Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDKO9OO)

• DOT Name: Cyclin-D-binding Myb-like transcription factor 1 (DMTF1)
• Synonyms: hDMTF1; Cyclin-D-interacting Myb-like protein 1; hDMP1
• Gene Name: DMTF1
• Related Disease:
  Non-small-cell lung cancer
  Acute leukaemia
  Advanced cancer
  Bipolar disorder
  Bladder cancer
  Carcinoma
  Dentinogenesis imperfecta
  Diabetic kidney disease
  Lung neoplasm
  Major depressive disorder
  Neoplasm
  Schizophrenia
  Urinary bladder cancer
  Urinary bladder neoplasm
  Acute respiratory failure
  Promyelocytic leukaemia
  Rheumatic fever
• UniProt ID: DMTF1_HUMAN
• PDB ID: 2LLK
• Pfam ID: PF20588 ; PF00249
• Sequence:
  MSTVEEDSDTVTVETVNSVTLTQDTEGNLILHCPQNEADEIDSEDSIEPPHKRLCLSSED
  DQSIDDSTPCISVVALPLSENDQSFEVTMTATTEVADDEVTEGTVTQIQILQNEQLDEIS
  PLGNEEVSAVSQAWFTTKEDKDSLTNKGHKWKQGMWSKEEIDILMNNIERYLKARGIKDA
  TEIIFEMSKDERKDFYRTIAWGLNRPLFAVYRRVLRMYDDRNHVGKYTPEEIEKLKELRI
  KHGNDWATIGAALGRSASSVKDRCRLMKDTCNTGKWTEEEEKRLAEVVHELTSTEPGDIV
  TQGVSWAAVAERVGTRSEKQCRSKWLNYLNWKQSGGTEWTKEDEINLILRIAELDVADEN
  DINWDLLAEGWSSVRSPQWLRSKWWTIKRQIANHKDVSFPVLIKGLKQLHENQKNNPTLL
  ENKSGSGVPNSNTNSSVQHVQIRVARLEDNTAISSSPMAALQIPVQITHVSSADSPATVD
  SETITLNSGTLQTFEILPSFHLQPTGTPGTYLLQTSSSQGLPLTLTASPTVTLTAAAPAS
  PEQIIVHALSPEHLLNTSDNVTVQCHTPRVIIQTVATEDITSSISQAELTVDSDIQSSDF
  PEPPDALEADTFPDEIHHPKMTVEPSFNDAHVSKFSDQNSTELMNSVMVRTEEEISDTDL
  KQEESPSDLASAYVTEGLESPTIEEQVDQTIDDETILIVPSPHGFIQASDVIDTESVLPL
  TTLTDPILQHHQEESNIIGSSLGSPVSEDSKDVEDLVNCH
• Function: Transcriptional activator which activates the CDKN2A/ARF locus in response to Ras-Raf signaling, thereby promoting p53/TP53-dependent growth arrest. Binds to the consensus sequence 5'-CCCG[GT]ATGT-3'. Isoform 1 may cooperate with MYB to activate transcription of the ANPEP gene. Isoform 2 may antagonize transcriptional activation by isoform 1.
• Tissue Specificity: Expressed at relatively low levels in colonic mucosa, ovary, peripheral leukocytes, prostate and small intestine, and at higher levels in spleen, testis and thymus. Expressed in multiple regions of the brain and CNS including amygdala, caudate, corpus callosum, hippocampus, substantia nigra and subthalamic nucleus. Isoform 1 is the predominant isoform in monocytes, macrophages and neutrophils, isoform 2 is most strongly expressed in peripheral blood leukocytes and quiescent CD34 positive cells, and isoform 3 is expressed at low levels in all hematopoietic cell types. Expression is frequently reduced in non-small-cell lung carcinomas (NSCLC) due to hemizygous gene deletion, strongly suggesting that this locus is haploinsufficient for tumor suppression. Loss of this locus frequently occurs in tumors which retain wild-type CDKN2A/ARF and p53/TP53 loci. Hemizygous gene deletion has also been observed in leukemic blasts from patients with abnormalities of the long arm of chromosome 7.

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Non-small-cell lung cancer	DIS5Y6R9	Definitive	Biomarker	[1]
Acute leukaemia	DISDQFDI	Strong	Genetic Variation	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Bipolar disorder	DISAM7J2	Strong	Genetic Variation	[4]
Bladder cancer	DISUHNM0	Strong	Biomarker	[5]
Carcinoma	DISH9F1N	Strong	Genetic Variation	[6]
Dentinogenesis imperfecta	DISJLZU4	Strong	Biomarker	[7]
Diabetic kidney disease	DISJMWEY	Strong	Biomarker	[8]
Lung neoplasm	DISVARNB	Strong	Biomarker	[6]
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[4]
Neoplasm	DISZKGEW	Strong	Biomarker	[9]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[10]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[5]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[5]
Acute respiratory failure	DIS5KQ5Y	Limited	Altered Expression	[11]
Promyelocytic leukaemia	DISYGG13	Limited	Altered Expression	[11]
Rheumatic fever	DISLUF66	Limited	Altered Expression	[11]

14 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 Cyclin-D-binding Myb-like transcription factor 1 (DMTF1).	[12]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Cyclin-D-binding Myb-like transcription factor 1 (DMTF1).	[13]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Cyclin-D-binding Myb-like transcription factor 1 (DMTF1).	[14]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Cyclin-D-binding Myb-like transcription factor 1 (DMTF1).	[15]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Cyclin-D-binding Myb-like transcription factor 1 (DMTF1).	[17]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Cyclin-D-binding Myb-like transcription factor 1 (DMTF1).	[18]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Cyclin-D-binding Myb-like transcription factor 1 (DMTF1).	[19]
Paclitaxel	DMLB81S	Approved	Paclitaxel decreases the expression of Cyclin-D-binding Myb-like transcription factor 1 (DMTF1).	[20]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Cyclin-D-binding Myb-like transcription factor 1 (DMTF1).	[21]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Cyclin-D-binding Myb-like transcription factor 1 (DMTF1).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Cyclin-D-binding Myb-like transcription factor 1 (DMTF1).	[22]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Cyclin-D-binding Myb-like transcription factor 1 (DMTF1).	[23]
geraniol	DMS3CBD	Investigative	geraniol increases the expression of Cyclin-D-binding Myb-like transcription factor 1 (DMTF1).	[24]
OXYBENZONE	DMMZYX6	Investigative	OXYBENZONE increases the expression of Cyclin-D-binding Myb-like transcription factor 1 (DMTF1).	[25]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Cyclin-D-binding Myb-like transcription factor 1 (DMTF1).	[16]

References

• [1] Role of DMP1 and its future in lung cancer diagnostics.Expert Rev Mol Diagn. 2008 Jul;8(4):435-47. doi: 10.1586/14737159.8.4.435.
• [2] Cloning and chromosomal localization of the gene encoding human cyclin D-binding Myb-like protein (hDMP1).Gene. 1999 Mar 18;229(1-2):223-8. doi: 10.1016/s0378-1119(98)00591-5.
• [3] c-MYB and DMTF1 in Cancer.Cancer Invest. 2019;37(1):46-65. doi: 10.1080/07357907.2018.1550090. Epub 2019 Jan 2.
• [4] Meta-analysis of genome-wide association data of bipolar disorder and major depressive disorder.Mol Psychiatry. 2011 Jan;16(1):2-4. doi: 10.1038/mp.2009.107. Epub 2010 Mar 30.
• [5] MicroRNA-155 promotes bladder cancer growth by repressing the tumor suppressor DMTF1.Oncotarget. 2015 Jun 30;6(18):16043-58. doi: 10.18632/oncotarget.3755.
• [6] Mutually exclusive inactivation of DMP1 and ARF/p53 in lung cancer.Cancer Cell. 2007 Oct;12(4):381-94. doi: 10.1016/j.ccr.2007.08.034.
• [7] Dentin matrix protein-1, a candidate gene for dentinogenesis imperfecta.Connect Tissue Res. 1996;35(1-4):267-72. doi: 10.3109/03008209609029200.
• [8] DMP-1 attenuates oxidative stress and inhibits TGF- activation in rats with diabetic kidney disease.Ren Fail. 2017 Nov;39(1):229-235. doi: 10.1080/0886022X.2016.1256319. Epub 2016 Nov 23.
• [9] Understanding Decision Making about Breast Cancer Prevention in Action: The Intersection of Perceived Risk, Perceived Control, and Social Context: NRG Oncology/NSABP DMP-1.Med Decis Making. 2019 Apr;39(3):217-227. doi: 10.1177/0272989X19827258. Epub 2019 Feb 25.
• [10] Genome-Wide Association Study Detected Novel Susceptibility Genes for Schizophrenia and Shared Trans-Populations/Diseases Genetic Effect.Schizophr Bull. 2019 Jun 18;45(4):824-834. doi: 10.1093/schbul/sby140.
• [11] Human DMTF1 antagonizes DMTF1 regulation of the p14(ARF) tumor suppressor and promotes cellular proliferation.Biochim Biophys Acta. 2015 Sep;1849(9):1198-208. doi: 10.1016/j.bbagrm.2015.07.009. Epub 2015 Jul 15.
• [12] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [13] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [14] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [15] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [16] 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.
• [17] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [18] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [19] 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.
• [20] Effects of paclitaxel on proliferation and apoptosis in human acute myeloid leukemia HL-60 cells. Acta Pharmacol Sin. 2004 Mar;25(3):378-84.
• [21] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [22] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [23] Linking site-specific loss of histone acetylation to repression of gene expression by the mycotoxin ochratoxin A. Arch Toxicol. 2018 Feb;92(2):995-1014.
• [24] Geraniol suppresses prostate cancer growth through down-regulation of E2F8. Cancer Med. 2016 Oct;5(10):2899-2908.
• [25] Chromatin modifiers: A new class of pollutants with potential epigenetic effects revealed by in vitro assays and transcriptomic analyses. Toxicology. 2023 Jan 15;484:153413. doi: 10.1016/j.tox.2022.153413. Epub 2022 Dec 26.