Details of Drug Off-Target (DOT)

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

• DOT Name: Fasciculation and elongation protein zeta-1 (FEZ1)
• Synonyms: Zygin I; Zygin-1
• Gene Name: FEZ1
• Related Disease:
  Epithelial neoplasm
  Acute myelogenous leukaemia
  Advanced cancer
  Attention deficit hyperactivity disorder
  Bardet biedl syndrome
  Bladder cancer
  Breast cancer
  Breast carcinoma
  Carcinoma
  Depression
  Kidney cancer
  Leukemia
  Lung cancer
  Lung carcinoma
  Major depressive disorder
  Neoplasm
  Parkinson disease
  Peripheral arterial disease
  Psychotic disorder
  Renal carcinoma
  Squamous cell carcinoma
  Stomach cancer
  Tarsal-carpal coalition syndrome
  Urinary bladder cancer
  Urinary bladder neoplasm
  Mental disorder
• UniProt ID: FEZ1_HUMAN
• Pfam ID: PF07763
• Sequence:
  MEAPLVSLDEEFEDLRPSCSEDPEEKPQCFYGSSPHHLEDPSLSELENFSSEIISFKSME
  DLVNEFDEKLNVCFRNYNAKTENLAPVKNQLQIQEEEETLQDEEVWDALTDNYIPSLSED
  WRDPNIEALNGNCSDTEIHEKEEEEFNEKSENDSGINEEPLLTADQVIEEIEEMMQNSPD
  PEEEEEVLEEEDGGETSSQADSVLLQEMQALTQTFNNNWSYEGLRHMSGSELTELLDQVE
  GAIRDFSEELVQQLARRDELEFEKEVKNSFITVLIEVQNKQKEQRELMKKRRKEKGLSLQ
  SSRIEKGNQMPLKRFSMEGISNILQSGIRQTFGSSGTDKQYLNTVIPYEKKASPPSVEDL
  QMLTNILFAMKEDNEKVPTLLTDYILKVLCPT
• Function: May be involved in axonal outgrowth as component of the network of molecules that regulate cellular morphology and axon guidance machinery. Able to restore partial locomotion and axonal fasciculation to C.elegans unc-76 mutants in germline transformation experiments. May participate in the transport of mitochondria and other cargos along microtubules.
• Tissue Specificity: Mainly expressed in brain.
• KEGG Pathway: Viral life cycle - HIV-1 (hsa03250)

Molecular Interaction Atlas (MIA) of This DOT

26 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Epithelial neoplasm	DIS0T594	Definitive	Altered Expression	[1]
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Attention deficit hyperactivity disorder	DISL8MX9	Strong	Genetic Variation	[4]
Bardet biedl syndrome	DISTBNZW	Strong	Biomarker	[5]
Bladder cancer	DISUHNM0	Strong	Biomarker	[6]
Breast cancer	DIS7DPX1	Strong	Genetic Variation	[7]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[7]
Carcinoma	DISH9F1N	Strong	Biomarker	[8]
Depression	DIS3XJ69	Strong	Biomarker	[9]
Kidney cancer	DISBIPKM	Strong	Biomarker	[10]
Leukemia	DISNAKFL	Strong	Biomarker	[11]
Lung cancer	DISCM4YA	Strong	Biomarker	[7]
Lung carcinoma	DISTR26C	Strong	Biomarker	[7]
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[4]
Neoplasm	DISZKGEW	Strong	Biomarker	[12]
Parkinson disease	DISQVHKL	Strong	Biomarker	[13]
Peripheral arterial disease	DIS78WFB	Strong	Genetic Variation	[14]
Psychotic disorder	DIS4UQOT	Strong	Biomarker	[15]
Renal carcinoma	DISER9XT	Strong	Biomarker	[10]
Squamous cell carcinoma	DISQVIFL	Strong	Posttranslational Modification	[16]
Stomach cancer	DISKIJSX	Strong	Biomarker	[8]
Tarsal-carpal coalition syndrome	DISY90L2	Strong	Biomarker	[17]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[6]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[6]
Mental disorder	DIS3J5R8	Limited	Genetic Variation	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Fasciculation and elongation protein zeta-1 (FEZ1) increases the response to substance of Arsenic.	[38]

21 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 Fasciculation and elongation protein zeta-1 (FEZ1).	[19]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Fasciculation and elongation protein zeta-1 (FEZ1).	[20]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Fasciculation and elongation protein zeta-1 (FEZ1).	[21]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Fasciculation and elongation protein zeta-1 (FEZ1).	[22]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Fasciculation and elongation protein zeta-1 (FEZ1).	[23]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Fasciculation and elongation protein zeta-1 (FEZ1).	[24]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Fasciculation and elongation protein zeta-1 (FEZ1).	[25]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Fasciculation and elongation protein zeta-1 (FEZ1).	[26]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Fasciculation and elongation protein zeta-1 (FEZ1).	[27]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Fasciculation and elongation protein zeta-1 (FEZ1).	[28]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Fasciculation and elongation protein zeta-1 (FEZ1).	[29]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Fasciculation and elongation protein zeta-1 (FEZ1).	[30]
Nicotine	DMWX5CO	Approved	Nicotine decreases the expression of Fasciculation and elongation protein zeta-1 (FEZ1).	[31]
Tubocurarine	DMBZIVP	Approved	Tubocurarine decreases the expression of Fasciculation and elongation protein zeta-1 (FEZ1).	[31]
Aripiprazole	DM3NUMH	Approved	Aripiprazole increases the expression of Fasciculation and elongation protein zeta-1 (FEZ1).	[32]
Mecamylamine	DMGQFYB	Approved	Mecamylamine decreases the expression of Fasciculation and elongation protein zeta-1 (FEZ1).	[31]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Fasciculation and elongation protein zeta-1 (FEZ1).	[34]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Fasciculation and elongation protein zeta-1 (FEZ1).	[35]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Fasciculation and elongation protein zeta-1 (FEZ1).	[36]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Fasciculation and elongation protein zeta-1 (FEZ1).	[29]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Fasciculation and elongation protein zeta-1 (FEZ1).	[37]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Fasciculation and elongation protein zeta-1 (FEZ1).	[33]

References

• [1] The FEZ1 gene at chromosome 8p22 encodes a leucine-zipper protein, and its expression is altered in multiple human tumors.Proc Natl Acad Sci U S A. 1999 Mar 30;96(7):3928-33. doi: 10.1073/pnas.96.7.3928.
• [2] Fasciculation and elongation zeta-1 protein (FEZ1) interacts with the retinoic acid receptor and participates in transcriptional regulation of the Hoxb4 gene.FEBS Open Bio. 2017 Dec 9;8(1):4-14. doi: 10.1002/2211-5463.12338. eCollection 2018 Jan.
• [3] In silico characterization of LZTS3, a potential tumor suppressor.Oncol Rep. 2005 Aug;14(2):547-51.
• [4] Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis.Lancet. 2013 Apr 20;381(9875):1371-1379. doi: 10.1016/S0140-6736(12)62129-1. Epub 2013 Feb 28.
• [5] Essential role for the Prader-Willi syndrome protein necdin in axonal outgrowth.Hum Mol Genet. 2005 Mar 1;14(5):627-37. doi: 10.1093/hmg/ddi059. Epub 2005 Jan 13.
• [6] Molecular genetics of bladder cancer: targets for diagnosis and therapy.J Exp Clin Cancer Res. 2006 Jun;25(2):145-60.
• [7] Reduced FEZ1/LZTS1 expression and outcome prediction in lung cancer.Cancer Res. 2005 Feb 15;65(4):1207-12. doi: 10.1158/0008-5472.CAN-04-3461.
• [8] Fez1/lzts1 alterations in gastric carcinoma.Clin Cancer Res. 2001 Jun;7(6):1546-52.
• [9] Fasciculation and Elongation Protein Zeta-1 Expression in Reactive Astrocytes in a Rat Model of Frontal Lobe Injury.J Neuropathol Exp Neurol. 2020 Feb 1;79(2):194-208. doi: 10.1093/jnen/nlz113.
• [10] Collecting duct carcinoma of the kidney: an immunohistochemical study of 11 cases.BMC Urol. 2004 Sep 9;4:11. doi: 10.1186/1471-2490-4-11.
• [11] Over-expression of GFP-FEZ1 causes generation of multi-lobulated nuclei mediated by microtubules in HEK293 cells.Exp Cell Res. 2008 Jun 10;314(10):2028-39. doi: 10.1016/j.yexcr.2008.02.012. Epub 2008 Mar 4.
• [12] The tumor-suppressor gene LZTS1 suppresses colorectal cancer proliferation through inhibition of the AKT-mTOR signaling pathway.Cancer Lett. 2015 Apr 28;360(1):68-75. doi: 10.1016/j.canlet.2015.02.004. Epub 2015 Feb 7.
• [13] Fasciculation and elongation protein zeta-1 (FEZ1) expression in reactive astrocytes in a rat model of Parkinson's disease.Neuropathol Appl Neurobiol. 2014 Feb;40(2):164-76. doi: 10.1111/nan.12077.
• [14] Genetic Variants in the Bone Morphogenic Protein Gene Family Modify the Association between Residential Exposure to Traffic and Peripheral Arterial Disease.PLoS One. 2016 Apr 15;11(4):e0152670. doi: 10.1371/journal.pone.0152670. eCollection 2016.
• [15] Interaction between FEZ1 and DISC1 in regulation of neuronal development and risk for schizophrenia.Neuron. 2011 Nov 17;72(4):559-71. doi: 10.1016/j.neuron.2011.09.032.
• [16] Down-regulation of FEZ1/LZTS1 gene with frequent loss of heterozygosity in oral squamous cell carcinomas.Int J Oncol. 2003 Aug;23(2):297-302.
• [17] FEZ1/LZTS1 is down-regulated in high-grade bladder cancer, and its restoration suppresses tumorigenicity in transitional cell carcinoma cells.Am J Pathol. 2002 Apr;160(4):1345-52. doi: 10.1016/S0002-9440(10)62561-8.
• [18] Failure to confirm the association between the FEZ1 gene and schizophrenia in a Japanese population.Neurosci Lett. 2007 May 7;417(3):326-9. doi: 10.1016/j.neulet.2007.02.055. Epub 2007 Feb 24.
• [19] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [20] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [21] 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.
• [22] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [23] 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.
• [24] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [25] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [26] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [27] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [28] 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.
• [29] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [30] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [31] Nicotine modulates the expression of a diverse set of genes in the neuronal SH-SY5Y cell line. J Biol Chem. 2003 May 2;278(18):15633-40.
• [32] Small Molecule Antipsychotic Aripiprazole Potentiates Ozone-Induced Inflammation in Airway Epithelium. Chem Res Toxicol. 2019 Oct 21;32(10):1997-2005. doi: 10.1021/acs.chemrestox.9b00149. Epub 2019 Sep 11.
• [33] 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.
• [34] 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.
• [35] Genome-wide gene expression profiling of low-dose, long-term exposure of human osteosarcoma cells to bisphenol A and its analogs bisphenols AF and S. Toxicol In Vitro. 2015 Aug;29(5):1060-9.
• [36] 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.
• [37] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.
• [38] Gene expression levels in normal human lymphoblasts with variable sensitivities to arsenite: identification of GGT1 and NFKBIE expression levels as possible biomarkers of susceptibility. Toxicol Appl Pharmacol. 2008 Jan 15;226(2):199-205. doi: 10.1016/j.taap.2007.09.004. Epub 2007 Sep 15.