Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTTKAVG4)

• DOT Name: Nuclear mitotic apparatus protein 1 (NUMA1)
• Synonyms: Nuclear matrix protein-22; NMP-22; Nuclear mitotic apparatus protein; NuMA protein; SP-H antigen
• Gene Name: NUMA1
• Related Disease:
  Advanced cancer
  Allergic contact dermatitis
  Bladder cancer
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Herpes simplex infection
  Leukemia
  Metabolic disorder
  Promyelocytic leukaemia
  Transitional cell carcinoma
  Type-1/2 diabetes
  Urinary bladder cancer
  Urinary bladder neoplasm
  Urothelial carcinoma
  Aplasia cutis congenita
  Classic lissencephaly
  Corpus callosum, agenesis of
  Cryptorchidism
  Myeloid neoplasm
  Myeloproliferative neoplasm
• UniProt ID: NUMA1_HUMAN
• PDB ID: 3RO2; 5GXW; 6HC2; 6QJA
• Pfam ID: PF21670
• Sequence:
  MTLHATRGAALLSWVNSLHVADPVEAVLQLQDCSIFIKIIDRIHGTEEGQQILKQPVSER
  LDFVCSFLQKNRKHPSSPECLVSAQKVLEGSELELAKMTMLLLYHSTMSSKSPRDWEQFE
  YKIQAELAVILKFVLDHEDGLNLNEDLENFLQKAPVPSTCSSTFPEELSPPSHQAKREIR
  FLELQKVASSSSGNNFLSGSPASPMGDILQTPQFQMRRLKKQLADERSNRDELELELAEN
  RKLLTEKDAQIAMMQQRIDRLALLNEKQAASPLEPKELEELRDKNESLTMRLHETLKQCQ
  DLKTEKSQMDRKINQLSEENGDLSFKLREFASHLQQLQDALNELTEEHSKATQEWLEKQA
  QLEKELSAALQDKKCLEEKNEILQGKLSQLEEHLSQLQDNPPQEKGEVLGDVLQLETLKQ
  EAATLAANNTQLQARVEMLETERGQQEAKLLAERGHFEEEKQQLSSLITDLQSSISNLSQ
  AKEELEQASQAHGARLTAQVASLTSELTTLNATIQQQDQELAGLKQQAKEKQAQLAQTLQ
  QQEQASQGLRHQVEQLSSSLKQKEQQLKEVAEKQEATRQDHAQQLATAAEEREASLRERD
  AALKQLEALEKEKAAKLEILQQQLQVANEARDSAQTSVTQAQREKAELSRKVEELQACVE
  TARQEQHEAQAQVAELELQLRSEQQKATEKERVAQEKDQLQEQLQALKESLKVTKGSLEE
  EKRRAADALEEQQRCISELKAETRSLVEQHKRERKELEEERAGRKGLEARLQQLGEAHQA
  ETEVLRRELAEAMAAQHTAESECEQLVKEVAAWRERYEDSQQEEAQYGAMFQEQLMTLKE
  ECEKARQELQEAKEKVAGIESHSELQISRQQNELAELHANLARALQQVQEKEVRAQKLAD
  DLSTLQEKMAATSKEVARLETLVRKAGEQQETASRELVKEPARAGDRQPEWLEEQQGRQF
  CSTQAALQAMEREAEQMGNELERLRAALMESQGQQQEERGQQEREVARLTQERGRAQADL
  ALEKAARAELEMRLQNALNEQRVEFATLQEALAHALTEKEGKDQELAKLRGLEAAQIKEL
  EELRQTVKQLKEQLAKKEKEHASGSGAQSEAAGRTEPTGPKLEALRAEVSKLEQQCQKQQ
  EQADSLERSLEAERASRAERDSALETLQGQLEEKAQELGHSQSALASAQRELAAFRTKVQ
  DHSKAEDEWKAQVARGRQEAERKNSLISSLEEEVSILNRQVLEKEGESKELKRLVMAESE
  KSQKLEERLRLLQAETASNSARAAERSSALREEVQSLREEAEKQRVASENLRQELTSQAE
  RAEELGQELKAWQEKFFQKEQALSTLQLEHTSTQALVSELLPAKHLCQQLQAEQAAAEKR
  HREELEQSKQAAGGLRAELLRAQRELGELIPLRQKVAEQERTAQQLRAEKASYAEQLSML
  KKAHGLLAEENRGLGERANLGRQFLEVELDQAREKYVQELAAVRADAETRLAEVQREAQS
  TARELEVMTAKYEGAKVKVLEERQRFQEERQKLTAQVEQLEVFQREQTKQVEELSKKLAD
  SDQASKVQQQKLKAVQAQGGESQQEAQRLQAQLNELQAQLSQKEQAAEHYKLQMEKAKTH
  YDAKKQQNQELQEQLRSLEQLQKENKELRAEAERLGHELQQAGLKTKEAEQTCRHLTAQV
  RSLEAQVAHADQQLRDLGKFQVATDALKSREPQAKPQLDLSIDSLDLSCEEGTPLSITSK
  LPRTQPDGTSVPGEPASPISQRLPPKVESLESLYFTPIPARSQAPLESSLDSLGDVFLDS
  GRKTRSARRRTTQIINITMTKKLDVEEPDSANSSFYSTRSAPASQASLRATSSTQSLARL
  GSPDYGNSALLSLPGYRPTTRSSARRSQAGVSSGAPPGRNSFYMGTCQDEPEQLDDWNRI
  AELQQRNRVCPPHLKTCYPLESRPSLSLGTITDEEMKTGDPQETLRRASMQPIQIAEGTG
  ITTRQQRKRVSLEPHQGPGTPESKKATSCFPRPMTPRDRHEGRKQSTTEAQKKAAPASTK
  QADRRQSMAFSILNTPKKLGNSLLRRGASKKALSKASPNTRSGTRRSPRIATTTASAATA
  AAIGATPRAKGKAKH
• Function: Microtubule (MT)-binding protein that plays a role in the formation and maintenance of the spindle poles and the alignement and the segregation of chromosomes during mitotic cell division. Functions to tether the minus ends of MTs at the spindle poles, which is critical for the establishment and maintenance of the spindle poles. Plays a role in the establishment of the mitotic spindle orientation during metaphase and elongation during anaphase in a dynein-dynactin-dependent manner. In metaphase, part of a ternary complex composed of GPSM2 and G(i) alpha proteins, that regulates the recruitment and anchorage of the dynein-dynactin complex in the mitotic cell cortex regions situated above the two spindle poles, and hence regulates the correct oritentation of the mitotic spindle. During anaphase, mediates the recruitment and accumulation of the dynein-dynactin complex at the cell membrane of the polar cortical region through direct association with phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2), and hence participates in the regulation of the spindle elongation and chromosome segregation. Binds also to other polyanionic phosphoinositides, such as phosphatidylinositol 3-phosphate (PIP), lysophosphatidic acid (LPA) and phosphatidylinositol triphosphate (PIP3), in vitro. Also required for proper orientation of the mitotic spindle during asymmetric cell divisions. Plays a role in mitotic MT aster assembly. Involved in anastral spindle assembly. Positively regulates TNKS protein localization to spindle poles in mitosis. Highly abundant component of the nuclear matrix where it may serve a non-mitotic structural role, occupies the majority of the nuclear volume. Required for epidermal differentiation and hair follicle morphogenesis.
• Reactome Pathway:
  Mitotic Prophase (R-HSA-68875)
  Recruitment of NuMA to mitotic centrosomes (R-HSA-380320)

Molecular Interaction Atlas (MIA) of This DOT

21 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Allergic contact dermatitis	DISFFVF9	Strong	Biomarker	[2]
Bladder cancer	DISUHNM0	Strong	Biomarker	[3]
Breast cancer	DIS7DPX1	Strong	Genetic Variation	[4]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[4]
Breast neoplasm	DISNGJLM	Strong	Genetic Variation	[4]
Herpes simplex infection	DISL1SAV	Strong	Biomarker	[5]
Leukemia	DISNAKFL	Strong	Biomarker	[6]
Metabolic disorder	DIS71G5H	Strong	Altered Expression	[7]
Promyelocytic leukaemia	DISYGG13	Strong	Genetic Variation	[1]
Transitional cell carcinoma	DISWVVDR	Strong	Biomarker	[8]
Type-1/2 diabetes	DISIUHAP	Strong	Altered Expression	[7]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[9]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[9]
Urothelial carcinoma	DISRTNTN	Strong	Biomarker	[8]
Aplasia cutis congenita	DISMDAYM	Limited	Biomarker	[10]
Classic lissencephaly	DISR8S3S	Limited	Biomarker	[11]
Corpus callosum, agenesis of	DISO9P40	Limited	Biomarker	[10]
Cryptorchidism	DISYUD2P	Limited	Altered Expression	[12]
Myeloid neoplasm	DIS2YOWO	Limited	Genetic Variation	[1]
Myeloproliferative neoplasm	DIS5KAPA	Limited	Biomarker	[1]

6 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 Nuclear mitotic apparatus protein 1 (NUMA1).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Nuclear mitotic apparatus protein 1 (NUMA1).	[28]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Nuclear mitotic apparatus protein 1 (NUMA1).	[29]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Nuclear mitotic apparatus protein 1 (NUMA1).	[30]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Nuclear mitotic apparatus protein 1 (NUMA1).	[32]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Nuclear mitotic apparatus protein 1 (NUMA1).	[30]

15 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 Nuclear mitotic apparatus protein 1 (NUMA1).	[14]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Nuclear mitotic apparatus protein 1 (NUMA1).	[15]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Nuclear mitotic apparatus protein 1 (NUMA1).	[16]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Nuclear mitotic apparatus protein 1 (NUMA1).	[17]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Nuclear mitotic apparatus protein 1 (NUMA1).	[18]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Nuclear mitotic apparatus protein 1 (NUMA1).	[19]
Decitabine	DMQL8XJ	Approved	Decitabine decreases the expression of Nuclear mitotic apparatus protein 1 (NUMA1).	[20]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Nuclear mitotic apparatus protein 1 (NUMA1).	[21]
Menthol	DMG2KW7	Approved	Menthol increases the expression of Nuclear mitotic apparatus protein 1 (NUMA1).	[22]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Nuclear mitotic apparatus protein 1 (NUMA1).	[23]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Nuclear mitotic apparatus protein 1 (NUMA1).	[25]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Nuclear mitotic apparatus protein 1 (NUMA1).	[26]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Nuclear mitotic apparatus protein 1 (NUMA1).	[33]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Nuclear mitotic apparatus protein 1 (NUMA1).	[34]
Forskolin	DM6ITNG	Investigative	Forskolin decreases the expression of Nuclear mitotic apparatus protein 1 (NUMA1).	[35]

2 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Rigosertib	DMOSTXF	Phase 3	Rigosertib affects the localization of Nuclear mitotic apparatus protein 1 (NUMA1).	[24]
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of Nuclear mitotic apparatus protein 1 (NUMA1).	[27]

1 Drug(s) Affected the Biochemical Pathways of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
PJ34	DMXO6YH	Preclinical	PJ34 increases the metabolism of Nuclear mitotic apparatus protein 1 (NUMA1).	[31]

References

• [1] Novel t(5;11)(q32;q13.4) with NUMA1-PDGFRB fusion in a myeloid neoplasm with eosinophilia with response to imatinib mesylate.Cancer Genet. 2017 Apr;212-213:38-44. doi: 10.1016/j.cancergen.2017.03.004. Epub 2017 Mar 27.
• [2] Gene transcripts as potential diagnostic markers for allergic contact dermatitis.Contact Dermatitis. 2005 Aug;53(2):100-6. doi: 10.1111/j.0105-1873.2005.00658.x.
• [3] Comparison of the diagnostic performance of fluorescence in situ hybridization (FISH), nuclear matrix protein 22 (NMP22), and their combination model in bladder carcinoma detection: a systematic review and meta-analysis.Onco Targets Ther. 2018 Dec 31;12:349-358. doi: 10.2147/OTT.S186065. eCollection 2019.
• [4] Comprehensive analysis of NuMA variation in breast cancer.BMC Cancer. 2008 Mar 10;8:71. doi: 10.1186/1471-2407-8-71.
• [5] Herpes simplex virus induces extensive modification and dynamic relocalisation of the nuclear mitotic apparatus (NuMA) protein in interphase cells.J Cell Sci. 2008 Jun 15;121(Pt 12):2087-96. doi: 10.1242/jcs.031450. Epub 2008 May 27.
• [6] Myeloid leukemia with promyelocytic features in transgenic mice expressing hCG-NuMA-RARalpha.Oncogene. 2004 Jan 22;23(3):665-78. doi: 10.1038/sj.onc.1207073.
• [7] Tankyrase as a Novel Molecular Target in Cancer and Fibrotic Diseases.Curr Drug Targets. 2017;18(10):1214-1224. doi: 10.2174/1389450117666160715152503.
• [8] A multigene urine test for the detection and stratification of bladder cancer in patients presenting with hematuria.J Urol. 2012 Sep;188(3):741-7. doi: 10.1016/j.juro.2012.05.003. Epub 2012 Jul 19.
• [9] In silico design and in vitro characterization of a recombinant antigen for specific recognition of NMP22.Int J Biol Macromol. 2019 Nov 1;140:69-77. doi: 10.1016/j.ijbiomac.2019.08.065. Epub 2019 Aug 9.
• [10] Detailed genome-wide SNP analysis of major salivary carcinomas localizes subtype-specific chromosome sites and oncogenes of potential clinical significance.Am J Pathol. 2013 Jun;182(6):2048-57. doi: 10.1016/j.ajpath.2013.02.020. Epub 2013 Apr 10.
• [11] NuMA1 promotes axon initial segment assembly through inhibition of endocytosis.J Cell Biol. 2020 Feb 3;219(2):e201907048. doi: 10.1083/jcb.201907048.
• [12] Identification of differentially expressed genes in human cryptorchid testes using suppression subtractive hybridization.J Urol. 2009 Mar;181(3):1330-7; discussion 1337. doi: 10.1016/j.juro.2008.11.034. Epub 2009 Jan 20.
• [13] 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.
• [14] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [15] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [16] 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.
• [17] Proteomics-based identification of differentially abundant proteins from human keratinocytes exposed to arsenic trioxide. J Proteomics Bioinform. 2014 Jul;7(7):166-178.
• [18] Inhibition of fatty acid synthase expression by 1alpha,25-dihydroxyvitamin D3 in prostate cancer cells. J Steroid Biochem Mol Biol. 2003 May;85(1):1-8. doi: 10.1016/s0960-0760(03)00142-0.
• [19] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [20] DNA methylation inhibits p53-mediated survivin repression. Oncogene. 2009 May 14;28(19):2046-50. doi: 10.1038/onc.2009.62. Epub 2009 Apr 13.
• [21] Progestins regulate genes that can elicit both proliferative and antiproliferative effects in breast cancer cells. Oncol Rep. 2008 Jun;19(6):1627-34.
• [22] Repurposing L-menthol for systems medicine and cancer therapeutics? L-menthol induces apoptosis through caspase 10 and by suppressing HSP90. OMICS. 2016 Jan;20(1):53-64.
• [23] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [24] Centmitor-1, a novel acridinyl-acetohydrazide, possesses similar molecular interaction field and antimitotic cellular phenotype as rigosertib, on 01910.Na. Mol Cancer Ther. 2014 May;13(5):1054-66. doi: 10.1158/1535-7163.MCT-13-0685. Epub 2014 Apr 18.
• [25] Quantitative proteomics and transcriptomics addressing the estrogen receptor subtype-mediated effects in T47D breast cancer cells exposed to the phytoestrogen genistein. Mol Cell Proteomics. 2011 Jan;10(1):M110.002170.
• [26] 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.
• [27] Proteomic analysis of the cellular response to a potent sensitiser unveils the dynamics of haptenation in living cells. Toxicology. 2020 Dec 1;445:152603. doi: 10.1016/j.tox.2020.152603. Epub 2020 Sep 28.
• [28] 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.
• [29] 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.
• [30] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [31] Exclusive destruction of mitotic spindles in human cancer cells. Oncotarget. 2017 Mar 28;8(13):20813-20824. doi: 10.18632/oncotarget.15343.
• [32] 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.
• [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] Cellular reactions to long-term volatile organic compound (VOC) exposures. Sci Rep. 2016 Dec 1;6:37842. doi: 10.1038/srep37842.
• [35] Identification of genes targeted by the androgen and PKA signaling pathways in prostate cancer cells. Oncogene. 2006 Nov 23;25(55):7311-23.