Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJCC3HS)

• DOT Name: E3 ubiquitin-protein ligase MIB2 (MIB2)
• Synonyms: EC 2.3.2.27; Mind bomb homolog 2; Novel zinc finger protein; Novelzin; Putative NF-kappa-B-activating protein 002N; RING-type E3 ubiquitin transferase MIB2; Skeletrophin; Zinc finger ZZ type with ankyrin repeat domain protein 1
• Gene Name: MIB2
• Related Disease:
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Gastric disease
  Plasma cell myeloma
  Thyroid gland carcinoma
  Cutaneous melanoma
  Left ventricular noncompaction
  Melanoma
  Neoplasm
• UniProt ID: MIB2_HUMAN
• EC Number: 2.3.2.27
• Pfam ID: PF00023 ; PF12796 ; PF06701 ; PF18346 ; PF13920 ; PF00569
• Sequence:
  MDPDPQAGVQVGMRVVRGVDWKWGQQDGGEGGVGTVVELGRHGSPSTPDRTVVVQWDQGT
  RTNYRAGYQGAHDLLLYDNAQIGVRHPNIICDCCKKHGLRGMRWKCRVCLDYDLCTQCYM
  HNKHELAHAFDRYETAHSRPVTLSPRQGLPRIPLRGIFQGAKVVRGPDWEWGSQDGGEGK
  PGRVVDIRGWDVETGRSVASVTWADGTTNVYRVGHKGKVDLKCVGEAAGGFYYKDHLPRL
  GKPAELQRRVSADSQPFQHGDKVKCLLDTDVLREMQEGHGGWNPRMAEFIGQTGTVHRIT
  DRGDVRVQFNHETRWTFHPGALTKHHSFWVGDVVRVIGDLDTVKRLQAGHGEWTDDMAPA
  LGRVGKVVKVFGDGNLRVAVAGQRWTFSPSCLVAYRPEEDANLDVAERARENKSSLSVAL
  DKLRAQKSDPEHPGRLVVEVALGNAARALDLLRRRPEQVDTKNQGRTALQVAAYLGQVEL
  IRLLLQARAGVDLPDDEGNTALHYAALGNQPEATRVLLSAGCRADAINSTQSTALHVAVQ
  RGFLEVVRALCERGCDVNLPDAHSDTPLHSAISAGTGASGIVEVLTEVPNIDVTATNSQG
  FTLLHHASLKGHALAVRKILARARQLVDAKKEDGFTALHLAALNNHREVAQILIREGRCD
  VNVRNRKLQSPLHLAVQQAHVGLVPLLVDAGCSVNAEDEEGDTALHVALQRHQLLPLVAD
  GAGGDPGPLQLLSRLQASGLPGSAELTVGAAVACFLALEGADVSYTNHRGRSPLDLAAEG
  RVLKALQGCAQRFRERQAGGGAAPGPRQTLGTPNTVTNLHVGAAPGPEAAECLVCSELAL
  LVLFSPCQHRTVCEECARRMKKCIRCQVVVSKKLRPDGSEVASAAPAPGPPRQLVEELQS
  RYRQMEERITCPICIDSHIRLVFQCGHGACAPCGSALSACPICRQPIRDRIQIFV
• Function: E3 ubiquitin-protein ligase that mediates ubiquitination of Delta receptors, which act as ligands of Notch proteins. Positively regulates the Delta-mediated Notch signaling by ubiquitinating the intracellular domain of Delta, leading to endocytosis of Delta receptors.
• Tissue Specificity: Expressed in skeletal muscle, and to a lesser extent in heart, brain and kidney.
• KEGG Pathway: Lipid and atherosclerosis (hsa05417)
• Reactome Pathway:
  Constitutive Signaling by NOTCH1 PEST Domain Mutants (R-HSA-2644606)
  Constitutive Signaling by NOTCH1 HD Domain Mutants (R-HSA-2691232)
  Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants (R-HSA-2894862)
  NOTCH2 Activation and Transmission of Signal to the Nucleus (R-HSA-2979096)
  TNFR1-induced proapoptotic signaling (R-HSA-5357786)
  Regulation of TNFR1 signaling (R-HSA-5357905)
  NOTCH3 Activation and Transmission of Signal to the Nucleus (R-HSA-9013507)
  Antigen processing (R-HSA-983168)
  Activated NOTCH1 Transmits Signal to the Nucleus (R-HSA-2122948)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Breast cancer	DIS7DPX1	Strong	Biomarker	[2]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[2]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[3]
Gastric disease	DISNZNTG	Strong	Genetic Variation	[4]
Plasma cell myeloma	DIS0DFZ0	Strong	Biomarker	[5]
Thyroid gland carcinoma	DISMNGZ0	Strong	Biomarker	[6]
Cutaneous melanoma	DIS3MMH9	moderate	Biomarker	[7]
Left ventricular noncompaction	DISJ4QEG	Limited	SusceptibilityMutation	[4]
Melanoma	DIS1RRCY	Limited	Biomarker	[8]
Neoplasm	DISZKGEW	Limited	Biomarker	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of E3 ubiquitin-protein ligase MIB2 (MIB2).	[10]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of E3 ubiquitin-protein ligase MIB2 (MIB2).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of E3 ubiquitin-protein ligase MIB2 (MIB2).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of E3 ubiquitin-protein ligase MIB2 (MIB2).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of E3 ubiquitin-protein ligase MIB2 (MIB2).	[11]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of E3 ubiquitin-protein ligase MIB2 (MIB2).	[12]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of E3 ubiquitin-protein ligase MIB2 (MIB2).	[14]
Ethinyl estradiol	DMODJ40	Approved	Ethinyl estradiol decreases the expression of E3 ubiquitin-protein ligase MIB2 (MIB2).	[15]
Enzalutamide	DMGL19D	Approved	Enzalutamide affects the expression of E3 ubiquitin-protein ligase MIB2 (MIB2).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of E3 ubiquitin-protein ligase MIB2 (MIB2).	[18]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of E3 ubiquitin-protein ligase MIB2 (MIB2).	[20]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of E3 ubiquitin-protein ligase MIB2 (MIB2).	[21]

References

• [1] Genomics and epigenetics: A study of ependymomas in pediatric patients.Clin Neurol Neurosurg. 2016 May;144:53-8. doi: 10.1016/j.clineuro.2016.02.041. Epub 2016 Mar 5.
• [2] ZNF121 interacts with ZBRK1 and BRCA1 to regulate their target genes in mammary epithelial cells.FEBS Open Bio. 2018 Nov 8;8(12):1943-1952. doi: 10.1002/2211-5463.12530. eCollection 2018 Dec.
• [3] ZNF652, a novel zinc finger protein, interacts with the putative breast tumor suppressor CBFA2T3 to repress transcription.Mol Cancer Res. 2006 Sep;4(9):655-65. doi: 10.1158/1541-7786.MCR-05-0249.
• [4] MIB2 variants altering NOTCH signalling result in left ventricle hypertrabeculation/non-compaction and are associated with Mntrier-like gastropathy.Hum Mol Genet. 2017 Jan 1;26(1):33-43. doi: 10.1093/hmg/ddw365.
• [5] Skeletrophin, a novel ubiquitin ligase to the intracellular region of Jagged-2, is aberrantly expressed in multiple myeloma.Am J Pathol. 2005 Jun;166(6):1817-26. doi: 10.1016/S0002-9440(10)62491-1.
• [6] RREB-1, a novel zinc finger protein, is involved in the differentiation response to Ras in human medullary thyroid carcinomas.Mol Cell Biol. 1996 Oct;16(10):5335-45. doi: 10.1128/MCB.16.10.5335.
• [7] Skeletrophin, a novel RING molecule controlled by the chromatin remodeling complex, is downregulated in malignant melanoma.DNA Cell Biol. 2005 May;24(5):339-44. doi: 10.1089/dna.2005.24.339.
• [8] A ubiquitin ligase, skeletrophin, is a negative regulator of melanoma invasion.Oncogene. 2006 Nov 9;25(53):7059-69. doi: 10.1038/sj.onc.1209688. Epub 2006 May 22.
• [9] Overexpression of the human ZNF300 gene enhances growth and metastasis of cancer cells through activating NF-kB pathway.J Cell Mol Med. 2012 May;16(5):1134-45. doi: 10.1111/j.1582-4934.2011.01388.x.
• [10] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [11] 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.
• [12] 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.
• [13] 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.
• [14] 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.
• [15] The genomic response of a human uterine endometrial adenocarcinoma cell line to 17alpha-ethynyl estradiol. Toxicol Sci. 2009 Jan;107(1):40-55.
• [16] 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.
• [17] 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.
• [18] 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.
• [19] 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.
• [20] 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.
• [21] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.