2019 Apr 8.
• [5] Restitution of tumor suppressor microRNAs using a systemic nanovector inhibits pancreatic cancer growth in mice.Mol Cancer Ther. 2011 Aug;10(8):1470-80. doi: 10.1158/1535-7163.MCT-11-0152. Epub 2011 May 27.
• [6] Genome-wide association study of advanced age-related macular degeneration identifies a role of the hepatic lipase gene (LIPC).Proc Natl Acad Sci U S A. 2010 Apr 20;107(16):7395-400. doi: 10.1073/pnas.0912019107. Epub 2010 Apr 12.
• [7] Distinct [(18)F]THK5351 binding patterns in primary progressive aphasia variants.Eur J Nucl Med Mol Imaging. 2018 Dec;45(13):2342-2357. doi: 10.1007/s00259-018-4075-3. Epub 2018 Jun 26.
• [8] Exploring the aggregation-prone regions from structural domains of human TDP-43.Biochim Biophys Acta Proteins Proteom. 2019 Mar;1867(3):286-296. doi: 10.1016/j.bbapap.2018.10.008. Epub 2018 Oct 11.
• [9] Sleeping Beauty Screen Identifies RREB1 and Other Genetic Drivers in Human B-cell Lymphoma.Mol Cancer Res. 2019 Feb;17(2):567-582. doi: 10.1158/1541-7786.MCR-18-0582. Epub 2018 Oct 24.
• [10] Whole-genome analysis reveals unexpected dynamics of mutant subclone development in a patient with JAK2-V617F-positive chronic myeloid leukemia.Exp Hematol. 2017 Sep;53:48-58. doi: 10.1016/j.exphem.2017.05.007. Epub 2017 Jun 8.
• [11] Adenovirus-induced alterations of the cell growth cycle: a requirement for expression of E1A but not of E1B.J Virol. 1983 Jan;45(1):192-9. doi: 10.1128/JVI.45.1.192-199.1983.
• [12] Genetic landscape of chronic obstructive pulmonary disease identifies heterogeneous cell-type and phenotype associations.Nat Genet. 2019 Mar;51(3):494-505. doi: 10.1038/s41588-018-0342-2. Epub 2019 Feb 25.
• [13] Identification of CDC42BPG as a novel susceptibility locus for hyperuricemia in a Japanese population.Mol Genet Genomics. 2018 Apr;293(2):371-379. doi: 10.1007/s00438-017-1394-1. Epub 2017 Nov 9.
• [14] Histone Modifier Genes Alter Conotruncal Heart Phenotypes in 22q11.2 Deletion Syndrome.Am J Hum Genet. 2015 Dec 3;97(6):869-77. doi: 10.1016/j.ajhg.2015.10.013. Epub 2015 Nov 19.
• [15] The ras responsive transcription factor RREB1 is a novel candidate gene for type 2 diabetes associated end-stage kidney disease.Hum Mol Genet. 2014 Dec 15;23(24):6441-7. doi: 10.1093/hmg/ddu362. Epub 2014 Jul 15.
• [16] Genome-wide association analyses identify 18 new loci associated with serum urate concentrations. Nat Genet. 2013 Feb;45(2):145-54. doi: 10.1038/ng.2500. Epub 2012 Dec 23.
• [17] The noncoding RNA linc-ADAMTS5 cooperates with RREB1 to protect from intervertebral disc degeneration through inhibiting ADAMTS5 expression.Clin Sci (Lond). 2017 May 1;131(10):965-979. doi: 10.1042/CS20160918. Epub 2017 Mar 24.
• [18] Inhibitor of DNA-Binding Protein 4 Suppresses Cancer Metastasis through the Regulation of Epithelial Mesenchymal Transition in Lung Adenocarcinoma.Cancers (Basel). 2019 Dec 14;11(12):2021. doi: 10.3390/cancers11122021.
• [19] RREB1-MKL2 fusion in biphenotypic "oropharyngeal" sarcoma: New entity or part of the spectrum of biphenotypic sinonasal sarcomas?.Genes Chromosomes Cancer. 2018 Apr;57(4):203-210. doi: 10.1002/gcc.22521. Epub 2018 Jan 25.
• [20] RREB-1, a novel zinc finger protein, is involved in the differentiation response to Ras in human medullary thyroid carcinomas.Mol Cell Biol. 1996 Oct;16(10):5335-45. doi: 10.1128/MCB.16.10.5335.
• [21] Presence of cytogenetic abnormalities in Spitz naevi: a diagnostic challenge for fluorescence in-situ hybridization analysis.Histopathology. 2012 Jan;60(2):336-46. doi: 10.1111/j.1365-2559.2011.04087.x.
• [22] Fluorescence In Situ Hybridization for Melanoma Diagnosis: A Review and a Reappraisal.Am J Dermatopathol. 2016 Apr;38(4):253-69. doi: 10.1097/DAD.0000000000000380.
• [23] A Functional Polymorphism in the Promoter of MiR-143/145 Is Associated With the Risk of Cervical Squamous Cell Carcinoma in Chinese Women: A Case-Control Study.Medicine (Baltimore). 2015 Aug;94(31):e1289. doi: 10.1097/MD.0000000000001289.
• [24] Identification of 28 new susceptibility loci for type 2 diabetes in the Japanese population.Nat Genet. 2019 Mar;51(3):379-386. doi: 10.1038/s41588-018-0332-4. Epub 2019 Feb 4.
• [25] The cytotoxic role of RREB1, ZIP3 zinc transporter, and zinc in human pancreatic adenocarcinoma.Cancer Biol Ther. 2014 Oct;15(10):1431-7. doi: 10.4161/cbt.29927. Epub 2014 Jul 22.
• [26] hZIP1 zinc transporter down-regulation in prostate cancer involves the overexpression of ras responsive element binding protein-1 (RREB-1).Prostate. 2011 Oct 1;71(14):1518-24. doi: 10.1002/pros.21368. Epub 2011 Feb 25.
• [27] Whole exome sequencing in three families segregating a pediatric case of sarcoidosis.BMC Med Genomics. 2018 Mar 6;11(1):23. doi: 10.1186/s12920-018-0338-x.
• [28] Decreased zinc and downregulation of ZIP3 zinc uptake transporter in the development of pancreatic adenocarcinoma.Cancer Biol Ther. 2011 Aug 15;12(4):297-303. doi: 10.4161/cbt.12.4.16356. Epub 2011 Aug 15.
• [29] Enteroviral Infection Leads to Transactive Response DNA-Binding Protein 43 Pathology inVivo.Am J Pathol. 2018 Dec;188(12):2853-2862. doi: 10.1016/j.ajpath.2018.08.013. Epub 2018 Sep 28.
• [30] Kaposi's Sarcoma-Associated Herpesvirus ORF68 Is a DNA Binding Protein Required for Viral Genome Cleavage and Packaging.J Virol. 2018 Jul 31;92(16):e00840-18. doi: 10.1128/JVI.00840-18. Print 2018 Aug 15.
• [31] Loss of SATB1 Induces p21-Dependent Cellular Senescence in Post-mitotic Dopaminergic Neurons.Cell Stem Cell. 2019 Oct 3;25(4):514-530.e8. doi: 10.1016/j.stem.2019.08.013. Epub 2019 Sep 19.
• [32] Differential Regulation of MeCP2 Phosphorylation by Laminin in Oligodendrocytes.J Mol Neurosci. 2017 Aug;62(3-4):309-317. doi: 10.1007/s12031-017-0939-4. Epub 2017 Jun 14.
• [33] Transactive DNA Binding Protein 43 Rather Than Other Misfolded Proteins in the Brain is Associated with Islet Amyloid Polypeptide in Pancreas in Aged Subjects with Diabetes Mellitus.J Alzheimers Dis. 2017;59(1):43-56. doi: 10.3233/JAD-170192.
• [34] 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.
• [35] 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.
• [36] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [37] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [38] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [39] 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.
• [40] Glucocorticoids inhibit cell death in ovarian cancer and up-regulate caspase inhibitor cIAP2. Clin Cancer Res. 2005 Sep 1;11(17):6325-32. doi: 10.1158/1078-0432.CCR-05-0182.
• [41] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [42] Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells. Mutat Res Genet Toxicol Environ Mutagen. 2014 Dec;775-776:48-54. doi: 10.1016/j.mrgentox.2014.10.011. Epub 2014 Nov 4.
• [43] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [44] 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.
• [45] 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.
• [46] 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.
• [47] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [48] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.