Paired Box Domains

1. Paired Box Domains MRCPath Self Help 2008

2. Identification of Paired Box Domain • First identified in the Drosophila pair-rule segmentation gene paired and the two segment polarity genes gooseberry-distal and gooseberry-proximal • These genes contain a domain similar to the homeobox domain and were called paired type homeobox genes or PAX genes • PAX genes later identified in a variety of organisms including mouse, chick, zebra fish and humans • Nine PAX genes in humans classified into four groups Google - Literature search

3. Paired Box Gene Expression in Drosophila Paired (Prd) expression defines segments in Drosophila Gooseberry-distal (Gsbd, red fluorophore) defines the distal side of segments Google Images and Google search

4. Structure and Function of Paired Box Domain • ~126 amino acid region capable of binding DNA • Usually located at N-terminal of protein • Paired box has a bipartite structure consisting of a C-terminal and N-terminal domain separated by a linker sequence • C-terminal subdomain - helix-turn-helix (HTH) motif binds major groove • N-terminal subdomain – β-turn and β-hairpin (wing) motifs participate in DNA binding • Linker – binds minor groove • Different subdomains are incorporated into different PAX genes and their alternatively spliced isoforms to confer specificity to a target sequence • Involved in activation or repression of eukaryotic transcription during embryogenesis PROSITE (http://www.expasy.org/prosite/), Hum. Mol. Gen, OMIM

5. Classification of Human PAX Genes • Class I • PAX1 and PAX9 • Contain Paired box + octapeptide (conserved region of 8 a.a. of unknown function) • Class II • PAX3 and PAX7 • Contain Paired box + octapeptide + paired type homeodomain • Class III • PAX2, PAX5 and PAX8 • Contain Paired box + octapeptide + partial homeodomain • Class IV • PAX4 and PAX6 • Paired box + homeodomain Literature search

6. PAX 5 – Protein Structure Protein Data Bank (http://www.pdb.org)

7. PAX Genes Show Interspecies Conservation Human Mouse Chicken Frog Zebra fish Degree of Conservation Tcoffee (http://www.tcoffee.org/), PROSITE (http://www.expasy.org/prosite/)

8. Paired Box Domain is Highly Conserved in Human PAX Genes N-terminal (paired-box) highly conserved C-terminal poorly conserved PROSITE (http://www.expasy.org/prosite/),ClustalW (http://www.ebi.ac.uk/Tools/clustalw2/index.html)

9. PAX Genes in Human Disease • PAX1 - role in embryo segmentation, defects cause vertebral malformations - ?Klippel-Feil and ?spina bifida • PAX2 - TF which may control kidney cell differentiation • PAX3 - expressed in early neurogenesis. Haploinsufficiency causes Waardenburg syndrome type I and III (pigmentary defects and deafness). • PAX4 - essential for differentiation of insulin-producing beta-cells in mammalian pancreas • PAX5 – aka B-cell specific transcription factor (BSAP). Role in B-cell differentiation as well as neural development and spermatogenesis • PAX6 - transcription factor with important functions in eye and nasal development. Defects cause aniridia type II (AN2), an AD disorder characterized by complete or partial absence of the iris. • PAX7 – TF required for neural crest formation • PAX8 – TF required in thyroid development (and kidney), defects cause congenital hypothyroidism • PAX9 - defects cause oligodontia (some teeth missing) PROSITE, OMIM, Literature search

10. Cancer Contribution of PAX Family Member Subgroups Robson EJD et al. (2006) A PANorama of PAX genes in cancer and development Nat. Rev. Cancer.6: 52–62 doi:10.1038/nrc1778

11. Characteristics Conferred by PAX Genes that are Favourable for Tumour Progression Robson EJD et al. (2006) A PANorama of PAX genes in cancer and development Nat. Rev. Cancer.6: 52–62 doi:10.1038/nrc1778

12. Cancers Associated with PAX Gene Defects