Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDQJVZ8)

• DOT Name: CUB and zona pellucida-like domain-containing protein 1 (CUZD1)
• Synonyms: CUB and ZP domain-containing protein 1; Transmembrane protein UO-44
• Gene Name: CUZD1
• Related Disease:
  Breast neoplasm
  Esophageal squamous cell carcinoma
  Inflammatory bowel disease
  Long QT syndrome
  Pancreatitis
  Primary sclerosing cholangitis
  Ulcerative colitis
  Advanced cancer
  Arrhythmia
  Crohn disease
  Matthew-Wood syndrome
  Neoplasm
  Prostate cancer
  Prostate carcinoma
  Schizophrenia
• UniProt ID: CUZD1_HUMAN
• Pfam ID: PF00431 ; PF00100
• Sequence:
  MELVRRLMPLTLLILSCLAELTMAEAEGNASCTVSLGGANMAETHKAMILQLNPSENCTW
  TIERPENKSIRIIFSYVQLDPDGSCESENIKVFDGTSSNGPLLGQVCSKNDYVPVFESSS
  STLTFQIVTDSARIQRTVFVFYYFFSPNISIPNCGGYLDTLEGSFTSPNYPKPHPELAYC
  VWHIQVEKDYKIKLNFKEIFLEIDKQCKFDFLAIYDGPSTNSGLIGQVCGRVTPTFESSS
  NSLTVVLSTDYANSYRGFSASYTSIYAENINTTSLTCSSDRMRVIISKSYLEAFNSNGNN
  LQLKDPTCRPKLSNVVEFSVPLNGCGTIRKVEDQSITYTNIITFSASSTSEVITRQKQLQ
  IIVKCEMGHNSTVEIIYITEDDVIQSQNALGKYNTSMALFESNSFEKTILESPYYVDLNQ
  TLFVQVSLHTSDPNLVVFLDTCRASPTSDFASPTYDLIKSGCSRDETCKVYPLFGHYGRF
  QFNAFKFLRSMSSVYLQCKVLICDSSDHQSRCNQGCVSRSKRDISSYKWKTDSIIGPIRL
  KRDRSASGNSGFQHETHAEETPNQPFNSVHLFSFMVLALNVVTVATITVRHFVNQRADYK
  YQKLQNY
• Function: Localized to zymogen granules, where it functions in trypsinogen activation. May indirectly regulate cell motility, cell-cell and cell/extracellular matrix interactions.
• Tissue Specificity: Detected in pancreas and epithelium of ovary. Expressed at higher levels in ovarian tumors than in normal tissue.

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast neoplasm	DISNGJLM	Strong	Biomarker	[1]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[2]
Inflammatory bowel disease	DISGN23E	Strong	Biomarker	[3]
Long QT syndrome	DISMKWS3	Strong	Biomarker	[4]
Pancreatitis	DIS0IJEF	Strong	Altered Expression	[5]
Primary sclerosing cholangitis	DISTH5WJ	Strong	Biomarker	[6]
Ulcerative colitis	DIS8K27O	Strong	Biomarker	[7]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[8]
Arrhythmia	DISFF2NI	Limited	Biomarker	[9]
Crohn disease	DIS2C5Q8	Limited	Biomarker	[7]
Matthew-Wood syndrome	DISA7HR7	Limited	Altered Expression	[10]
Neoplasm	DISZKGEW	Limited	Altered Expression	[10]
Prostate cancer	DISF190Y	Limited	Altered Expression	[11]
Prostate carcinoma	DISMJPLE	Limited	Altered Expression	[11]
Schizophrenia	DISSRV2N	No Known	Unknown	[12]

7 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 CUB and zona pellucida-like domain-containing protein 1 (CUZD1).	[13]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of CUB and zona pellucida-like domain-containing protein 1 (CUZD1).	[14]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of CUB and zona pellucida-like domain-containing protein 1 (CUZD1).	[16]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of CUB and zona pellucida-like domain-containing protein 1 (CUZD1).	[17]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of CUB and zona pellucida-like domain-containing protein 1 (CUZD1).	[18]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of CUB and zona pellucida-like domain-containing protein 1 (CUZD1).	[19]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of CUB and zona pellucida-like domain-containing protein 1 (CUZD1).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of CUB and zona pellucida-like domain-containing protein 1 (CUZD1).	[15]

References

• [1] Aberrantly high expression of the CUB and zona pellucida-like domain-containing protein 1 (CUZD1) in mammary epithelium leads to breast tumorigenesis.J Biol Chem. 2018 Feb 23;293(8):2850-2864. doi: 10.1074/jbc.RA117.000162. Epub 2018 Jan 10.
• [2] TCF7L2 and EGR1 synergistic activation of transcription of LCN2 via an ERK1/2-dependent pathway in esophageal squamous cell carcinoma cells.Cell Signal. 2019 Mar;55:8-16. doi: 10.1016/j.cellsig.2018.12.007. Epub 2018 Dec 14.
• [3] A proteome-wide immuno-mass spectrometric identification of serum autoantibodies.Clin Proteomics. 2019 Jun 20;16:25. doi: 10.1186/s12014-019-9246-0. eCollection 2019.
• [4] Identification of two nervous system-specific members of the erg potassium channel gene family.J Neurosci. 1997 Dec 15;17(24):9423-32. doi: 10.1523/JNEUROSCI.17-24-09423.1997.
• [5] Protection from pancreatitis by the zymogen granule membrane protein integral membrane-associated protein-1.J Biol Chem. 2002 Dec 27;277(52):50725-33. doi: 10.1074/jbc.M204159200. Epub 2002 Oct 24.
• [6] Significance of serological markers in the disease course of ulcerative colitis in a prospective clinical cohort of patients.PLoS One. 2018 Mar 28;13(3):e0194166. doi: 10.1371/journal.pone.0194166. eCollection 2018.
• [7] Novel immunoassays for detection of CUZD1 autoantibodies in serum of patients with inflammatory bowel diseases.Clin Chem Lab Med. 2017 Aug 28;55(10):1574-1581. doi: 10.1515/cclm-2016-1120.
• [8] False biomarker discovery due to reactivity of a commercial ELISA for CUZD1 with cancer antigen CA125.Clin Chem. 2014 Feb;60(2):381-8. doi: 10.1373/clinchem.2013.215236. Epub 2013 Oct 4.
• [9] Deciphering hERG channels: molecular basis of the rapid component of the delayed rectifier potassium current.J Mol Cell Cardiol. 2012 Sep;53(3):369-74. doi: 10.1016/j.yjmcc.2012.06.011. Epub 2012 Jun 26.
• [10] hERG1 channels drive tumour malignancy and may serve as prognostic factor in pancreatic ductal adenocarcinoma.Br J Cancer. 2015 Mar 17;112(6):1076-87. doi: 10.1038/bjc.2015.28.
• [11] Delineation of TMPRSS2-ERG splice variants in prostate cancer.Clin Cancer Res. 2008 Aug 1;14(15):4719-25. doi: 10.1158/1078-0432.CCR-08-0531.
• [12] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [13] 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.
• [14] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [15] 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.
• [16] 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.
• [17] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [18] 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.
• [19] Dose- and time-dependent transcriptional response of Ishikawa cells exposed to genistein. Toxicol Sci. 2016 May;151(1):71-87.