PAX2 explained

Paired box gene 2, also known as Pax-2, is a protein which in humans is encoded by the PAX2 gene.^{[1] [2]}

Function

The Pax Genes, or Paired-Box Containing Genes, play important roles in the development and proliferation of multiple cell lines, development of organs, and development and organization of the central nervous system.^[3] The transcription factor gene PAX2 is important in the regionalized embryological development of the central nervous system. In mammals, the brain is developed in three regions: the forebrain, midbrain, and the hindbrain.^[4] Concentration gradients of fibroblast growth factor 8 (FGF8) and Wingless-Type MMTV Integration Site Family, Member 1 (Wnt1) control expression of Pax-2 during development of the Mesencephalon, or midbrain. Similar patterning during embryological development can be observed in “basal chordates or ascidians,” in which organization of the central nervous system in ascidian larvae are also controlled by fibroblast growth factor genes. PAX2 encodes for the transcription factor which appears to be essential in the organization of the midbrain and hindbrain regions, and at the earliest can be detected on either side of the sulcus limitans, which separates motor and sensory nerve nuclei.^[5]

PAX2 encodes paired box gene 2, one of many human homologues of the Drosophila melanogaster gene prd. The central feature of this transcription factor gene family is the conserved DNA-binding paired box domain. PAX2 is believed to be a target of transcriptional suppression by the tumor suppressor gene WT1. Pax 2 is a transcription factor controlled by the signaling molecules Wnt1 and Fgf8. Pax2 along with other transcription factors Pax5, Pax8, En1, and En 2 are expressed across the Otx2-Gbx2 boundary in the mid-hindbrain region. These transcription factors work with the signaling molecules Wnt1 and Fgf8 to maintain the MHB organizer. The MHB controls midbrain and cerebellum development. Pax2 is the earliest known gene to be expressed across the Otx2-Gbx2 boundary. It is first expressed in the late primitive streak stage and is expressed in a narrow ring centered at the MHB during somitogenesis. Transgene expression of the mid-hindbrain and developing kidney is directed by Pax2. There are three distinct MHB-specific enhancers in the upstream region of Pax2. Expression at the MHB from the four-somite stage onwards is directed by the two late enhancers in the proximal and distal regions of Pax2. The early enhancer located in the intermediate region activates the mid-hindbrain region of late gastrula embryos. The activation of Pax2, Pax5, and Pax8 is a conserved feature of all vertebrates.

Clinical significance

Pathologically, Pax2 has been demonstrated to activate hepatocyte growth factor (HGF) gene promoter, and both have been indicated as playing a role in human prostate cancers.^[6]

Mutations within PAX2 have been shown to result in optic nerve colobomas and renal hypoplasia. Alternative splicing of this gene results in multiple transcript variants.^[7] Pax2 and Pax8 are also necessary for the formation of the pronephros and subsequent kidney structures. Pax2 and Pax8 regulate the expression of Gata3. Without these genes mutations in the urogenital system arise.

Pax2 misexpression is frequently observed in proliferative disorders of the kidney. For example, Pax2 is highly expressed in polycystic kidney disease (PKD), Wilms' tumor (WT), and renal cell carcinoma (RCC).^[8] Pax2 expression in these diseases appears fuel cell cycling, inhibit cell death, and confer resistance to chemotherapy.^[8] Due to its role in these diseases, Pax2 is an attractive therapeutic target and a number of methods for inhibiting its activity have been investigated. In fact, a small-molecule was recently identified with the ability to disrupt Pax2 mediated transcription by blocking Pax2 from binding to DNA.^{[9] [10]}

Interactions

PAX2 has been shown to interact with PAXIP1.^[11]

See also

• Pax genes

Further reading

• Noll M . Evolution and role of Pax genes . Current Opinion in Genetics & Development . 3 . 4 . 595–605 . Aug 1993 . 8241771 . 10.1016/0959-437X(93)90095-7 .
• Dahl E, Koseki H, Balling R . Pax genes and organogenesis . BioEssays . 19 . 9 . 755–65 . Sep 1997 . 9297966 . 10.1002/bies.950190905 . 23755557 .
• Eccles MR, He S, Legge M, Kumar R, Fox J, Zhou C, French M, Tsai RW . PAX genes in development and disease: the role of PAX2 in urogenital tract development . The International Journal of Developmental Biology . 46 . 4 . 535–44 . 2003 . 12141441 .
• Eccles MR, Wallis LJ, Fidler AE, Spurr NK, Goodfellow PJ, Reeve AE . Expression of the PAX2 gene in human fetal kidney and Wilms' tumor . Cell Growth & Differentiation . 3 . 5 . 279–89 . May 1992 . 1378753 .
• Sanyanusin P, Schimmenti LA, McNoe LA, Ward TA, Pierpont ME, Sullivan MJ, Dobyns WB, Eccles MR . Mutation of the PAX2 gene in a family with optic nerve colobomas, renal anomalies and vesicoureteral reflux . Nature Genetics . 9 . 4 . 358–64 . Apr 1995 . 7795640 . 10.1038/ng0495-358 . 29180124 .
• Ward TA, Nebel A, Reeve AE, Eccles MR . Alternative messenger RNA forms and open reading frames within an additional conserved region of the human PAX-2 gene . Cell Growth & Differentiation . 5 . 9 . 1015–21 . Sep 1994 . 7819127 .
• Stapleton P, Weith A, Urbánek P, Kozmik Z, Busslinger M . Chromosomal localization of seven PAX genes and cloning of a novel family member, PAX-9 . Nature Genetics . 3 . 4 . 292–8 . Apr 1993 . 7981748 . 10.1038/ng0493-292 . 21338655 .
• Pilz AJ, Povey S, Gruss P, Abbott CM . Mapping of the human homologs of the murine paired-box-containing genes . Mammalian Genome . 4 . 2 . 78–82 . 1993 . 8431641 . 10.1007/BF00290430 . 30845070 .
• Sanyanusin P, McNoe LA, Sullivan MJ, Weaver RG, Eccles MR . Mutation of PAX2 in two siblings with renal-coloboma syndrome . Human Molecular Genetics . 4 . 11 . 2183–4 . Nov 1995 . 8589702 . 10.1093/hmg/4.11.2183 .
• Sanyanusin P, Norrish JH, Ward TA, Nebel A, McNoe LA, Eccles MR . Genomic structure of the human PAX2 gene . Genomics . 35 . 1 . 258–61 . Jul 1996 . 8661132 . 10.1006/geno.1996.0350 .
• Dehbi M, Ghahremani M, Lechner M, Dressler G, Pelletier J . The paired-box transcription factor, PAX2, positively modulates expression of the Wilms' tumor suppressor gene (WT1) . Oncogene . 13 . 3 . 447–53 . Aug 1996 . 8760285 .
• Bonaldo MF, Lennon G, Soares MB . Normalization and subtraction: two approaches to facilitate gene discovery . Genome Research . 6 . 9 . 791–806 . Sep 1996 . 8889548 . 10.1101/gr.6.9.791 . free .
• Schimmenti LA, Cunliffe HE, McNoe LA, Ward TA, French MC, Shim HH, Zhang YH, Proesmans W, Leys A, Byerly KA, Braddock SR, Masuno M, Imaizumi K, Devriendt K, Eccles MR . Further delineation of renal-coloboma syndrome in patients with extreme variability of phenotype and identical PAX2 mutations . American Journal of Human Genetics . 60 . 4 . 869–78 . Apr 1997 . 9106533 . 1712484 .
• Narahara K, Baker E, Ito S, Yokoyama Y, Yu S, Hewitt D, Sutherland GR, Eccles MR, Richards RI . Grant Robert Sutherland . Localisation of a 10q breakpoint within the PAX2 gene in a patient with a de novo t(10;13) translocation and optic nerve coloboma-renal disease . Journal of Medical Genetics . 34 . 3 . 213–6 . Mar 1997 . 9132492 . 1050895 . 10.1136/jmg.34.3.213 .
• Tavassoli K, Rüger W, Horst J . Alternative splicing in PAX2 generates a new reading frame and an extended conserved coding region at the carboxy terminus . Human Genetics . 101 . 3 . 371–5 . Dec 1997 . 9439670 . 10.1007/s004390050644 . 43590139 .
• Stayner CK, Cunliffe HE, Ward TA, Eccles MR . Cloning and characterization of the human PAX2 promoter . The Journal of Biological Chemistry . 273 . 39 . 25472–9 . Sep 1998 . 9738017 . 10.1074/jbc.273.39.25472 . free .
• Devriendt K, Matthijs G, Van Damme B, Van Caesbroeck D, Eccles M, Vanrenterghem Y, Fryns JP, Leys A . Missense mutation and hexanucleotide duplication in the PAX2 gene in two unrelated families with renal-coloboma syndrome (MIM 120330) . Human Genetics . 103 . 2 . 149–53 . Aug 1998 . 9760197 . 10.1007/s004390050798 . 8930257 .
• Schimmenti LA, Shim HH, Wirtschafter JD, Panzarino VA, Kashtan CE, Kirkpatrick SJ, Wargowski DS, France TD, Michel E, Dobyns WB . Homonucleotide expansion and contraction mutations of PAX2 and inclusion of Chiari 1 malformation as part of renal-coloboma syndrome . Human Mutation . 14 . 5 . 369–76 . 2000 . 10533062 . 10.1002/(SICI)1098-1004(199911)14:5<369::AID-HUMU2>3.0.CO;2-E . 25564812 . free .

External links

• GeneReviews/NCBI/NIH/UW entry on Renal Coloboma Syndrome

Notes and References

1. Pilz AJ, Povey S, Gruss P, Abbott CM . Mapping of the human homologs of the murine paired-box-containing genes . Mammalian Genome . 4 . 2 . 78–82 . 1993 . 8431641 . 10.1007/BF00290430 . 30845070 .
2. Stapleton P, Weith A, Urbánek P, Kozmik Z, Busslinger M . Chromosomal localization of seven PAX genes and cloning of a novel family member, PAX-9 . Nature Genetics . 3 . 4 . 292–8 . Apr 1993 . 7981748 . 10.1038/ng0493-292 . 21338655 .
3. Book: Hughes K, Maloy K . Mansouri A, Gruss P . Brenner's Encyclopedia of Genetics . 2nd . Pax Gene . 2013 . 246–248 . Elsevier Science . San Diego . 10.1016/B978-0-12-374984-0.01128-1 . 978-0-08-096156-9 .
4. Imai KS, Satoh N, Satou Y . Region specific gene expressions in the central nervous system of the ascidian embryo . Mechanisms of Development . 119 . S275–7 . 2002 . Suppl 1 . 14516697 . 10.1016/S0925-4773(03)00128-X . 16714343 . free .
5. Book: John . Nolte . The human brain: an introduction to its functional anatomy . 2009 . Mosby/Elsevier . Philadelphia, PA . 978-0-323-04131-7 . 6th . 685 .
6. Ueda T, Ito S, Shiraishi T, Taniguchi H, Kayukawa N, Nakanishi H, Nakamura T, Naya Y, Hongo F, Kamoi K, Okihara K, Kawauchi A, Miki T . PAX2 promoted prostate cancer cell invasion through transcriptional regulation of HGF in an in vitro model . Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease . 1852 . 11 . 2467–73 . 2015 . 26296757 . 10.1016/j.bbadis.2015.08.008 .
7. Web site: Entrez Gene: PAX2 paired box gene 2.
8. Sharma R, Sanchez-Ferras O, Bouchard M . Pax genes in renal development, disease and regeneration . Seminars in Cell and Developmental Biology . 44 . 97–106 . 2015 . 26410163 . 10.1016/j.semcdb.2015.09.016 .
9. Grimley E, Liao C, Ranghini E, Nikolovska-Coleska Z, Dressler G . Inhibition of Pax2 Transcription Activation with a Small Molecule that Targets the DNA Binding Domain . ACS Chemical Biology . 12 . 3 . 724–734 . 2017 . 28094913 . 10.1021/acschembio.6b00782 . 5761330 .
10. Grimley E, Dressler GR . Are Pax proteins potential therapeutic targets in kidney disease and cancer? . Kidney International . 2018 . 94 . 2 . 259–267 . 29685496 . 10.1016/j.kint.2018.01.025 . 6054895 .
11. Lechner MS, Levitan I, Dressler GR . PTIP, a novel BRCT domain-containing protein interacts with Pax2 and is associated with active chromatin . Nucleic Acids Research . 28 . 14 . 2741–51 . Jul 2000 . 10908331 . 102659 . 10.1093/nar/28.14.2741 .