Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTP7KC3D)

• DOT Name: Wilms tumor protein
• Synonyms: WT33
• Gene Name: WT1
• Related Disease:
  Denys-Drash syndrome
  Frasier syndrome
  Wilms tumor 1
  Familial idiopathic steroid-resistant nephrotic syndrome
• UniProt ID: WT1_HUMAN
• PDB ID: 1XF7; 2JP9; 2JPA; 2PRT; 3HPJ; 3MYJ; 4R2E; 4R2P; 4R2Q; 4R2R; 4R2S; 4WUU; 5KL2; 5KL3; 5KL4; 5KL5; 5KL6; 5KL7; 6B0O; 6B0P; 6B0Q; 6B0R; 6BLW; 6RSY; 6WLH; 7BBG
• Pfam ID: PF02165 ; PF00096
• Sequence:
  MGSDVRDLNALLPAVPSLGGGGGCALPVSGAAQWAPVLDFAPPGASAYGSLGGPAPPPAP
  PPPPPPPPHSFIKQEPSWGGAEPHEEQCLSAFTVHFSGQFTGTAGACRYGPFGPPPPSQA
  SSGQARMFPNAPYLPSCLESQPAIRNQGYSTVTFDGTPSYGHTPSHHAAQFPNHSFKHED
  PMGQQGSLGEQQYSVPPPVYGCHTPTDSCTGSQALLLRTPYSSDNLYQMTSQLECMTWNQ
  MNLGATLKGVAAGSSSSVKWTEGQSNHSTGYESDNHTTPILCGAQYRIHTHGVFRGIQDV
  RRVPGVAPTLVRSASETSEKRPFMCAYPGCNKRYFKLSHLQMHSRKHTGEKPYQCDFKDC
  ERRFSRSDQLKRHQRRHTGVKPFQCKTCQRKFSRSDHLKTHTRTHTGKTSEKPFSCRWPS
  CQKKFARSDELVRHHNMHQRNMTKLQLAL
• Function: Transcription factor that plays an important role in cellular development and cell survival. Recognizes and binds to the DNA sequence 5'-GCG(T/G)GGGCG-3'. Regulates the expression of numerous target genes, including EPO. Plays an essential role for development of the urogenital system. It has a tumor suppressor as well as an oncogenic role in tumor formation. Function may be isoform-specific: isoforms lacking the KTS motif may act as transcription factors. Isoforms containing the KTS motif may bind mRNA and play a role in mRNA metabolism or splicing. Isoform 1 has lower affinity for DNA, and can bind RNA.
• Tissue Specificity: Expressed in the kidney and a subset of hematopoietic cells.
• KEGG Pathway: Transcriptio.l misregulation in cancer (hsa05202)
• Reactome Pathway: Transcriptional regulation of testis differentiation (R-HSA-9690406)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Denys-Drash syndrome	DISSORMZ	Definitive	Autosomal dominant	[1]
Frasier syndrome	DISED8FH	Definitive	Autosomal dominant	[2]
Wilms tumor 1	DISQBKN1	Definitive	Autosomal dominant	[1]
Familial idiopathic steroid-resistant nephrotic syndrome	DISQ53RS	Supportive	Autosomal dominant	[3]

This DOT Affected the Drug Response of 4 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Wilms tumor protein decreases the response to substance of Cisplatin.	[25]
Estradiol	DMUNTE3	Approved	Wilms tumor protein decreases the response to substance of Estradiol.	[26]
Fulvestrant	DM0YZC6	Approved	Wilms tumor protein decreases the response to substance of Fulvestrant.	[26]
DTI-015	DMXZRW0	Approved	Wilms tumor protein decreases the response to substance of DTI-015.	[25]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Wilms tumor protein.	[4]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Wilms tumor protein.	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Wilms tumor protein.	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Wilms tumor protein.	[5]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Wilms tumor protein.	[6]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Wilms tumor protein.	[7]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Wilms tumor protein.	[8]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Wilms tumor protein.	[9]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Wilms tumor protein.	[10]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Wilms tumor protein.	[11]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of Wilms tumor protein.	[12]
Malathion	DMXZ84M	Approved	Malathion increases the expression of Wilms tumor protein.	[13]
Imatinib	DM7RJXL	Approved	Imatinib decreases the expression of Wilms tumor protein.	[14]
Curcumin	DMQPH29	Phase 3	Curcumin decreases the expression of Wilms tumor protein.	[15]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Wilms tumor protein.	[17]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Wilms tumor protein.	[19]
Manganese	DMKT129	Investigative	Manganese decreases the expression of Wilms tumor protein.	[20]
Forskolin	DM6ITNG	Investigative	Forskolin increases the expression of Wilms tumor protein.	[21]
Rapamycin Immunosuppressant Drug	DM678IB	Investigative	Rapamycin Immunosuppressant Drug decreases the expression of Wilms tumor protein.	[22]
Staurosporine	DM0E9BR	Investigative	Staurosporine increases the expression of Wilms tumor protein.	[23]
DEMETHOXYCURCUMIN	DMO5UGV	Investigative	DEMETHOXYCURCUMIN decreases the expression of Wilms tumor protein.	[15]
GW-788388	DMIBUW5	Investigative	GW-788388 increases the expression of Wilms tumor protein.	[24]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] Frasier syndrome is caused by defective alternative splicing of WT1 leading to an altered ratio of WT1 +/-KTS splice isoforms. Hum Mol Genet. 1998 Apr;7(4):709-14. doi: 10.1093/hmg/7.4.709.
• [3] A novel WT1 gene mutation in a three-generation family with progressive isolated focal segmental glomerulosclerosis. Clin J Am Soc Nephrol. 2010 Apr;5(4):698-702. doi: 10.2215/CJN.05670809. Epub 2010 Feb 11.
• [4] 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.
• [5] Changes in expression of WT1 isoforms during induced differentiation of the NB4 cell line. Haematologica. 2005 Mar;90(3):403-5.
• [6] Quercetin and Its Fermented Extract as a Potential Inhibitor of Bisphenol A-Exposed HT-29 Colon Cancer Cells' Viability. Int J Mol Sci. 2023 Mar 15;24(6):5604. doi: 10.3390/ijms24065604.
• [7] Down-regulation of wt1 expression in leukemia cell lines as part of apoptotic effect in arsenic treatment using two compounds. Leuk Lymphoma. 2006 Aug;47(8):1629-38. doi: 10.1080/10428190600625398.
• [8] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [9] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [10] Progesterone up-regulates WT1 mRNA and protein, and alters the relative expression of WT1 transcripts in cultured endometrial stromal cells. J Soc Gynecol Investig. 2003 Dec;10(8):509-16. doi: 10.1016/s1071-5576(03)00147-3.
• [11] In vitro effects of cannabidiol and its main metabolites in mouse and human Sertoli cells. Food Chem Toxicol. 2022 Jan;159:112722. doi: 10.1016/j.fct.2021.112722. Epub 2021 Dec 3.
• [12] Synergistic antiproliferative effect of arsenic trioxide combined with bortezomib in HL60 cell line and primary blasts from patients affected by myeloproliferative disorders. Cancer Genet Cytogenet. 2010 Jun;199(2):110-20. doi: 10.1016/j.cancergencyto.2010.02.010.
• [13] Malathion induced cancer-linked gene expression in human lymphocytes. Environ Res. 2020 Mar;182:109131. doi: 10.1016/j.envres.2020.109131. Epub 2020 Jan 10.
• [14] Sensitivity to imatinib therapy may be predicted by testing Wilms tumor gene expression and colony growth after a short in vitro incubation. Cancer. 2004 Sep 1;101(5):979-88. doi: 10.1002/cncr.20457.
• [15] Effect of pure curcumin, demethoxycurcumin, and bisdemethoxycurcumin on WT1 gene expression in leukemic cell lines. Cancer Chemother Pharmacol. 2008 Sep;62(4):585-94. doi: 10.1007/s00280-007-0642-1. Epub 2007 Nov 23.
• [16] 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.
• [17] Highly active combination of BRD4 antagonist and histone deacetylase inhibitor against human acute myelogenous leukemia cells. Mol Cancer Ther. 2014 May;13(5):1142-54.
• [18] 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.
• [19] 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.
• [20] Gene expression profiling of human primary astrocytes exposed to manganese chloride indicates selective effects on several functions of the cells. Neurotoxicology. 2007 May;28(3):478-89.
• [21] Expression, regulation, and function of paired-box gene 8 in the human placenta and placental cancer cell lines. Endocrinology. 2005 Sep;146(9):4009-15. doi: 10.1210/en.2005-0084. Epub 2005 Jun 16.
• [22] Sirolimus interacts with pathways essential for podocyte integrity. Nephrol Dial Transplant. 2009 Feb;24(2):630-8. doi: 10.1093/ndt/gfn574. Epub 2008 Oct 16.
• [23] Wilms' tumor suppressor (WT1) is a mediator of neuronal degeneration associated with the pathogenesis of Alzheimer's disease. Brain Res. 2003 Sep 5;983(1-2):84-96. doi: 10.1016/s0006-8993(03)03032-4.
• [24] Capturing time-dependent activation of genes and stress-response pathways using transcriptomics in iPSC-derived renal proximal tubule cells. Cell Biol Toxicol. 2023 Aug;39(4):1773-1793. doi: 10.1007/s10565-022-09783-5. Epub 2022 Dec 31.
• [25] Wilms' tumor 1 silencing decreases the viability and chemoresistance of glioblastoma cells in vitro: a potential role for IGF-1R de-repression. J Neurooncol. 2011 May;103(1):87-102. doi: 10.1007/s11060-010-0374-7. Epub 2010 Sep 4.
• [26] The Wilms' tumor suppressor WT1 induces estrogen-independent growth and anti-estrogen insensitivity in ER-positive breast cancer MCF7 cells. Oncol Rep. 2010 Apr;23(4):1109-17. doi: 10.3892/or_00000739.