Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYX91DX)

• DOT Name: E3 ubiquitin-protein ligase DTX1 (DTX1)
• Synonyms: EC 2.3.2.27; Protein deltex-1; Deltex1; hDTX1; RING-type E3 ubiquitin transferase DTX1
• Gene Name: DTX1
• Related Disease:
  Adult glioblastoma
  Glioblastoma multiforme
  Autoimmune disease
  Bone osteosarcoma
  Hepatitis B virus infection
  HIV infectious disease
  Huntington disease
  Lung cancer
  Lung carcinoma
  Non-small-cell lung cancer
  Noonan syndrome
  Osteosarcoma
  Polyp
  Systemic lupus erythematosus
  Head-neck squamous cell carcinoma
  Neoplasm
  Gastric cancer
  Small lymphocytic lymphoma
  Stomach cancer
• UniProt ID: DTX1_HUMAN
• PDB ID: 6Y5N; 6Y5P
• EC Number: 2.3.2.27
• Pfam ID: PF18102 ; PF02825 ; PF00097
• Sequence:
  MSRPGHGGLMPVNGLGFPPQNVARVVVWEWLNEHSRWRPYTATVCHHIENVLKEDARGSV
  VLGQVDAQLVPYIIDLQSMHQFRQDTGTMRPVRRNFYDPSSAPGKGIVWEWENDGGAWTA
  YDMDICITIQNAYEKQHPWLDLSSLGFCYLIYFNSMSQMNRQTRRRRRLRRRLDLAYPLT
  VGSIPKSQSWPVGASSGQPCSCQQCLLVNSTRAASNAILASQRRKAPPAPPLPPPPPPGG
  PPGALAVRPSATFTGAALWAAPAAGPAEPAPPPGAPPRSPGAPGGARTPGQNNLNRPGPQ
  RTTSVSARASIPPGVPALPVKNLNGTGPVHPALAGMTGILLCAAGLPVCLTRAPKPILHP
  PPVSKSDVKPVPGVPGVCRKTKKKHLKKSKNPEDVVRRYMQKVKNPPDEDCTICMERLVT
  ASGYEGVLRHKGVRPELVGRLGRCGHMYHLLCLVAMYSNGNKDGSLQCPTCKAIYGEKTG
  TQPPGKMEFHLIPHSLPGFPDTQTIRIVYDIPTGIQGPEHPNPGKKFTARGFPRHCYLPN
  NEKGRKVLRLLITAWERRLIFTIGTSNTTGESDTVVWNEIHHKTEFGSNLTGHGYPDASY
  LDNVLAELTAQGVSEAAAKA
• Function: Functions as a ubiquitin ligase protein in vivo, mediating ubiquitination and promoting degradation of MEKK1, suggesting that it may regulate the Notch pathway via some ubiquitin ligase activity. Regulator of Notch signaling, a signaling pathway involved in cell-cell communications that regulates a broad spectrum of cell-fate determinations. Mainly acts as a positive regulator of Notch, but it also acts as a negative regulator, depending on the developmental and cell context. Mediates the antineural activity of Notch, possibly by inhibiting the transcriptional activation mediated by MATCH1. Involved in neurogenesis, lymphogenesis and myogenesis, and may also be involved in MZB (Marginal zone B) cell differentiation. Promotes B-cell development at the expense of T-cell development, suggesting that it can antagonize NOTCH1.
• Tissue Specificity: Widely expressed. Strongly expressed in blood vessel. Also expressed in embryonic nervous system, pancreas, lung, adrenal gland, digestive tube and muscles. Expressed in MZB cells and developing B- and T-cells.
• KEGG Pathway: Notch sig.ling pathway (hsa04330)
• Reactome Pathway: Activated NOTCH1 Transmits Signal to the Nucleus (R-HSA-2122948)

Molecular Interaction Atlas (MIA) of This DOT

19 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult glioblastoma	DISVP4LU	Definitive	Biomarker	[1]
Glioblastoma multiforme	DISK8246	Definitive	Biomarker	[1]
Autoimmune disease	DISORMTM	Strong	Biomarker	[2]
Bone osteosarcoma	DIST1004	Strong	Biomarker	[3]
Hepatitis B virus infection	DISLQ2XY	Strong	Genetic Variation	[4]
HIV infectious disease	DISO97HC	Strong	Biomarker	[5]
Huntington disease	DISQPLA4	Strong	Genetic Variation	[6]
Lung cancer	DISCM4YA	Strong	Biomarker	[7]
Lung carcinoma	DISTR26C	Strong	Biomarker	[7]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Genetic Variation	[7]
Noonan syndrome	DIS7Q7DN	Strong	Biomarker	[8]
Osteosarcoma	DISLQ7E2	Strong	Biomarker	[3]
Polyp	DISRSLYF	Strong	Genetic Variation	[6]
Systemic lupus erythematosus	DISI1SZ7	Strong	Altered Expression	[2]
Head-neck squamous cell carcinoma	DISF7P24	moderate	Altered Expression	[9]
Neoplasm	DISZKGEW	moderate	Altered Expression	[9]
Gastric cancer	DISXGOUK	Limited	Biomarker	[10]
Small lymphocytic lymphoma	DIS30POX	Limited	Altered Expression	[11]
Stomach cancer	DISKIJSX	Limited	Biomarker	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of E3 ubiquitin-protein ligase DTX1 (DTX1).	[12]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of E3 ubiquitin-protein ligase DTX1 (DTX1).	[13]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of E3 ubiquitin-protein ligase DTX1 (DTX1).	[14]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of E3 ubiquitin-protein ligase DTX1 (DTX1).	[17]
Paraquat	DMR8O3X	Investigative	Paraquat affects the expression of E3 ubiquitin-protein ligase DTX1 (DTX1).	[18]

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 decreases the methylation of E3 ubiquitin-protein ligase DTX1 (DTX1).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of E3 ubiquitin-protein ligase DTX1 (DTX1).	[16]

References

• [1] Aberrant expression of Notch1, HES1, and DTX1 genes in glioblastoma formalin-fixed paraffin-embedded tissues.Tumour Biol. 2016 May;37(5):6935-42. doi: 10.1007/s13277-015-4592-7. Epub 2015 Dec 11.
• [2] Deltex1 suppresses T cell function and is a biomarker for diagnosis and disease activity of systemic lupus erythematosus.Rheumatology (Oxford). 2019 Apr 1;58(4):719-728. doi: 10.1093/rheumatology/key418.
• [3] Regulation of NOTCH signaling by reciprocal inhibition of HES1 and Deltex 1 and its role in osteosarcoma invasiveness.Oncogene. 2010 May 20;29(20):2916-26. doi: 10.1038/onc.2010.62. Epub 2010 Mar 8.
• [4] Deltex1 Polymorphisms Are Associated with Hepatitis B Vaccination Non-Response in Southwest China.PLoS One. 2016 Feb 19;11(2):e0149199. doi: 10.1371/journal.pone.0149199. eCollection 2016.
• [5] Molecular signatures of T-cell inhibition in HIV-1 infection.Retrovirology. 2013 Mar 20;10:31. doi: 10.1186/1742-4690-10-31.
• [6] Intrabodies binding the proline-rich domains of mutant huntingtin increase its turnover and reduce neurotoxicity.J Neurosci. 2008 Sep 3;28(36):9013-20. doi: 10.1523/JNEUROSCI.2747-08.2008.
• [7] Genetic Variant of Notch Regulator DTX1 Predicts Survival After Lung Cancer Surgery.Ann Surg Oncol. 2019 Oct;26(11):3756-3764. doi: 10.1245/s10434-019-07614-2. Epub 2019 Jul 16.
• [8] Chromosomal localization, genomic characterization, and mapping to the Noonan syndrome critical region of the human Deltex (DTX1) gene.Hum Genet. 2000 Dec;107(6):577-81. doi: 10.1007/s004390000431.
• [9] Integrative computational analysis of transcriptional and epigenetic alterations implicates DTX1 as a putative tumor suppressor gene in HNSCC.Oncotarget. 2017 Feb 28;8(9):15349-15363. doi: 10.18632/oncotarget.14856.
• [10] c-FLIP is a target of the E3 ligase deltex1 in gastric cancer.Cell Death Dis. 2018 Jan 26;9(2):135. doi: 10.1038/s41419-017-0165-6.
• [11] Ectopic ILT3 controls BCR-dependent activation of Akt in B-cell chronic lymphocytic leukemia.Blood. 2017 Nov 2;130(18):2006-2017. doi: 10.1182/blood-2017-03-775858. Epub 2017 Sep 20.
• [12] 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.
• [13] Differential responses to retinoic acid and endocrine disruptor compounds of subpopulations within human embryonic stem cell lines. Differentiation. 2012 Nov;84(4):330-43. doi: 10.1016/j.diff.2012.07.006. Epub 2012 Aug 18.
• [14] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [15] 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.
• [16] 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.
• [17] 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.
• [18] [Paraquat involves differentiation of human neural stem cells via Notch signaling]. Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi. 2013 Jul;31(7):492-5.