Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTWN1PGU)

• DOT Name: E3 ubiquitin-protein ligase Midline-1 (MID1)
• Synonyms: EC 2.3.2.27; Midin; Putative transcription factor XPRF; RING finger protein 59; RING finger protein Midline-1; RING-type E3 ubiquitin transferase Midline-1; Tripartite motif-containing protein 18
• Gene Name: MID1
• Related Disease:
  X-linked Opitz G/BBB syndrome
  Alzheimer disease
  Asthma
  Bone osteosarcoma
  Castration-resistant prostate carcinoma
  Cerebellar ataxia
  Chondrosarcoma
  Cleft lip/palate
  Cryptococcosis
  Eosinophilic esophagitis
  Hypospadias
  Lung adenocarcinoma
  Lung cancer
  Lung carcinoma
  Osteosarcoma
  Prostate cancer
  Prostate carcinoma
  Pulmonary disease
  Pulmonary fibrosis
  Split hand-foot malformation
  Syndactyly
  Tauopathy
  Advanced cancer
  Colorectal carcinoma
  Epileptic encephalopathy
  Intellectual disability
  Neoplasm
• UniProt ID: TRI18_HUMAN
• PDB ID: 2DQ5; 2FFW; 2JUN; 5IM8; 7QRY
• EC Number: 2.3.2.27
• Pfam ID: PF18568 ; PF00041 ; PF00622 ; PF00643 ; PF13445
• Sequence:
  METLESELTCPICLELFEDPLLLPCAHSLCFNCAHRILVSHCATNESVESITAFQCPTCR
  HVITLSQRGLDGLKRNVTLQNIIDRFQKASVSGPNSPSETRRERAFDANTMTSAEKVLCQ
  FCDQDPAQDAVKTCVTCEVSYCDECLKATHPNKKPFTGHRLIEPIPDSHIRGLMCLEHED
  EKVNMYCVTDDQLICALCKLVGRHRDHQVAALSERYDKLKQNLESNLTNLIKRNTELETL
  LAKLIQTCQHVEVNASRQEAKLTEECDLLIEIIQQRRQIIGTKIKEGKVMRLRKLAQQIA
  NCKQCIERSASLISQAEHSLKENDHARFLQTAKNITERVSMATASSQVLIPEINLNDTFD
  TFALDFSREKKLLECLDYLTAPNPPTIREELCTASYDTITVHWTSDDEFSVVSYELQYTI
  FTGQANVVSLCNSADSWMIVPNIKQNHYTVHGLQSGTKYIFMVKAINQAGSRSSEPGKLK
  TNSQPFKLDPKSAHRKLKVSHDNLTVERDESSSKKSHTPERFTSQGSYGVAGNVFIDSGR
  HYWEVVISGSTWYAIGLAYKSAPKHEWIGKNSASWALCRCNNNWVVRHNSKEIPIEPAPH
  LRRVGILLDYDNGSIAFYDALNSIHLYTFDVAFAQPVCPTFTVWNKCLTIITGLPIPDHL
  DCTEQLP
• Function: Has E3 ubiquitin ligase activity towards IGBP1, promoting its monoubiquitination, which results in deprotection of the catalytic subunit of protein phosphatase PP2A, and its subsequent degradation by polyubiquitination.
• Tissue Specificity: In the fetus, highest expression found in kidney, followed by brain and lung. Expressed at low levels in fetal liver. In the adult, most abundant in heart, placenta and brain.
• KEGG Pathway: Ubiquitin mediated proteolysis (hsa04120)
• Reactome Pathway: Interferon gamma signaling (R-HSA-877300)

Molecular Interaction Atlas (MIA) of This DOT

27 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
X-linked Opitz G/BBB syndrome	DISQ14EC	Definitive	X-linked	[1]
Alzheimer disease	DISF8S70	Strong	Biomarker	[2]
Asthma	DISW9QNS	Strong	Biomarker	[3]
Bone osteosarcoma	DIST1004	Strong	Altered Expression	[4]
Castration-resistant prostate carcinoma	DISVGAE6	Strong	Biomarker	[5]
Cerebellar ataxia	DIS9IRAV	Strong	Altered Expression	[5]
Chondrosarcoma	DIS4I7JB	Strong	Biomarker	[6]
Cleft lip/palate	DIS14IG3	Strong	Genetic Variation	[7]
Cryptococcosis	DISDYDTK	Strong	Altered Expression	[8]
Eosinophilic esophagitis	DISR8WSB	Strong	Altered Expression	[9]
Hypospadias	DIS48CCP	Strong	Genetic Variation	[10]
Lung adenocarcinoma	DISD51WR	Strong	Altered Expression	[3]
Lung cancer	DISCM4YA	Strong	Biomarker	[11]
Lung carcinoma	DISTR26C	Strong	Biomarker	[11]
Osteosarcoma	DISLQ7E2	Strong	Altered Expression	[4]
Prostate cancer	DISF190Y	Strong	Biomarker	[5]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[5]
Pulmonary disease	DIS6060I	Strong	Biomarker	[3]
Pulmonary fibrosis	DISQKVLA	Strong	Altered Expression	[12]
Split hand-foot malformation	DIS8PKGD	Strong	Biomarker	[13]
Syndactyly	DISZK2BT	Strong	Genetic Variation	[14]
Tauopathy	DISY2IPA	Strong	Biomarker	[2]
Advanced cancer	DISAT1Z9	moderate	Altered Expression	[15]
Colorectal carcinoma	DIS5PYL0	Limited	Biomarker	[16]
Epileptic encephalopathy	DISZOCA3	Limited	Genetic Variation	[17]
Intellectual disability	DISMBNXP	Limited	Genetic Variation	[18]
Neoplasm	DISZKGEW	Limited	Biomarker	[19]

16 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 E3 ubiquitin-protein ligase Midline-1 (MID1).	[20]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of E3 ubiquitin-protein ligase Midline-1 (MID1).	[21]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of E3 ubiquitin-protein ligase Midline-1 (MID1).	[22]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of E3 ubiquitin-protein ligase Midline-1 (MID1).	[23]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of E3 ubiquitin-protein ligase Midline-1 (MID1).	[24]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of E3 ubiquitin-protein ligase Midline-1 (MID1).	[25]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of E3 ubiquitin-protein ligase Midline-1 (MID1).	[26]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of E3 ubiquitin-protein ligase Midline-1 (MID1).	[27]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of E3 ubiquitin-protein ligase Midline-1 (MID1).	[28]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of E3 ubiquitin-protein ligase Midline-1 (MID1).	[29]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of E3 ubiquitin-protein ligase Midline-1 (MID1).	[30]
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the expression of E3 ubiquitin-protein ligase Midline-1 (MID1).	[31]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate increases the expression of E3 ubiquitin-protein ligase Midline-1 (MID1).	[32]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of E3 ubiquitin-protein ligase Midline-1 (MID1).	[21]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of E3 ubiquitin-protein ligase Midline-1 (MID1).	[33]
GW7647	DM9RD0C	Investigative	GW7647 increases the expression of E3 ubiquitin-protein ligase Midline-1 (MID1).	[34]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] Resveratrol induces dephosphorylation of Tau by interfering with the MID1-PP2A complex.Sci Rep. 2017 Oct 23;7(1):13753. doi: 10.1038/s41598-017-12974-4.
• [3] MID1-PP2A complex functions as new insights in human lung adenocarcinoma.J Cancer Res Clin Oncol. 2018 May;144(5):855-864. doi: 10.1007/s00432-018-2601-0. Epub 2018 Feb 15.
• [4] Osteogenic BMPs promote tumor growth of human osteosarcomas that harbor differentiation defects.Lab Invest. 2008 Dec;88(12):1264-77. doi: 10.1038/labinvest.2008.98. Epub 2008 Oct 6.
• [5] A hormone-dependent feedback-loop controls androgen receptor levels by limiting MID1, a novel translation enhancer and promoter of oncogenic signaling.Mol Cancer. 2014 Jun 9;13:146. doi: 10.1186/1476-4598-13-146.
• [6] Novel mTORC1 Mechanism Suggests Therapeutic Targets for COMPopathies.Am J Pathol. 2019 Jan;189(1):132-146. doi: 10.1016/j.ajpath.2018.09.008.
• [7] Structural and functional observations of the P151L MID1 mutation reveal alpha4 plays a significant role in X-linked Opitz Syndrome.FEBS J. 2017 Jul;284(14):2183-2193. doi: 10.1111/febs.14121. Epub 2017 Jun 14.
• [8] Roles of Cch1 and Mid1 in morphogenesis, oxidative stress response and virulence in Candida albicans.Mycopathologia. 2012 Dec;174(5-6):359-69. doi: 10.1007/s11046-012-9569-0. Epub 2012 Aug 12.
• [9] TRAIL deficiency and PP2A activation with salmeterol ameliorates egg allergen-driven eosinophilic esophagitis.Am J Physiol Gastrointest Liver Physiol. 2016 Dec 1;311(6):G998-G1008. doi: 10.1152/ajpgi.00151.2016. Epub 2016 Oct 13.
• [10] Complex rearrangement of the exon 6 genomic region among Opitz G/BBB Syndrome MID1 alterations.Eur J Med Genet. 2013 Aug;56(8):404-10. doi: 10.1016/j.ejmg.2013.05.009. Epub 2013 Jun 19.
• [11] Rational combinations of indirubin and arylidene derivatives exhibit synergism in human non-small cell lung carcinoma cells.J Food Biochem. 2019 Jul;43(7):e12861. doi: 10.1111/jfbc.12861. Epub 2019 Apr 24.
• [12] TRAIL signals through the ubiquitin ligase MID1 to promote pulmonary fibrosis.BMC Pulm Med. 2019 Feb 7;19(1):31. doi: 10.1186/s12890-019-0786-x.
• [13] Genes causing clefting syndromes as candidates for non-syndromic cleft lip with or without cleft palate: a family-based association study.Eur J Oral Sci. 2008 Dec;116(6):507-11. doi: 10.1111/j.1600-0722.2008.00574.x.
• [14] X-linked Opitz syndrome: novel mutations in the MID1 gene and redefinition of the clinical spectrum.Am J Med Genet A. 2003 Jul 15;120A(2):222-8. doi: 10.1002/ajmg.a.10265.
• [15] MicroRNAs miR-19, miR-340, miR-374 and miR-542 regulate MID1 protein expression.PLoS One. 2018 Jan 2;13(1):e0190437. doi: 10.1371/journal.pone.0190437. eCollection 2018.
• [16] A five-gene signature as a potential predictor of metastasis and survival in colorectal cancer.J Pathol. 2010 Mar;220(4):475-89. doi: 10.1002/path.2668.
• [17] Hypospadias associated with hypertelorism, the mildest phenotype of Opitz syndrome.J Hum Genet. 2011 May;56(5):348-51. doi: 10.1038/jhg.2011.17. Epub 2011 Feb 17.
• [18] The E3 ubiquitin ligase MID1/TRIM18 promotes atypical ubiquitination of the BRCA2-associated factor 35, BRAF35.Biochim Biophys Acta Mol Cell Res. 2017 Oct;1864(10):1844-1854. doi: 10.1016/j.bbamcr.2017.07.014. Epub 2017 Jul 29.
• [19] Endothelial-to-Osteoblast Conversion Generates Osteoblastic Metastasis of Prostate Cancer.Dev Cell. 2017 Jun 5;41(5):467-480.e3. doi: 10.1016/j.devcel.2017.05.005.
• [20] Design principles of concentration-dependent transcriptome deviations in drug-exposed differentiating stem cells. Chem Res Toxicol. 2014 Mar 17;27(3):408-20.
• [21] 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.
• [22] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [23] 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.
• [24] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [25] Persistent and non-persistent changes in gene expression result from long-term estrogen exposure of MCF-7 breast cancer cells. J Steroid Biochem Mol Biol. 2011 Feb;123(3-5):140-50.
• [26] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [27] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [28] 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.
• [29] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [30] Effects of progesterone treatment on expression of genes involved in uterine quiescence. Reprod Sci. 2011 Aug;18(8):781-97.
• [31] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [32] Epigallocatechin-3-gallate (EGCG) protects against chromate-induced toxicity in vitro. Toxicol Appl Pharmacol. 2012 Jan 15;258(2):166-75.
• [33] 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.
• [34] Identifying qualitative differences in PPAR signaling networks in human and rat hepatocytes and their significance for next generation chemical risk assessment methods. Toxicol In Vitro. 2020 Apr;64:104463. doi: 10.1016/j.tiv.2019.02.017. Epub 2019 Oct 15.