Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTVH3M4Z)

• DOT Name: Ninein (NIN)
• Synonyms: hNinein; Glycogen synthase kinase 3 beta-interacting protein; GSK3B-interacting protein
• Gene Name: NIN
• Related Disease:
  Brain neoplasm
  Breast cancer
  Breast carcinoma
  Myeloproliferative neoplasm
  Spondyloepimetaphyseal dysplasia with multiple dislocations
  Nasopharyngeal carcinoma
  Tropical pancreatitis
  Carcinoma
  Lupus nephritis
  Seckel syndrome
  Seckel syndrome 7
  Systemic lupus erythematosus
• UniProt ID: NIN_HUMAN
• Sequence:
  MDEVEQDQHEARLKELFDSFDTTGTGSLGQEELTDLCHMLSLEEVAPVLQQTLLQDNLLG
  RVHFDQFKEALILILSRTLSNEEHFQEPDCSLEAQPKYVRGGKRYGRRSLPEFQESVEEF
  PEVTVIEPLDEEARPSHIPAGDCSEHWKTQRSEEYEAEGQLRFWNPDDLNASQSGSSPPQ
  DWIEEKLQEVCEDLGITRDGHLNRKKLVSICEQYGLQNVDGEMLEEVFHNLDPDGTMSVE
  DFFYGLFKNGKSLTPSASTPYRQLKRHLSMQSFDESGRRTTTSSAMTSTIGFRVFSCLDD
  GMGHASVERILDTWQEEGIENSQEILKALDFSLDGNINLTELTLALENELLVTKNSIHQA
  ALASFKAEIRHLLERVDQVVREKEKLRSDLDKAEKLKSLMASEVDDHHAAIERRNEYNLR
  KLDEEYKERIAALKNELRKEREQILQQAGKQRLELEQEIEKAKTEENYIRDRLALSLKEN
  SRLENELLENAEKLAEYENLTNKLQRNLENVLAEKFGDLDPSSAEFFLQEERLTQMRNEY
  ERQCRVLQDQVDELQSELEEYRAQGRVLRLPLKNSPSEEVEANSGGIEPEHGLGSEECNP
  LNMSIEAELVIEQMKEQHHRDICCLRLELEDKVRHYEKQLDETVVSCKKAQENMKQRHEN
  ETHTLEKQISDLKNEIAELQGQAAVLKEAHHEATCRHEEEKKQLQVKLEEEKTHLQEKLR
  LQHEMELKARLTQAQASFEREREGLQSSAWTEEKVRGLTQELEQFHQEQLTSLVEKHTLE
  KEELRKELLEKHQRELQEGREKMETECNRRTSQIEAQFQSDCQKVTERCESALQSLEGRY
  RQELKDLQEQQREEKSQWEFEKDELTQECAEAQELLKETLKREKTTSLVLTQEREMLEKT
  YKEHLNSMVVERQQLLQDLEDLRNVSETQQSLLSDQILELKSSHKRELREREEVLCQAGA
  SEQLASQRLERLEMEHDQERQEMMSKLLAMENIHKATCETADRERAEMSTEISRLQSKIK
  EMQQATSPLSMLQSGCQVIGEEEVEGDGALSLLQQGEQLLEENGDVLLSLQRAHEQAVKE
  NVKMATEISRLQQRLQKLEPGLVMSSCLDEPATEFFGNTAEQTEQFLQQNRTKQVEGVTR
  RHVLSDLEDDEVRDLGSTGTSSVQRQEVKIEESEASVEGFSELENSEETRTESWELKNQI
  SQLQEQLMMLCADCDRASEKKQDLLFDVSVLKKKLKMLERIPEASPKYKLLYEDVSREND
  CLQEELRMMETRYDEALENNKELTAEVFRLQDELKKMEEVTETFLSLEKSYDEVKIENEG
  LNVLVLRLQGKIEKLQESVVQRCDCCLWEASLENLEIEPDGNILQLNQTLEECVPRVRSV
  HHVIEECKQENQYLEGNTQLLEKVKAHEIAWLHGTIQTHQERPRVQNQVILEENTTLLGF
  QDKHFQHQATIAELELEKTKLQELTRKLKERVTILVKQKDVLSHGEKEEELKAMMHDLQI
  TCSEMQQKVELLRYESEKLQQENSILRNEITTLNEEDSISNLKLGTLNGSQEEMWQKTET
  VKQENAAVQKMVENLKKQISELKIKNQQLDLENTELSQKNSQNQEKLQELNQRLTEMLCQ
  KEKEPGNSALEEREQEKFNLKEELERCKVQSSTLVSSLEAELSEVKIQTHIVQQENHLLK
  DELEKMKQLHRCPDLSDFQQKISSVLSYNEKLLKEKEALSEELNSCVDKLAKSSLLEHRI
  ATMKQEQKSWEHQSASLKSQLVASQEKVQNLEDTVQNVNLQMSRMKSDLRVTQQEKEALK
  QEVMSLHKQLQNAGGKSWAPEIATHPSGLHNQQKRLSWDKLDHLMNEEQQLLWQENERLQ
  TMVQNTKAELTHSREKVRQLESNLLPKHQKHLNPSGTMNPTEQEKLSLKRECDQFQKEQS
  PANRKVSQMNSLEQELETIHLENEGLKKKQVKLDEQLMEMQHLRSTATPSPSPHAWDLQL
  LQQQACPMVPREQFLQLQRQLLQAERINQHLQEELENRTSETNTPQGNQEQLVTVMEERM
  IEVEQKLKLVKRLLQEKVNQLKEQVSLPGHLCSPTSHSSFNSSFTSLYCH
• Function: Centrosomal protein required in the positioning and anchorage of the microtubule minus-end in epithelial cells. May also act as a centrosome maturation factor. May play a role in microtubule nucleation, by recruiting the gamma-tubulin ring complex to the centrosome. Overexpression does not perturb nucleation or elongation of microtubules but suppresses release of microtubules. Required for centriole organization and microtubule anchoring at the mother centriole.
• Tissue Specificity: Ubiquitous. Highly expressed in heart and skeletal muscle. Isoform 1 is more expressed than isoform 5.

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Brain neoplasm	DISY3EKS	Strong	Altered Expression	[1]
Breast cancer	DIS7DPX1	Strong	Genetic Variation	[2]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[3]
Myeloproliferative neoplasm	DIS5KAPA	Strong	Genetic Variation	[4]
Spondyloepimetaphyseal dysplasia with multiple dislocations	DISBNIZ6	Strong	Genetic Variation	[5]
Nasopharyngeal carcinoma	DISAOTQ0	moderate	Altered Expression	[6]
Tropical pancreatitis	DIS3OT4T	moderate	Genetic Variation	[7]
Carcinoma	DISH9F1N	Limited	Biomarker	[8]
Lupus nephritis	DISCVGPZ	Limited	Genetic Variation	[9]
Seckel syndrome	DISEVUBA	Limited	Genetic Variation	[5]
Seckel syndrome 7	DISF75J3	Limited	Autosomal recessive	[10]
Systemic lupus erythematosus	DISI1SZ7	Limited	Genetic Variation	[9]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Temozolomide	DMKECZD	Approved	Ninein (NIN) affects the response to substance of Temozolomide.	[22]
DTI-015	DMXZRW0	Approved	Ninein (NIN) affects the response to substance of DTI-015.	[22]

3 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 Ninein (NIN).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Ninein (NIN).	[19]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Ninein (NIN).	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Ninein (NIN).	[12]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Ninein (NIN).	[13]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Ninein (NIN).	[14]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Ninein (NIN).	[12]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Ninein (NIN).	[15]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Ninein (NIN).	[16]
Nicotine	DMWX5CO	Approved	Nicotine increases the expression of Ninein (NIN).	[17]
Cidofovir	DMA13GD	Approved	Cidofovir decreases the expression of Ninein (NIN).	[12]
Ifosfamide	DMCT3I8	Approved	Ifosfamide decreases the expression of Ninein (NIN).	[12]
Clodronate	DM9Y6X7	Approved	Clodronate decreases the expression of Ninein (NIN).	[12]
Tubocurarine	DMBZIVP	Approved	Tubocurarine decreases the expression of Ninein (NIN).	[17]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Ninein (NIN).	[16]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate increases the expression of Ninein (NIN).	[18]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Ninein (NIN).	[20]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Ninein (NIN).	[16]

References

• [1] A novel ninein-interaction protein, CGI-99, blocks ninein phosphorylation by GSK3beta and is highly expressed in brain tumors.FEBS Lett. 2004 May 21;566(1-3):162-8. doi: 10.1016/j.febslet.2004.04.024.
• [2] Centrosome-related genes, genetic variation, and risk of breast cancer.Breast Cancer Res Treat. 2011 Jan;125(1):221-8. doi: 10.1007/s10549-010-0950-8. Epub 2010 May 28.
• [3] Genome-wide association study of germline variants and breast cancer-specific mortality.Br J Cancer. 2019 Mar;120(6):647-657. doi: 10.1038/s41416-019-0393-x. Epub 2019 Feb 21.
• [4] Novel microcephalic primordial dwarfism disorder associated with variants in the centrosomal protein ninein. J Clin Endocrinol Metab. 2012 Nov;97(11):E2140-51. doi: 10.1210/jc.2012-2150. Epub 2012 Aug 29.
• [5] Identification of a Ninein (NIN) mutation in a family with spondyloepimetaphyseal dysplasia with joint laxity (leptodactylic type)-like phenotype.Matrix Biol. 2013 Oct-Nov;32(7-8):387-92. doi: 10.1016/j.matbio.2013.05.001. Epub 2013 May 9.
• [6] Genome-wide expression profiling reveals EBV-associated inhibition of MHC class I expression in nasopharyngeal carcinoma.Cancer Res. 2006 Aug 15;66(16):7999-8006. doi: 10.1158/0008-5472.CAN-05-4399.
• [7] Five novel transcription factors as potential regulators of OsNHX1 gene expression in a salt tolerant rice genotype.Plant Mol Biol. 2017 Jan;93(1-2):61-77. doi: 10.1007/s11103-016-0547-7. Epub 2016 Oct 20.
• [8] Clinical significance of NOB1 expression in breast infiltrating ductal carcinoma.Int J Clin Exp Pathol. 2013 Sep 15;6(10):2137-44. eCollection 2013.
• [9] Lupus nephritis susceptibility loci in women with systemic lupus erythematosus.J Am Soc Nephrol. 2014 Dec;25(12):2859-70. doi: 10.1681/ASN.2013050446. Epub 2014 Jun 12.
• [10] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [11] 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.
• [12] Transcriptomics hit the target: monitoring of ligand-activated and stress response pathways for chemical testing. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):7-18.
• [13] 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.
• [14] 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.
• [15] Protein expression profiling identifies molecular targets of quercetin as a major dietary flavonoid in human colon cancer cells. Proteomics. 2004 Jul;4(7):2160-74.
• [16] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [17] Nicotinic modulation of gene expression in SH-SY5Y neuroblastoma cells. Brain Res. 2006 Oct 20;1116(1):39-49.
• [18] Application of the adverse outcome pathway concept for investigating developmental neurotoxicity potential of Chinese herbal medicines by using human neural progenitor cells in vitro. Cell Biol Toxicol. 2023 Feb;39(1):319-343. doi: 10.1007/s10565-022-09730-4. Epub 2022 Jun 15.
• [19] 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.
• [20] 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.
• [21] 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.
• [22] Tumor necrosis factor-alpha-induced protein 3 as a putative regulator of nuclear factor-kappaB-mediated resistance to O6-alkylating agents in human glioblastomas. J Clin Oncol. 2006 Jan 10;24(2):274-87. doi: 10.1200/JCO.2005.02.9405. Epub 2005 Dec 19.