Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTVQR4R9)

• DOT Name: Transcriptional activator MN1 (MN1)
• Synonyms: Probable tumor suppressor protein MN1
• Gene Name: MN1
• Related Disease:
  Acute myelogenous leukaemia
  Advanced cancer
  Breast carcinoma
  CEBALID syndrome
  Chromosomal disorder
  Colorectal carcinoma
  Myeloid leukaemia
  Neuroepithelial neoplasm
  Intellectual disability
  Cleft palate
  Craniosynostosis
  Deafness
  Familial meningioma
  Isolated cleft palate
  Neoplasm
  Neurofibromatosis type 2
• UniProt ID: MN1_HUMAN
• Sequence:
  MFGLDQFEPQVNSRNAGQGERNFNETGLSMNTHFKAPAFHTGGPPGPVDPAMSALGEPPI
  LGMNMEPYGFHARGHSELHAGGLQAQPVHGFFGGQQPHHGHPGSHHPHQHHPHFGGNFGG
  PDPGASCLHGGRLLGYGGAAGGLGSQPPFAEGYEHMAESQGPESFGPQRPGNLPDFHSSG
  ASSHAVPAPCLPLDQSPNRAASFHGLPSSSGSDSHSLEPRRVTNQGAVDSLEYNYPGEAP
  SGHFDMFSPSDSEGQLPHYAAGRQVPGGAFPGASAMPRAAGMVGLSKMHAQPPQQQPQQQ
  QQPQQQQQQHGVFFERFSGARKMPVGLEPSVGSRHPLMQPPQQAPPPPQQQPPQQPPQQQ
  PPPPPGLLVRQNSCPPALPRPQQGEAGTPSGGLQDGGPMLPSQHAQFEYPIHRLENRSMH
  PYSEPVFSMQHPPPQQAPNQRLQHFDAPPYMNVAKRPRFDFPGSAGVDRCASWNGSMHNG
  ALDNHLSPSAYPGLPGEFTPPVPDSFPSGPPLQHPAPDHQSLQQQQQQQQQQQQQQQQQQ
  QQQQQQQQQQRQNAALMIKQMASRNQQQRLRQPNLAQLGHPGDVGQGGLVHGGPVGGLAQ
  PNFEREGGSTGAGRLGTFEQQAPHLAQESAWFSGPHPPPGDLLPRRMGGSGLPADCGPHD
  PSLAPPPPPGGSGVLFRGPLQEPMRMPGEGHVPALPSPGLQFGGSLGGLGQLQSPGAGVG
  LPSAASERRPPPPDFATSALGGQPGFPFGAAGRQSTPHSGPGVNSPPSAGGGGGSSGGGG
  GGGAYPPQPDFQPSQRTSASKLGALSLGSFNKPSSKDNLFGQSCLAALSTACQNMIASLG
  APNLNVTFNKKNPPEGKRKLSQNETDGAAVAGNPGSDYFPGGTAPGAPGPGGPSGTSSSG
  SKASGPPNPPAQGDGTSLSPNYTLESTSGNDGKPVSGGGGRGRGRRKRDSGHVSPGTFFD
  KYSAAPDSGGAPGVSPGQQQASGAAVGGSSAGETRGAPTPHEKALTSPSWGKGAELLLGD
  QPDLIGSLDGGAKSDSSSPNVGEFASDEVSTSYANEDEVSSSSDNPQALVKASRSPLVTG
  SPKLPPRGVGAGEHGPKAPPPALGLGIMSNSTSTPDSYGGGGGPGHPGTPGLEQVRTPTS
  SSGAPPPDEIHPLEILQAQIQLQRQQFSISEDQPLGLKGGKKGECAVGASGAQNGDSELG
  SCCSEAVKSAMSTIDLDSLMAEHSAAWYMPADKALVDSADDDKTLAPWEKAKPQNPNSKE
  AHDLPANKASASQPGSHLQCLSVHCTDDVGDAKARASVPTWRSLHSDISNRFGTFVAALT
• Function: Transcriptional activator which specifically regulates expression of TBX22 in the posterior region of the developing palate. Required during later stages of palate development for growth and medial fusion of the palatal shelves. Promotes maturation and normal function of calvarial osteoblasts, including expression of the osteoclastogenic cytokine TNFSF11/RANKL. Necessary for normal development of the membranous bones of the skull. May play a role in tumor suppression (Probable).
• Tissue Specificity: Widely expressed in fetal and adult tissues. Highest expression is observed in fetal brain and skeletal muscle, and adult skeletal muscle.

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[2]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[3]
CEBALID syndrome	DISNT9JK	Strong	Autosomal dominant	[4]
Chromosomal disorder	DISM5BB5	Strong	Genetic Variation	[5]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[6]
Myeloid leukaemia	DISMN944	Strong	Biomarker	[7]
Neuroepithelial neoplasm	DISCYKLP	Strong	Biomarker	[8]
Intellectual disability	DISMBNXP	moderate	Genetic Variation	[9]
Cleft palate	DIS6G5TF	Limited	Biomarker	[10]
Craniosynostosis	DIS6J405	Limited	Biomarker	[11]
Deafness	DISKCLH4	Limited	Biomarker	[11]
Familial meningioma	DIS30G91	Limited	Autosomal dominant	[4]
Isolated cleft palate	DISV80CD	Limited	Biomarker	[10]
Neoplasm	DISZKGEW	Limited	Altered Expression	[12]
Neurofibromatosis type 2	DISI8ECS	Limited	Genetic Variation	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Transcriptional activator MN1 (MN1).	[14]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Transcriptional activator MN1 (MN1).	[15]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Transcriptional activator MN1 (MN1).	[16]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Transcriptional activator MN1 (MN1).	[17]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Transcriptional activator MN1 (MN1).	[18]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Transcriptional activator MN1 (MN1).	[19]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Transcriptional activator MN1 (MN1).	[20]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Transcriptional activator MN1 (MN1).	[21]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Transcriptional activator MN1 (MN1).	[22]
Troglitazone	DM3VFPD	Approved	Troglitazone increases the expression of Transcriptional activator MN1 (MN1).	[23]
Seocalcitol	DMKL9QO	Phase 3	Seocalcitol increases the expression of Transcriptional activator MN1 (MN1).	[24]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Transcriptional activator MN1 (MN1).	[26]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Transcriptional activator MN1 (MN1).	[27]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Transcriptional activator MN1 (MN1).	[29]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Transcriptional activator MN1 (MN1).	[30]

2 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 increases the methylation of Transcriptional activator MN1 (MN1).	[25]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Transcriptional activator MN1 (MN1).	[28]

References

• [1] MN1 and PTEN gene expression in acute myeloid leukemia.Cancer Biomark. 2017;18(2):177-182. doi: 10.3233/CBM-160235.
• [2] Two unbalanced translocations, t(12;22)(p13;q11) and t(12;?)(p13;?), in an aggressive chronic B-cell leukemia: TEL gene analysis using FISH.Cancer Genet Cytogenet. 1997 Jun;95(2):137-40. doi: 10.1016/s0165-4608(96)00257-9.
• [3] Association analysis identifies 65 new breast cancer risk loci.Nature. 2017 Nov 2;551(7678):92-94. doi: 10.1038/nature24284. Epub 2017 Oct 23.
• [4] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [5] Myeloid neoplasms with t(12;22)(p13;q12)/MN1-EVT6: a systematic review of 12 cases.Ann Hematol. 2018 Mar;97(3):417-424. doi: 10.1007/s00277-017-3208-2. Epub 2017 Dec 22.
• [6] High expression of meningioma 1 is correlated with reduced survival rates in colorectal cancer patients.Acta Histochem. 2019 Jul;121(5):628-637. doi: 10.1016/j.acthis.2019.05.006. Epub 2019 May 24.
• [7] MN1, a novel player in human AML.Blood Cells Mol Dis. 2007 Nov-Dec;39(3):336-9. doi: 10.1016/j.bcmd.2007.06.009. Epub 2007 Aug 14.
• [8] Multimodal molecular analysis of astroblastoma enables reclassification of most cases into more specific molecular entities.Brain Pathol. 2018 Mar;28(2):192-202. doi: 10.1111/bpa.12561. Epub 2017 Oct 27.
• [9] Craniofacial abnormalities and developmental delay in two families with overlapping 22q12.1 microdeletions involving the MN1 gene.Am J Med Genet A. 2015 May;167A(5):1047-53. doi: 10.1002/ajmg.a.36839. Epub 2015 Mar 21.
• [10] Chromosome 22q12.1 microdeletions: confirmation of the MN1 gene as a candidate gene for cleft palate.Eur J Hum Genet. 2016 Jan;24(1):51-8. doi: 10.1038/ejhg.2015.65. Epub 2015 May 6.
• [11] Targeted disruption of the Mn1 oncogene results in severe defects in development of membranous bones of the cranial skeleton.Mol Cell Biol. 2005 May;25(10):4229-36. doi: 10.1128/MCB.25.10.4229-4236.2005.
• [12] Cloning and characterization of MN1, a gene from chromosome 22q11, which is disrupted by a balanced translocation in a meningioma.Oncogene. 1995 Apr 20;10(8):1521-8.
• [13] Exome sequencing on malignant meningiomas identified mutations in neurofibromatosis type 2 (NF2) and meningioma 1 (MN1) genes.Discov Med. 2014 Dec;18(101):301-311.
• [14] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [15] 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.
• [16] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [17] 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.
• [18] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [19] 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.
• [20] The 1,25(OH)2D3-regulated transcription factor MN1 stimulates vitamin D receptor-mediated transcription and inhibits osteoblastic cell proliferation. Mol Endocrinol. 2005 Sep;19(9):2234-44. doi: 10.1210/me.2005-0081. Epub 2005 May 12.
• [21] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [22] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [23] Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
• [24] Expression profiling in squamous carcinoma cells reveals pleiotropic effects of vitamin D3 analog EB1089 signaling on cell proliferation, differentiation, and immune system regulation. Mol Endocrinol. 2002 Jun;16(6):1243-56.
• [25] 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.
• [26] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [27] 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.
• [28] 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.
• [29] 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.
• [30] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.