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Pax4  -  paired box 4

Mus musculus

Synonyms: Paired box protein Pax-4, Pax-4
 
 
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Disease relevance of Pax4

  • Activation of Pax4 resulted in the expression of the late-stage transcription factors, including Pax6, Isl-1, and MafA, and generated a gene expression profile for WB-1A cells similar to that of functional rat insulinoma INS-1 cells [1].
 

High impact information on Pax4

  • As mice lacking Pax4 and Pax6 fail to develop any mature endocrine cells, we conclude that both Pax genes are required for endocrine fate in the pancreas [2].
  • Pancreas development is known to be abolished in Pdx1-mutant mice and Pax4 mutants lack insulin-producing beta-cells [2].
  • We propose that the early expression of Pax4 in a subset of endocrine progenitors is essential for the differentiation of the beta and delta cell lineages [3].
  • Our study indicates a requirement of Arx for alpha-cell fate acquisition and a repressive action on beta-and delta-cell destiny, which is exactly the opposite of the action of Pax4 in endocrine commitment [4].
  • The expansion of ghrelin-producing cells at the expense of beta cells may be a general phenomenon, because we demonstrate that Pax4 mutant mice display a similar phenotype [5].
 

Biological context of Pax4

  • By inactivating the homeobox gene Pax4, we previously demonstrated that its function is required for the formation of mature insulin-producing cells [6].
  • We conclude that constitutive expression of Pax4 in combination with histotypic cultivation facilitates ES cell differentiation into the pancreatic lineage, which leads to the formation of islet-like spheroid structures that produce increased levels of insulin [7].
  • In this study, we characterized the DNA-binding and transactivation properties of mouse Pax4 [8].
  • We isolated and sequenced a 2.4-kb mouse genomic DNA fragment containing the 5' flanking sequence of Pax4 and identified a previously unrecognized intron [9].
  • Cloning of the mouse Pax4 gene promoter and identification of a pancreatic beta cell specific enhancer [9].
 

Anatomical context of Pax4

  • We propose that the antagonistic functions of Arx and Pax4 for proper islet cell specification are related to the pancreatic levels of the respective transcripts [4].
  • The concerted activities of Pax4 and Nkx2.2 are essential to initiate pancreatic beta-cell differentiation [6].
  • Here, we show that during pancreas ontogeny, Pax4 is expressed in differentiating endocrine cells, including beta cells [6].
  • Expression of Pax4 in embryonic stem cells promotes differentiation of nestin-positive progenitor and insulin-producing cells [7].
  • As Pax4 promotes late-stage beta-cell differentiation and maturation, we generated lentiviral vector (LV) containing mouse Pax4 gene and developed two hepatic cell lines expressing Pax4 in the absence (WB-2 cells) or presence (WB-1A cells) of Pdx1-VP16, via LV-mediated gene transfer [1].
 

Associations of Pax4 with chemical compounds

  • In response to glucose, Pax4(+) and wild-type ES-derived cells release insulin [7].
  • We hereby report that deletion of the Pax 4 gene virtually eliminates duodenal and jejunal hormone-secreting cells, as well as serotonin and somatostatin cells of the distal stomach, while deletion of the Pax 6 gene eliminates duodenal GIP cells as well as gastrin and somatostatin cells of the distal stomach [10].
 

Physical interactions of Pax4

 

Regulatory relationships of Pax4

  • The overexpression of Pax4 in HIT-T15 cells dose dependently inhibited the basal transcriptional activity as well as Pax6-induced activity [8].
  • The Pax4 gene is expressed in the early pancreas, but is later restricted to beta cells [3].
 

Other interactions of Pax4

 

Analytical, diagnostic and therapeutic context of Pax4

References

  1. Role of Pax4 in Pdx1-VP16-mediated liver-to-endocrine pancreas transdifferentiation. Tang, D.Q., Cao, L.Z., Chou, W., Shun, L., Farag, C., Atkinson, M.A., Li, S.W., Chang, L.J., Yang, L.J. Lab. Invest. (2006) [Pubmed]
  2. Pax6 is required for differentiation of glucagon-producing alpha-cells in mouse pancreas. St-Onge, L., Sosa-Pineda, B., Chowdhury, K., Mansouri, A., Gruss, P. Nature (1997) [Pubmed]
  3. The Pax4 gene is essential for differentiation of insulin-producing beta cells in the mammalian pancreas. Sosa-Pineda, B., Chowdhury, K., Torres, M., Oliver, G., Gruss, P. Nature (1997) [Pubmed]
  4. Opposing actions of Arx and Pax4 in endocrine pancreas development. Collombat, P., Mansouri, A., Hecksher-Sorensen, J., Serup, P., Krull, J., Gradwohl, G., Gruss, P. Genes Dev. (2003) [Pubmed]
  5. Ghrelin cells replace insulin-producing beta cells in two mouse models of pancreas development. Prado, C.L., Pugh-Bernard, A.E., Elghazi, L., Sosa-Pineda, B., Sussel, L. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  6. The concerted activities of Pax4 and Nkx2.2 are essential to initiate pancreatic beta-cell differentiation. Wang, J., Elghazi, L., Parker, S.E., Kizilocak, H., Asano, M., Sussel, L., Sosa-Pineda, B. Dev. Biol. (2004) [Pubmed]
  7. Expression of Pax4 in embryonic stem cells promotes differentiation of nestin-positive progenitor and insulin-producing cells. Blyszczuk, P., Czyz, J., Kania, G., Wagner, M., Roll, U., St-Onge, L., Wobus, A.M. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  8. Identification of a portable repression domain and an E1A-responsive activation domain in Pax4: a possible role of Pax4 as a transcriptional repressor in the pancreas. Fujitani, Y., Kajimoto, Y., Yasuda, T., Matsuoka, T.A., Kaneto, H., Umayahara, Y., Fujita, N., Watada, H., Miyazaki, J.I., Yamasaki, Y., Hori, M. Mol. Cell. Biol. (1999) [Pubmed]
  9. Cloning of the mouse Pax4 gene promoter and identification of a pancreatic beta cell specific enhancer. Xu, W., Murphy, L.J. Mol. Cell. Endocrinol. (2000) [Pubmed]
  10. Pax 4 and 6 regulate gastrointestinal endocrine cell development. Larsson, L.I., St-Onge, L., Hougaard, D.M., Sosa-Pineda, B., Gruss, P. Mech. Dev. (1998) [Pubmed]
  11. DNA binding and transactivating properties of the paired and homeobox protein Pax4. Kalousová, A., Benes, V., Paces, J., Paces, V., Kozmik, Z. Biochem. Biophys. Res. Commun. (1999) [Pubmed]
  12. High glucose is necessary for complete maturation of Pdx1-VP16-expressing hepatic cells into functional insulin-producing cells. Cao, L.Z., Tang, D.Q., Horb, M.E., Li, S.W., Yang, L.J. Diabetes (2004) [Pubmed]
  13. The pancreatic beta-cell-specific transcription factor Pax-4 inhibits glucagon gene expression through Pax-6. Ritz-Laser, B., Estreicher, A., Gauthier, B.R., Mamin, A., Edlund, H., Philippe, J. Diabetologia (2002) [Pubmed]
  14. Neurogenin3 and hepatic nuclear factor 1 cooperate in activating pancreatic expression of Pax4. Smith, S.B., Gasa, R., Watada, H., Wang, J., Griffen, S.C., German, M.S. J. Biol. Chem. (2003) [Pubmed]
  15. Embryonic stem cells differentiate into insulin-producing cells without selection of nestin-expressing cells. Blyszczuk, P., Asbrand, C., Rozzo, A., Kania, G., St-Onge, L., Rupnik, M., Wobus, A.M. Int. J. Dev. Biol. (2004) [Pubmed]
  16. Paired-homeodomain transcription factor PAX4 acts as a transcriptional repressor in early pancreatic development. Smith, S.B., Ee, H.C., Conners, J.R., German, M.S. Mol. Cell. Biol. (1999) [Pubmed]
  17. Molecular cloning of mouse paired-box-containing gene (Pax)-4 from an islet beta cell line and deduced sequence of human Pax-4. Matsushita, T., Yamaoka, T., Otsuka, S., Moritani, M., Matsumoto, T., Itakura, M. Biochem. Biophys. Res. Commun. (1998) [Pubmed]
 
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