Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTU91HAU)

• DOT Name: Mitotic checkpoint protein BUB3 (BUB3)
• Gene Name: BUB3
• Related Disease:
  Oral lichen planus
  Adult glioblastoma
  Advanced cancer
  Bone osteosarcoma
  Carcinoma
  Glioblastoma multiforme
  Hepatocellular carcinoma
  Lung cancer
  Mosaic variegated aneuploidy syndrome 1
  Osteosarcoma
  Polyposis
  Prostate cancer
  Prostate carcinoma
  Urinary bladder neoplasm
  Oral cancer
  Squamous cell carcinoma
  Stomach cancer
  Mosaic variegated aneuploidy syndrome
  Gastric cancer
  Pancreatic cancer
  Thyroid gland carcinoma
  Thyroid gland follicular carcinoma
  Thyroid gland papillary carcinoma
• UniProt ID: BUB3_HUMAN
• Pfam ID: PF00400
• Sequence:
  MTGSNEFKLNQPPEDGISSVKFSPNTSQFLLVSSWDTSVRLYDVPANSMRLKYQHTGAVL
  DCAFYDPTHAWSGGLDHQLKMHDLNTDQENLVGTHDAPIRCVEYCPEVNVMVTGSWDQTV
  KLWDPRTPCNAGTFSQPEKVYTLSVSGDRLIVGTAGRRVLVWDLRNMGYVQQRRESSLKY
  QTRCIRAFPNKQGYVLSSIEGRVAVEYLDPSPEVQKKKYAFKCHRLKENNIEQIYPVNAI
  SFHNIHNTFATGGSDGFVNIWDPFNKKRLCQFHRYPTSIASLAFSNDGTTLAIASSYMYE
  MDDTEHPEDGIFIRQVTDAETKPKSPCT
• Function: Has a dual function in spindle-assembly checkpoint signaling and in promoting the establishment of correct kinetochore-microtubule (K-MT) attachments. Promotes the formation of stable end-on bipolar attachments. Necessary for kinetochore localization of BUB1. Regulates chromosome segregation during oocyte meiosis. The BUB1/BUB3 complex plays a role in the inhibition of anaphase-promoting complex or cyclosome (APC/C) when spindle-assembly checkpoint is activated and inhibits the ubiquitin ligase activity of APC/C by phosphorylating its activator CDC20. This complex can also phosphorylate MAD1L1.
• KEGG Pathway:
  Cell cycle (hsa04110)
  Human T-cell leukemia virus 1 infection (hsa05166)
• Reactome Pathway:
  Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal (R-HSA-141444)
  Cdc20 (R-HSA-174184)
  APC/C (R-HSA-176409)
  APC-Cdc20 mediated degradation of Nek2A (R-HSA-179409)
  Separation of Sister Chromatids (R-HSA-2467813)
  Resolution of Sister Chromatid Cohesion (R-HSA-2500257)
  RHO GTPases Activate Formins (R-HSA-5663220)
  Mitotic Prometaphase (R-HSA-68877)
  EML4 and NUDC in mitotic spindle formation (R-HSA-9648025)
  Inactivation of APC/C via direct inhibition of the APC/C complex (R-HSA-141430)

Molecular Interaction Atlas (MIA) of This DOT

23 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Oral lichen planus	DISVEAJA	Definitive	Biomarker	[1]
Adult glioblastoma	DISVP4LU	Strong	Altered Expression	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Bone osteosarcoma	DIST1004	Strong	Biomarker	[4]
Carcinoma	DISH9F1N	Strong	Altered Expression	[5]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[2]
Hepatocellular carcinoma	DIS0J828	Strong	Genetic Variation	[6]
Lung cancer	DISCM4YA	Strong	Biomarker	[7]
Mosaic variegated aneuploidy syndrome 1	DISOV0CG	Strong	Genetic Variation	[8]
Osteosarcoma	DISLQ7E2	Strong	Biomarker	[4]
Polyposis	DISZSPOK	Strong	Biomarker	[8]
Prostate cancer	DISF190Y	Strong	Genetic Variation	[9]
Prostate carcinoma	DISMJPLE	Strong	Genetic Variation	[9]
Urinary bladder neoplasm	DIS7HACE	Strong	Genetic Variation	[6]
Oral cancer	DISLD42D	moderate	Altered Expression	[10]
Squamous cell carcinoma	DISQVIFL	moderate	Altered Expression	[10]
Stomach cancer	DISKIJSX	moderate	Genetic Variation	[11]
Mosaic variegated aneuploidy syndrome	DIS5QTMU	Supportive	Autosomal dominant	[12]
Gastric cancer	DISXGOUK	Limited	Genetic Variation	[11]
Pancreatic cancer	DISJC981	Limited	Biomarker	[13]
Thyroid gland carcinoma	DISMNGZ0	Limited	Genetic Variation	[14]
Thyroid gland follicular carcinoma	DISFK2QT	Limited	Genetic Variation	[14]
Thyroid gland papillary carcinoma	DIS48YMM	Limited	Genetic Variation	[14]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Mitotic checkpoint protein BUB3 (BUB3) decreases the response to substance of Doxorubicin.	[30]

13 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 Mitotic checkpoint protein BUB3 (BUB3).	[15]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Mitotic checkpoint protein BUB3 (BUB3).	[16]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Mitotic checkpoint protein BUB3 (BUB3).	[17]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Mitotic checkpoint protein BUB3 (BUB3).	[18]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Mitotic checkpoint protein BUB3 (BUB3).	[19]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Mitotic checkpoint protein BUB3 (BUB3).	[20]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of Mitotic checkpoint protein BUB3 (BUB3).	[21]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of Mitotic checkpoint protein BUB3 (BUB3).	[22]
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the expression of Mitotic checkpoint protein BUB3 (BUB3).	[23]
Paclitaxel	DMLB81S	Approved	Paclitaxel increases the expression of Mitotic checkpoint protein BUB3 (BUB3).	[24]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Mitotic checkpoint protein BUB3 (BUB3).	[25]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Mitotic checkpoint protein BUB3 (BUB3).	[26]
CH-223191	DMMJZYC	Investigative	CH-223191 decreases the expression of Mitotic checkpoint protein BUB3 (BUB3).	[29]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Mitotic checkpoint protein BUB3 (BUB3).	[27]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Mitotic checkpoint protein BUB3 (BUB3).	[28]

References

• [1] Oral lichen planus and malignant transformation: The role of p16, Ki-67, Bub-3 and SOX4 in assessing precancerous potential.Exp Ther Med. 2018 May;15(5):4157-4166. doi: 10.3892/etm.2018.5971. Epub 2018 Mar 20.
• [2] PKM2 regulates chromosome segregation and mitosis progression of tumor cells.Mol Cell. 2014 Jan 9;53(1):75-87. doi: 10.1016/j.molcel.2013.11.001. Epub 2013 Dec 5.
• [3] Over expression of DNA damage and cell cycle dependent proteins are associated with poor survival in patients with adrenocortical carcinoma.Surgery. 2019 Jan;165(1):202-210. doi: 10.1016/j.surg.2018.04.080. Epub 2018 Nov 7.
• [4] Allelic loss at 10q26 in osteosarcoma in the region of the BUB3 and FGFR2 genes.Cancer Genet Cytogenet. 2005 Apr 15;158(2):142-7. doi: 10.1016/j.cancergencyto.2004.08.035.
• [5] Overexpression of the mitotic checkpoint genes BUB1, BUBR1, and BUB3 in gastric cancer--association with tumour cell proliferation.J Pathol. 2003 May;200(1):16-22. doi: 10.1002/path.1324.
• [6] Molecular analyses of the mitotic checkpoint components hsMAD2, hBUB1 and hBUB3 in human cancer.Int J Cancer. 2001 Jul 20;95(4):223-7. doi: 10.1002/1097-0215(20010720)95:4<223::aid-ijc1038>3.0.co;2-l.
• [7] Molecular analysis of the mitotic checkpoint genes BUB1, BUBR1 and BUB3 in human lung cancers.Cancer Lett. 2001 Jan 26;162(2):201-5. doi: 10.1016/s0304-3835(00)00675-3.
• [8] Germline mutations in the spindle assembly checkpoint genes BUB1 and BUB3 are infrequent in familial colorectal cancer and polyposis.Mol Cancer. 2018 Feb 15;17(1):23. doi: 10.1186/s12943-018-0762-8.
• [9] Prognostic value of mitotic checkpoint protein BUB3, cyclin B1, and pituitary tumor-transforming 1 expression in prostate cancer.Mod Pathol. 2020 May;33(5):905-915. doi: 10.1038/s41379-019-0418-2. Epub 2019 Dec 4.
• [10] Spindly and Bub3 expression in oral cancer: Prognostic and therapeutic implications.Oral Dis. 2019 Jul;25(5):1291-1301. doi: 10.1111/odi.13089. Epub 2019 Apr 4.
• [11] Single nucleotide polymorphisms rs911160 in AURKA and rs2289590 in AURKB mitotic checkpoint genes contribute to gastric cancer susceptibility.Environ Mol Mutagen. 2017 Dec;58(9):701-711. doi: 10.1002/em.22129. Epub 2017 Aug 26.
• [12] Germline mutations in the spindle assembly checkpoint genes BUB1 and BUB3 are risk factors for colorectal cancer. Gastroenterology. 2013 Sep;145(3):544-7. doi: 10.1053/j.gastro.2013.06.001. Epub 2013 Jun 5.
• [13] Correction to: c-Src confers resistance to mitotic stress through inhibition of DMAP1/Bub3 complex formation in pancreatic cancer.Mol Cancer. 2019 Nov 29;18(1):172. doi: 10.1186/s12943-019-1067-2.
• [14] Overexpression of the mitotic spindle assembly checkpoint genes hBUB1, hBUBR1 and hMAD2 in thyroid carcinomas with aggressive nature.Anticancer Res. 2008 Jan-Feb;28(1A):139-44.
• [15] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [16] 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.
• [17] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [18] Nuclear proteome analysis of cisplatin-treated HeLa cells. Mutat Res. 2010 Sep 10;691(1-2):1-8. doi: 10.1016/j.mrfmmm.2010.06.002. Epub 2010 Jun 9.
• [19] 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.
• [20] 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.
• [21] Proteomic analysis of antiproliferative effects by treatment of 5-fluorouracil in cervical cancer cells. DNA Cell Biol. 2004 Nov;23(11):769-76.
• [22] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [23] 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.
• [24] Proteomic analysis of anti-cancer effects by paclitaxel treatment in cervical cancer cells. Gynecol Oncol. 2005 Jul;98(1):45-53. doi: 10.1016/j.ygyno.2005.04.010.
• [25] Interactive gene expression pattern in prostate cancer cells exposed to phenolic antioxidants. Life Sci. 2002 Mar 1;70(15):1821-39.
• [26] Gene expression changes associated with altered growth and differentiation in benzo[a]pyrene or arsenic exposed normal human epidermal keratinocytes. J Appl Toxicol. 2008 May;28(4):491-508.
• [27] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [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] Adaptive changes in global gene expression profile of lung carcinoma A549 cells acutely exposed to distinct types of AhR ligands. Toxicol Lett. 2018 Aug;292:162-174.
• [30] Nuclear proteomics with XRCC3 knockdown to reveal the development of doxorubicin-resistant uterine cancer. Toxicol Sci. 2014 Jun;139(2):396-406. doi: 10.1093/toxsci/kfu051. Epub 2014 Mar 27.