Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTKP1N8F)

• DOT Name: Paired box protein Pax-2 (PAX2)
• Gene Name: PAX2
• Related Disease:
  Adenocarcinoma
  Chronic kidney disease
  Chronic renal failure
  Focal segmental glomerulosclerosis 7
  Nephrotic syndrome, type 2
  Renal coloboma syndrome
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Carcinoma
  Cardiovascular disease
  Coloboma
  Colon cancer
  Colon carcinoma
  Congenital anomaly of kidney and urinary tract
  Diabetic kidney disease
  End-stage renal disease
  Endometrial cancer
  Endometrial carcinoma
  Endometriosis
  Epithelial ovarian cancer
  Kidney failure
  Melanoma
  Metastatic malignant neoplasm
  Microphthalmia
  Nail-patella syndrome
  Nephritis
  Nephrotic syndrome
  Ovarian cancer
  Ovarian neoplasm
  Prostate cancer
  Renal hypoplasia
  Renal tubular dysgenesis
  Trichohepatoenteric syndrome
  Vascular purpura
  Nephropathy
  Neuralgia
  Familial idiopathic steroid-resistant nephrotic syndrome
  Multicystic dysplastic kidney
  Adult kidney Wilms tumor
  Advanced cancer
  Autosomal dominant polycystic kidney disease
  Cystic kidney disease
  Kidney neoplasm
  Type-1/2 diabetes
  Vesicoureteral reflux
• UniProt ID: PAX2_HUMAN
• Pfam ID: PF00292 ; PF12403
• Sequence:
  MDMHCKADPFSAMHPGHGGVNQLGGVFVNGRPLPDVVRQRIVELAHQGVRPCDISRQLRV
  SHGCVSKILGRYYETGSIKPGVIGGSKPKVATPKVVDKIAEYKRQNPTMFAWEIRDRLLA
  EGICDNDTVPSVSSINRIIRTKVQQPFHPTPDGAGTGVTAPGHTIVPSTASPPVSSASND
  PVGSYSINGILGIPRSNGEKRKRDEVEVYTDPAHIRGGGGLHLVWTLRDVSEGSVPNGDS
  QSGVDSLRKHLRADTFTQQQLEALDRVFERPSYPDVFQASEHIKSEQGNEYSLPALTPGL
  DEVKSSLSASTNPELGSNVSGTQTYPVVTGRDMASTTLPGYPPHVPPTGQGSYPTSTLAG
  MVPGSEFSGNPYSHPQYTAYNEAWRFSNPALLSSPYYYSAAPRGSAPAAAAAAYDRH
• Function: Transcription factor that may have a role in kidney cell differentiation. Has a critical role in the development of the urogenital tract, the eyes, and the CNS.
• Tissue Specificity: Expressed in primitive cells of the kidney, ureter, eye, ear and central nervous system.
• Reactome Pathway: Formation of intermediate mesoderm (R-HSA-9761174)

Molecular Interaction Atlas (MIA) of This DOT

46 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adenocarcinoma	DIS3IHTY	Definitive	Biomarker	[1]
Chronic kidney disease	DISW82R7	Definitive	Genetic Variation	[2]
Chronic renal failure	DISGG7K6	Definitive	Genetic Variation	[3]
Focal segmental glomerulosclerosis 7	DIS9T10W	Definitive	Autosomal dominant	[4]
Nephrotic syndrome, type 2	DISIRFO1	Definitive	GermlineCausalMutation	[5]
Renal coloboma syndrome	DISXZ9F3	Definitive	Autosomal dominant	[6]
Breast cancer	DIS7DPX1	Strong	Biomarker	[7]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[8]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[8]
Carcinoma	DISH9F1N	Strong	Biomarker	[9]
Cardiovascular disease	DIS2IQDX	Strong	Genetic Variation	[10]
Coloboma	DISP39N5	Strong	Genetic Variation	[11]
Colon cancer	DISVC52G	Strong	Altered Expression	[12]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[12]
Congenital anomaly of kidney and urinary tract	DIS84IVH	Strong	Genetic Variation	[13]
Diabetic kidney disease	DISJMWEY	Strong	Biomarker	[14]
End-stage renal disease	DISXA7GG	Strong	Genetic Variation	[3]
Endometrial cancer	DISW0LMR	Strong	Biomarker	[15]
Endometrial carcinoma	DISXR5CY	Strong	Biomarker	[15]
Endometriosis	DISX1AG8	Strong	Altered Expression	[16]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[17]
Kidney failure	DISOVQ9P	Strong	Genetic Variation	[18]
Melanoma	DIS1RRCY	Strong	Altered Expression	[19]
Metastatic malignant neoplasm	DIS86UK6	Strong	Biomarker	[20]
Microphthalmia	DISGEBES	Strong	Genetic Variation	[21]
Nail-patella syndrome	DIS8C4CT	Strong	Biomarker	[3]
Nephritis	DISQZQ70	Strong	Genetic Variation	[22]
Nephrotic syndrome	DISSPSC2	Strong	Biomarker	[23]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[17]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[17]
Prostate cancer	DISF190Y	Strong	Altered Expression	[24]
Renal hypoplasia	DISJ5F10	Strong	Genetic Variation	[2]
Renal tubular dysgenesis	DISZ2OFK	Strong	CausalMutation	[25]
Trichohepatoenteric syndrome	DISL3ODF	Strong	Genetic Variation	[26]
Vascular purpura	DIS6ZZMF	Strong	Genetic Variation	[22]
Nephropathy	DISXWP4P	moderate	Biomarker	[27]
Neuralgia	DISWO58J	moderate	Altered Expression	[28]
Familial idiopathic steroid-resistant nephrotic syndrome	DISQ53RS	Supportive	Autosomal dominant	[5]
Multicystic dysplastic kidney	DISJ9R1F	Disputed	Biomarker	[29]
Adult kidney Wilms tumor	DIS79FJF	Limited	Biomarker	[30]
Advanced cancer	DISAT1Z9	Limited	Altered Expression	[17]
Autosomal dominant polycystic kidney disease	DISBHWUI	Limited	Biomarker	[31]
Cystic kidney disease	DISRT1LM	Limited	Biomarker	[32]
Kidney neoplasm	DISBNZTN	Limited	Biomarker	[33]
Type-1/2 diabetes	DISIUHAP	Limited	Altered Expression	[34]
Vesicoureteral reflux	DISUL6SA	Limited	Genetic Variation	[3]

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 Paired box protein Pax-2 (PAX2).	[35]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Paired box protein Pax-2 (PAX2).	[38]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the methylation of Paired box protein Pax-2 (PAX2).	[39]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Paired box protein Pax-2 (PAX2).	[36]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Paired box protein Pax-2 (PAX2).	[37]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Paired box protein Pax-2 (PAX2).	[37]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Paired box protein Pax-2 (PAX2).	[40]

References

• [1] Application of immunohistochemistry in the diagnosis of epithelioid mesothelioma: a review and update.Hum Pathol. 2013 Jan;44(1):1-19. doi: 10.1016/j.humpath.2012.05.014. Epub 2012 Sep 7.
• [2] New PAX2 heterozygous mutation in a child with chronic kidney disease: a case report and review of the literature.BMC Nephrol. 2018 Sep 21;19(1):245. doi: 10.1186/s12882-018-1044-9.
• [3] Could the interaction between LMX1B and PAX2 influence the severity of renal symptoms?.Eur J Hum Genet. 2018 Nov;26(11):1708-1712. doi: 10.1038/s41431-018-0213-4. Epub 2018 Jul 4.
• [4] 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.
• [5] Mutations in PAX2 associate with adult-onset FSGS. J Am Soc Nephrol. 2014 Sep;25(9):1942-53. doi: 10.1681/ASN.2013070686. Epub 2014 Mar 27.
• [6] Missense mutation and hexanucleotide duplication in the PAX2 gene in two unrelated families with renal-coloboma syndrome (MIM 120330). Hum Genet. 1998 Aug;103(2):149-53. doi: 10.1007/s004390050798.
• [7] The role of AIB1 and PAX2 in primary breast cancer: validation of AIB1 as a negative prognostic factor.Ann Oncol. 2013 May;24(5):1244-52. doi: 10.1093/annonc/mds613. Epub 2012 Dec 9.
• [8] PAX2 expression is correlated with better survival in tamoxifen-treated breast carcinoma patients.Tissue Cell. 2018 Jun;52:135-142. doi: 10.1016/j.tice.2018.05.005. Epub 2018 May 9.
• [9] Is PAX2 a reliable marker in differentiating diffuse malignant mesotheliomas of peritoneum from serous carcinomas of mllerian origin?.Appl Immunohistochem Mol Morphol. 2012 May;20(3):272-6. doi: 10.1097/PAI.0b013e3182366531.
• [10] Leveraging Polygenic Functional Enrichment to Improve GWAS Power.Am J Hum Genet. 2019 Jan 3;104(1):65-75. doi: 10.1016/j.ajhg.2018.11.008. Epub 2018 Dec 27.
• [11] Association of PAX2 and Other Gene Mutations with the Clinical Manifestations of Renal Coloboma Syndrome.PLoS One. 2015 Nov 16;10(11):e0142843. doi: 10.1371/journal.pone.0142843. eCollection 2015.
• [12] PAX2 protein induces expression of cyclin D1 through activating AP-1 protein and promotes proliferation of colon cancer cells.J Biol Chem. 2012 Dec 28;287(53):44164-72. doi: 10.1074/jbc.M112.401521. Epub 2012 Nov 7.
• [13] Prioritization and burden analysis of rare variants in 208 candidate genes suggest they do not play a major role in CAKUT. Kidney Int. 2016 Feb;89(2):476-86. doi: 10.1038/ki.2015.319.
• [14] Suppression of chaperone-mediated autophagy in the renal cortex during acute diabetes mellitus.Kidney Int. 2004 Jun;65(6):2135-44. doi: 10.1111/j.1523-1755.2004.00639.x.
• [15] PAX2 in endometrial carcinogenesis and in differential diagnosis of endometrial hyperplasia: A systematic review and meta-analysis of diagnostic accuracy.Acta Obstet Gynecol Scand. 2019 Mar;98(3):287-299. doi: 10.1111/aogs.13512. Epub 2019 Jan 8.
• [16] Paired-box gene 2 is down-regulated in endometriosis and correlates with low epidermal growth factor receptor expression.Hum Reprod. 2012 Jun;27(6):1676-84. doi: 10.1093/humrep/des124. Epub 2012 Apr 3.
• [17] UnPAXing the Divergent Roles of PAX2 and PAX8 in High-Grade Serous Ovarian Cancer.Cancers (Basel). 2018 Aug 8;10(8):262. doi: 10.3390/cancers10080262.
• [18] PAX2 gene mutations in pediatric and young adult transplant recipients: kidney and urinary tract malformations without ocular anomalies.Clin Genet. 2011 Dec;80(6):581-5. doi: 10.1111/j.1399-0004.2010.01588.x. Epub 2010 Nov 25.
• [19] PAX2 regulates ADAM10 expression and mediates anchorage-independent cell growth of melanoma cells.PLoS One. 2011;6(8):e22312. doi: 10.1371/journal.pone.0022312. Epub 2011 Aug 18.
• [20] Upregulation of PAX2 promotes the metastasis of esophageal cancer through interleukin-5.Cell Physiol Biochem. 2015;35(2):740-54. doi: 10.1159/000369734. Epub 2015 Jan 30.
• [21] PAX2 mutations in renal-coloboma syndrome: mutational hotspot and germline mosaicism.Eur J Hum Genet. 2000 Nov;8(11):820-6. doi: 10.1038/sj.ejhg.5200539.
• [22] Association of the paired box 2 gene polymorphism with the susceptibility and pathogenesis of HenochSchnlein purpura in children.Mol Med Rep. 2015 Mar;11(3):1997-2003. doi: 10.3892/mmr.2014.2908. Epub 2014 Nov 10.
• [23] Dominant PAX2 mutations may cause steroid-resistant nephrotic syndrome and FSGS in children.Pediatr Nephrol. 2019 Sep;34(9):1607-1613. doi: 10.1007/s00467-019-04256-0. Epub 2019 Apr 17.
• [24] Paired box 2 upregulates androgen receptor gene expression in androgen-independent prostate cancer.FEBS J. 2014 Oct;281(19):4506-18. doi: 10.1111/febs.12959. Epub 2014 Aug 26.
• [25] Whole-exome sequencing in the molecular diagnosis of individuals with congenital anomalies of the kidney and urinary tract and identification of a new causative gene.Genet Med. 2017 Apr;19(4):412-420. doi: 10.1038/gim.2016.131. Epub 2016 Sep 22.
• [26] Papillorenal syndrome after Beta-interferon treatment in pregnancy.Ren Fail. 2009;31(7):602-5. doi: 10.1080/08860220902968862.
• [27] PAX2 in human kidney malformations and disease.Pediatr Nephrol. 2012 Aug;27(8):1265-75. doi: 10.1007/s00467-011-2053-0. Epub 2011 Dec 3.
• [28] MicroRNA-362-3p attenuates motor deficit following spinal cord injury via targeting paired box gene 2.J Integr Neurosci. 2019 Mar 30;18(1):57-64. doi: 10.31083/j.jin.2019.01.12.
• [29] Multicystic dysplastic kidney and variable phenotype in a family with a novel deletion mutation of PAX2.J Am Soc Nephrol. 2005 Sep;16(9):2754-61. doi: 10.1681/ASN.2005030239. Epub 2005 Jul 27.
• [30] A rodent model for Wilms tumors: embryonal kidney neoplasms induced by N-nitroso-N'-methylurea.Proc Natl Acad Sci U S A. 1994 Oct 11;91(21):9931-5. doi: 10.1073/pnas.91.21.9931.
• [31] Pax2 gene dosage influences cystogenesis in autosomal dominant polycystic kidney disease.Hum Mol Genet. 2006 Dec 15;15(24):3520-8. doi: 10.1093/hmg/ddl428. Epub 2006 Nov 2.
• [32] Reduced Pax2 gene dosage increases apoptosis and slows the progression of renal cystic disease.Dev Biol. 2000 Mar 15;219(2):250-8. doi: 10.1006/dbio.2000.9618.
• [33] Immunohistochemical diagnosis of renal neoplasms.Arch Pathol Lab Med. 2011 Jan;135(1):92-109. doi: 10.5858/2010-0478-RAR.1.
• [34] Gas1 expression in parietal cells of Bowman's capsule in experimental diabetic nephropathy.Histochem Cell Biol. 2017 Jul;148(1):33-47. doi: 10.1007/s00418-017-1550-z. Epub 2017 Mar 18.
• [35] 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.
• [36] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [37] 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.
• [38] 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.
• [39] 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.
• [40] 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.