Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTH2N3T8)

• DOT Name: Transcription factor MafB (MAFB)
• Synonyms: Maf-B; V-maf musculoaponeurotic fibrosarcoma oncogene homolog B
• Gene Name: MAFB
• Related Disease:
  Lymphatic malformation 1
  Multicentric carpo-tarsal osteolysis with or without nephropathy
  T-cell acute lymphoblastic leukaemia
  Acute myelogenous leukaemia
  Arteriosclerosis
  Atherosclerosis
  Cleft lip/palate
  Duane retraction syndrome 2
  Duane retraction syndrome 3 with or without deafness
  Fibrosarcoma
  Focal segmental glomerulosclerosis
  Hepatocellular carcinoma
  Hypospadias
  Lymphoma
  Neoplasm
  Neuralgia
  Osteoporosis
  Plasma cell myeloma
  Trichohepatoenteric syndrome
  Nasopharyngeal carcinoma
  Duane retraction syndrome
  Coronary atherosclerosis
  Coronary heart disease
  Non-insulin dependent diabetes
  Secondary hyperparathyroidism
  Tuberculosis
• UniProt ID: MAFB_HUMAN
• Pfam ID: PF03131 ; PF08383
• Sequence:
  MAAELSMGPELPTSPLAMEYVNDFDLLKFDVKKEPLGRAERPGRPCTRLQPAGSVSSTPL
  STPCSSVPSSPSFSPTEQKTHLEDLYWMASNYQQMNPEALNLTPEDAVEALIGSHPVPQP
  LQSFDSFRGAHHHHHHHHPHPHHAYPGAGVAHDELGPHAHPHHHHHHQASPPPSSAASPA
  QQLPTSHPGPGPHATASATAAGGNGSVEDRFSDDQLVSMSVRELNRHLRGFTKDEVIRLK
  QKRRTLKNRGYAQSCRYKRVQQKHHLENEKTQLIQQVEQLKQEVSRLARERDAYKVKCEK
  LANSGFREAGSTSDSPSSPEFFL
• Function: Acts as a transcriptional activator or repressor. Plays a pivotal role in regulating lineage-specific hematopoiesis by repressing ETS1-mediated transcription of erythroid-specific genes in myeloid cells. Required for monocytic, macrophage, osteoclast, podocyte and islet beta cell differentiation. Involved in renal tubule survival and F4/80 maturation. Activates the insulin and glucagon promoters. Together with PAX6, transactivates weakly the glucagon gene promoter through the G1 element. SUMO modification controls its transcriptional activity and ability to specify macrophage fate. Binds element G1 on the glucagon promoter. Involved either as an oncogene or as a tumor suppressor, depending on the cell context. Required for the transcriptional activation of HOXB3 in the rhombomere r5 in the hindbrain.
• Tissue Specificity: Ubiquitous.
• KEGG Pathway: Parathyroid hormone synthesis, secretion and action (hsa04928)
• Reactome Pathway: Activation of anterior HOX genes in hindbrain development during early embryogenesis (R-HSA-5617472)

Molecular Interaction Atlas (MIA) of This DOT

26 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Lymphatic malformation 1	DIS857QZ	Definitive	Biomarker	[1]
Multicentric carpo-tarsal osteolysis with or without nephropathy	DISIMDQA	Definitive	Autosomal dominant	[2]
T-cell acute lymphoblastic leukaemia	DIS17AI2	Definitive	Altered Expression	[3]
Acute myelogenous leukaemia	DISCSPTN	Strong	Altered Expression	[4]
Arteriosclerosis	DISK5QGC	Strong	Altered Expression	[5]
Atherosclerosis	DISMN9J3	Strong	Altered Expression	[5]
Cleft lip/palate	DIS14IG3	Strong	Genetic Variation	[6]
Duane retraction syndrome 2	DISE6LRF	Strong	CausalMutation	[7]
Duane retraction syndrome 3 with or without deafness	DIS49SAN	Strong	Autosomal dominant	[7]
Fibrosarcoma	DISWX7MU	Strong	Genetic Variation	[8]
Focal segmental glomerulosclerosis	DISJNHH0	Strong	Genetic Variation	[9]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[10]
Hypospadias	DIS48CCP	Strong	Biomarker	[11]
Lymphoma	DISN6V4S	Strong	Biomarker	[12]
Neoplasm	DISZKGEW	Strong	Altered Expression	[13]
Neuralgia	DISWO58J	Strong	Altered Expression	[14]
Osteoporosis	DISF2JE0	Strong	Genetic Variation	[15]
Plasma cell myeloma	DIS0DFZ0	Strong	Altered Expression	[16]
Trichohepatoenteric syndrome	DISL3ODF	Strong	Genetic Variation	[17]
Nasopharyngeal carcinoma	DISAOTQ0	moderate	Biomarker	[18]
Duane retraction syndrome	DISOEBK2	Supportive	Autosomal dominant	[7]
Coronary atherosclerosis	DISKNDYU	Limited	Genetic Variation	[19]
Coronary heart disease	DIS5OIP1	Limited	Genetic Variation	[19]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Biomarker	[20]
Secondary hyperparathyroidism	DISZX24B	Limited	Biomarker	[21]
Tuberculosis	DIS2YIMD	Limited	Genetic Variation	[22]

1 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 Transcription factor MafB (MAFB).	[23]

26 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 Transcription factor MafB (MAFB).	[24]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Transcription factor MafB (MAFB).	[25]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Transcription factor MafB (MAFB).	[26]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Transcription factor MafB (MAFB).	[27]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Transcription factor MafB (MAFB).	[28]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Transcription factor MafB (MAFB).	[29]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Transcription factor MafB (MAFB).	[30]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Transcription factor MafB (MAFB).	[31]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Transcription factor MafB (MAFB).	[32]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Transcription factor MafB (MAFB).	[33]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Transcription factor MafB (MAFB).	[34]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Transcription factor MafB (MAFB).	[35]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Transcription factor MafB (MAFB).	[32]
Azacitidine	DMTA5OE	Approved	Azacitidine increases the expression of Transcription factor MafB (MAFB).	[36]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Transcription factor MafB (MAFB).	[37]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Transcription factor MafB (MAFB).	[32]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Transcription factor MafB (MAFB).	[38]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Transcription factor MafB (MAFB).	[39]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Transcription factor MafB (MAFB).	[40]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Transcription factor MafB (MAFB).	[41]
Celastrol	DMWQIJX	Preclinical	Celastrol decreases the expression of Transcription factor MafB (MAFB).	[42]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Transcription factor MafB (MAFB).	[43]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Transcription factor MafB (MAFB).	[44]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Transcription factor MafB (MAFB).	[45]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Transcription factor MafB (MAFB).	[46]
ORG2058	DMH1M6N	Investigative	ORG2058 increases the expression of Transcription factor MafB (MAFB).	[47]

References

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• [2] Multicentric carpotarsal osteolysis is caused by mutations clustering in the amino-terminal transcriptional activation domain of MAFB. Am J Hum Genet. 2012 Mar 9;90(3):494-501. doi: 10.1016/j.ajhg.2012.01.003. Epub 2012 Mar 1.
• [3] MAFB enhances oncogenic Notch signaling in T cell acute lymphoblastic leukemia.Sci Signal. 2017 Nov 14;10(505):eaam6846. doi: 10.1126/scisignal.aam6846.
• [4] DNMT3A R882 mutation is associated with elevated expression of MAFB and M4/M5 immunophenotype of acute myeloid leukemia blasts.Leuk Lymphoma. 2015;56(10):2914-22. doi: 10.3109/10428194.2015.1015123. Epub 2015 Jul 6.
• [5] Transcription Factor MafB Suppresses Type I Interferon Production by CD14(+) Monocytes in Patients With Chronic Hepatitis C.Front Microbiol. 2019 Aug 7;10:1814. doi: 10.3389/fmicb.2019.01814. eCollection 2019.
• [6] Polymorphic Variants of V-Maf Musculoaponeurotic Fibrosarcoma Oncogene Homolog B (rs13041247 and rs11696257) and Risk of Non-Syndromic Cleft Lip/Palate: Systematic Review and Meta-Analysis.Int J Environ Res Public Health. 2019 Aug 5;16(15):2792. doi: 10.3390/ijerph16152792.
• [7] Loss of MAFB Function in Humans and Mice Causes Duane Syndrome, Aberrant Extraocular Muscle Innervation, and Inner-Ear Defects. Am J Hum Genet. 2016 Jun 2;98(6):1220-1227. doi: 10.1016/j.ajhg.2016.03.023. Epub 2016 May 12.
• [8] The identification of MAFB mutations in eight patients with multicentric carpo-tarsal osteolysis supports genetic homogeneity but clinical variability.Am J Med Genet A. 2013 Dec;161A(12):3023-9. doi: 10.1002/ajmg.a.36151. Epub 2013 Aug 16.
• [9] A mutation in transcription factor MAFB causes Focal Segmental Glomerulosclerosis with Duane Retraction Syndrome.Kidney Int. 2018 Aug;94(2):396-407. doi: 10.1016/j.kint.2018.02.025. Epub 2018 May 18.
• [10] Transcription Factor MafB Promotes Hepatocellular Carcinoma Cell Proliferation through Up-Regulation of Cyclin D1.Cell Physiol Biochem. 2016;39(2):700-8. doi: 10.1159/000445661. Epub 2016 Jul 25.
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• [19] Association of polymorphisms in the MAFB gene and the risk of coronary artery disease and ischemic stroke: a case-control study.Lipids Health Dis. 2015 Jul 25;14:79. doi: 10.1186/s12944-015-0078-2.
• [20] Inactivation of specific cell transcription factors in type 2 diabetes.J Clin Invest. 2013 Aug;123(8):3305-16. doi: 10.1172/JCI65390. Epub 2013 Jul 1.
• [21] Transcription factor MafB may play an important role in secondary hyperparathyroidism.Kidney Int. 2018 Jan;93(1):54-68. doi: 10.1016/j.kint.2017.06.023. Epub 2017 Sep 28.
• [22] Genome-wide association studies of tuberculosis in Asians identify distinct at-risk locus for young tuberculosis.J Hum Genet. 2012 Jun;57(6):363-7. doi: 10.1038/jhg.2012.35. Epub 2012 May 3.
• [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] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
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• [28] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
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• [31] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
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• [33] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [34] 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.
• [35] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [36] CRISPR-based DNA methylation editing of NNT rescues the cisplatin resistance of lung cancer cells by reducing autophagy. Arch Toxicol. 2023 Feb;97(2):441-456. doi: 10.1007/s00204-022-03404-0. Epub 2022 Nov 6.
• [37] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [38] The molecular basis of genistein-induced mitotic arrest and exit of self-renewal in embryonal carcinoma and primary cancer cell lines. BMC Med Genomics. 2008 Oct 10;1:49.
• [39] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [40] Synergistic effect of JQ1 and rapamycin for treatment of human osteosarcoma. Int J Cancer. 2015 May 1;136(9):2055-64.
• [41] 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.
• [42] Gene expression signature-based chemical genomic prediction identifies a novel class of HSP90 pathway modulators. Cancer Cell. 2006 Oct;10(4):321-30.
• [43] Bisphenol A and bisphenol S induce distinct transcriptional profiles in differentiating human primary preadipocytes. PLoS One. 2016 Sep 29;11(9):e0163318.
• [44] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [45] Identification of gene markers for formaldehyde exposure in humans. Environ Health Perspect. 2007 Oct;115(10):1460-6. doi: 10.1289/ehp.10180.
• [46] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.
• [47] The antiproliferative effects of progestins in T47D breast cancer cells are tempered by progestin induction of the ETS transcription factor Elf5. Mol Endocrinol. 2010 Jul;24(7):1380-92. doi: 10.1210/me.2009-0516. Epub 2010 Jun 2.