Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZFV53Z)

• DOT Name: Mastermind-like protein 3 (MAML3)
• Synonyms: Mam-3
• Gene Name: MAML3
• Related Disease:
  Advanced cancer
  Atrial fibrillation
  Cardiac failure
  Chronic obstructive pulmonary disease
  Congenital heart defects, multiple types, 2
  Endometrial cancer
  Endometrial carcinoma
  Ewing sarcoma
  Familial hypertrophic cardiomyopathy
  Gastric cancer
  Gastroesophageal reflux disease
  Hepatitis B virus infection
  Heterotaxy, visceral, 1, X-linked
  Malignant soft tissue neoplasm
  Mammary analogue secretory carcinoma
  Neuroendocrine neoplasm
  Pancreatic cancer
  Paraganglioma
  Pheochromocytoma
  Sarcoma
  Schizophrenia
  Small-cell lung cancer
  Stomach cancer
  Stroke
  Type-1/2 diabetes
  Asthma
  Neoplasm
• UniProt ID: MAML3_HUMAN
• Pfam ID: PF09596 ; PF20802 ; PF20801
• Sequence:
  MGDFAAPAAAANGSSICINSSLNSSLGGAGIGVNNTPNSTPAAPSSNHPAAGGCGGSGGP
  GGGSAAVPKHSTVVERLRQRIEGCRRHHVNCENRYQQAQVEQLELERRDTVSLYQRTLEQ
  RAKKSGAGTGKQQHPSKPQQDAEAASAEQRNHTLIMLQETVKRKLEGARSPLNGDQQNGA
  CDGNFSPTSKRIRKDISAGMEAINNLPSNMPLPSASPLHQLDLKPSLPLQNSGTHTPGLL
  EDLSKNGRLPEIKLPVNGCSDLEDSFTILQSKDLKQEPLDDPTCIDTSETSLSNQNKLFS
  DINLNDQEWQELIDELANTVPEDDIQDLFNEDFEEKKEPEFSQPATETPLSQESASVKSD
  PSHSPFAHVSMGSPQARPSSSGPPFSTVSTATSLPSVASTPAAPNPASSPANCAVQSPQT
  PNQAHTPGQAPPRPGNGYLLNPAAVTVAGSASGPVAVPSSDMSPAEQLKQMAAQQQQRAK
  LMQQKQQQQQQQQQQQQQQQQQQQQQQQQQHSNQTSNWSPLGPPSSPYGAAFTAEKPNSP
  MMYPQAFNNQNPIVPPMANNLQKTTMNNYLPQNHMNMINQQPNNLGTNSLNKQHNILTYG
  NTKPLTHFNADLSQRMTPPVANPNKNPLMPYIQQQQQQQQQQQQQQQQQQPPPPQLQAPR
  AHLSEDQKRLLLMKQKGVMNQPMAYAALPSHGQEQHPVGLPRTTGPMQSSVPPGSGGMVS
  GASPAGPGFLGSQPQAAIMKQMLIDQRAQLIEQQKQQFLREQRQQQQQQQQQILAEQQLQ
  QSHLPRQHLQPQRNPYPVQQVNQFQGSPQDIAAVRSQAALQSMRTSRLMAQNAGMMGIGP
  SQNPGTMATAAAQSEMGLAPYSTTPTSQPGMYNMSTGMTQMLQHPNQSGMSITHNQAQGP
  RQPASGQGVGMVSGFGQSMLVNSAITQQHPQMKGPVGQALPRPQAPPRLQSLMGTVQQGA
  QSWQQRSLQGMPGRTSGELGPFNNGASYPLQAGQPRLTKQHFPQGLSQSVVDANTGTVRT
  LNPAAMGRQMMPSLPGQQGTSQARPMVMSGLSQGVPGMPAFSQPPAQQQIPSGSFAPSSQ
  SQAYERNAPQDVSYNYSGDGAGGSFPGLPDGADLVDSIIKGGPGDEWMQELDELFGNP
• Function: Acts as a transcriptional coactivator for NOTCH proteins. Has been shown to amplify NOTCH-induced transcription of HES1.
• KEGG Pathway:
  Notch sig.ling pathway (hsa04330)
  Th1 and Th2 cell differentiation (hsa04658)
  Human papillomavirus infection (hsa05165)
• Reactome Pathway:
  Regulation of gene expression in late stage (branching morphogenesis) pancreatic bud precursor cells (R-HSA-210744)
  NOTCH1 Intracellular Domain Regulates Transcription (R-HSA-2122947)
  NOTCH2 intracellular domain regulates transcription (R-HSA-2197563)
  Constitutive Signaling by NOTCH1 PEST Domain Mutants (R-HSA-2644606)
  Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants (R-HSA-2894862)
  Notch-HLH transcription pathway (R-HSA-350054)
  RUNX3 regulates NOTCH signaling (R-HSA-8941856)
  NOTCH3 Intracellular Domain Regulates Transcription (R-HSA-9013508)
  NOTCH4 Intracellular Domain Regulates Transcription (R-HSA-9013695)
  Formation of paraxial mesoderm (R-HSA-9793380)
  Pre-NOTCH Transcription and Translation (R-HSA-1912408)

Molecular Interaction Atlas (MIA) of This DOT

27 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[1]
Atrial fibrillation	DIS15W6U	Strong	Genetic Variation	[2]
Cardiac failure	DISDC067	Strong	Genetic Variation	[2]
Chronic obstructive pulmonary disease	DISQCIRF	Strong	Genetic Variation	[3]
Congenital heart defects, multiple types, 2	DISU2NC3	Strong	Genetic Variation	[4]
Endometrial cancer	DISW0LMR	Strong	Altered Expression	[5]
Endometrial carcinoma	DISXR5CY	Strong	Altered Expression	[5]
Ewing sarcoma	DISQYLV3	Strong	Genetic Variation	[6]
Familial hypertrophic cardiomyopathy	DISQ89HN	Strong	Genetic Variation	[3]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[7]
Gastroesophageal reflux disease	DISQ8G5S	Strong	Genetic Variation	[8]
Hepatitis B virus infection	DISLQ2XY	Strong	Altered Expression	[9]
Heterotaxy, visceral, 1, X-linked	DIS01H96	Strong	Genetic Variation	[4]
Malignant soft tissue neoplasm	DISTC6NO	Strong	Biomarker	[10]
Mammary analogue secretory carcinoma	DISGXZ2Q	Strong	Biomarker	[11]
Neuroendocrine neoplasm	DISNPLOO	Strong	Genetic Variation	[12]
Pancreatic cancer	DISJC981	Strong	Biomarker	[13]
Paraganglioma	DIS2XXH5	Strong	Genetic Variation	[12]
Pheochromocytoma	DIS56IFV	Strong	Genetic Variation	[12]
Sarcoma	DISZDG3U	Strong	Biomarker	[10]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[14]
Small-cell lung cancer	DISK3LZD	Strong	Biomarker	[13]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[7]
Stroke	DISX6UHX	Strong	Genetic Variation	[2]
Type-1/2 diabetes	DISIUHAP	Strong	Genetic Variation	[2]
Asthma	DISW9QNS	Limited	Biomarker	[15]
Neoplasm	DISZKGEW	Limited	Biomarker	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Mastermind-like protein 3 (MAML3).	[17]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Mastermind-like protein 3 (MAML3).	[18]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Mastermind-like protein 3 (MAML3).	[19]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Mastermind-like protein 3 (MAML3).	[20]
Mifepristone	DMGZQEF	Approved	Mifepristone increases the expression of Mastermind-like protein 3 (MAML3).	[21]
Enzalutamide	DMGL19D	Approved	Enzalutamide affects the expression of Mastermind-like protein 3 (MAML3).	[22]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Mastermind-like protein 3 (MAML3).	[23]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Mastermind-like protein 3 (MAML3).	[24]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Mastermind-like protein 3 (MAML3).	[17]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Mastermind-like protein 3 (MAML3).	[26]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the methylation of Mastermind-like protein 3 (MAML3).	[25]

References

• [1] Mastermind-Like 3 Controls Proliferation and Differentiation in Neuroblastoma.Mol Cancer Res. 2016 May;14(5):411-22. doi: 10.1158/1541-7786.MCR-15-0291-T. Epub 2016 Jan 19.
• [2] Pleiotropic Meta-Analyses of Longitudinal Studies Discover Novel Genetic Variants Associated with Age-Related Diseases.Front Genet. 2016 Oct 13;7:179. doi: 10.3389/fgene.2016.00179. eCollection 2016.
• [3] Dissecting the genetics of chronic mucus hypersecretion in smokers with and without COPD.Eur Respir J. 2015 Jan;45(1):60-75. doi: 10.1183/09031936.00093314. Epub 2014 Sep 18.
• [4] A genome-wide association study identifies two risk loci for congenital heart malformations in Han Chinese populations.Nat Genet. 2013 Jul;45(7):818-21. doi: 10.1038/ng.2636. Epub 2013 May 26.
• [5] SOX17 is a tumor suppressor in endometrial cancer.Oncotarget. 2016 Nov 15;7(46):76036-76046. doi: 10.18632/oncotarget.12582.
• [6] BCOR-CCNB3 Fusion Positive Sarcomas: A Clinicopathologic and Molecular Analysis of 36 Cases With Comparison to Morphologic Spectrum and Clinical Behavior of Other Round Cell Sarcomas.Am J Surg Pathol. 2018 May;42(5):604-615. doi: 10.1097/PAS.0000000000000965.
• [7] MiR-2392 suppresses metastasis and epithelial-mesenchymal transition by targeting MAML3 and WHSC1 in gastric cancer.FASEB J. 2017 Sep;31(9):3774-3786. doi: 10.1096/fj.201601140RR. Epub 2017 May 16.
• [8] Gastroesophageal reflux GWAS identifies risk loci that also associate with subsequent severe esophageal diseases.Nat Commun. 2019 Sep 16;10(1):4219. doi: 10.1038/s41467-019-11968-2.
• [9] Applying a highly specific and reproducible cDNA RDA method to clone garlic up-regulated genes in human gastric cancer cells.World J Gastroenterol. 2002 Apr;8(2):213-6. doi: 10.3748/wjg.v8.i2.213.
• [10] Recurrent PAX3-MAML3 fusion in biphenotypic sinonasal sarcoma.Nat Genet. 2014 Jul;46(7):666-8. doi: 10.1038/ng.2989. Epub 2014 May 25.
• [11] Novel gene fusions in secretory carcinoma of the salivary glands: enlarging the ETV6 family.Hum Pathol. 2019 Jan;83:50-58. doi: 10.1016/j.humpath.2018.08.011. Epub 2018 Aug 18.
• [12] Master regulator analysis of paragangliomas carrying SDHx, VHL, or MAML3 genetic alterations.BMC Cancer. 2019 Jun 24;19(1):619. doi: 10.1186/s12885-019-5813-z.
• [13] RBPJ and MAML3: Potential Therapeutic Targets for Small Cell Lung Cancer. Anticancer Res. 2018 Aug;38(8):4543-4547.
• [14] Pleiotropic Meta-Analysis of Cognition, Education, and Schizophrenia Differentiates Roles of Early Neurodevelopmental and Adult Synaptic Pathways.Am J Hum Genet. 2019 Aug 1;105(2):334-350. doi: 10.1016/j.ajhg.2019.06.012.
• [15] PTTG1IP and MAML3, novel genomewide association study genes for severity of hyperresponsiveness in adult asthma.Allergy. 2017 May;72(5):792-801. doi: 10.1111/all.13062. Epub 2016 Nov 21.
• [16] Hypoxia but not normoxia promotes Smoothened transcription through upregulation of RBPJ and Mastermind-like 3 in pancreatic cancer.Cancer Lett. 2016 Feb 28;371(2):143-50. doi: 10.1016/j.canlet.2015.11.012. Epub 2015 Nov 30.
• [17] 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.
• [18] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [19] 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.
• [20] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [21] Mifepristone induced progesterone withdrawal reveals novel regulatory pathways in human endometrium. Mol Hum Reprod. 2007 Sep;13(9):641-54.
• [22] NOTCH signaling is activated in and contributes to resistance in enzalutamide-resistant prostate cancer cells. J Biol Chem. 2019 May 24;294(21):8543-8554. doi: 10.1074/jbc.RA118.006983. Epub 2019 Apr 2.
• [23] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [24] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [25] 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.
• [26] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.