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Gene Review

PAX4  -  paired box 4

Homo sapiens

Synonyms: KPD, MODY9, Paired box protein Pax-4
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Disease relevance of PAX4

  • RESULTS: There was no evidence of linkage with the markers for NEUROD1 and PAX4 either with MODY or late-onset Type II diabetes [1].
  • The paired homeodomain transcription factor Pax4 is implicated in the differentiation of the insulin-producing beta-cell lineage because disruption of the pax4 gene results in a severe deficiency of beta-cells and the manifestation of diabetes mellitus in mice [2].
  • Association of childhood type 1 diabetes mellitus with a variant of PAX4: possible link to beta cell regenerative capacity [3].
  • Expression of dominant negative form of PAX4 in human insulinoma [4].
  • Aberrant DNA demethylation in promoter region and aberrant expression of mRNA of PAX4 gene in hematologic malignancies [5].

High impact information on PAX4


Biological context of PAX4


Anatomical context of PAX4

  • Together with earlier reports, these new findings suggest an important functional role for NRSF in the expression of the pax4 gene and infer a role for NRSF in pancreatic islet development [2].
  • In both cell lines and transgenic animals, a 4.9-kilobase pair region directly upstream of the human PAX4 gene transcriptional start site acts as a potent pancreas-specific promoter [11].
  • During pancreatic development, the paired homeodomain transcription factor PAX4 is required for the differentiation of the insulin-producing beta cells and somatostatin-producing delta cells [11].
  • The paired-homeodomain transcription factor PAX4 is expressed in the early pancreas, but is later restricted to beta cells and not expressed in mature islets, suggesting an important role of PAX4 in differentiation and development of pancreatic islet [4].
  • PAX4 is a transcription factor essential for the development of insulin-producing pancreatic beta-cells [8].

Associations of PAX4 with chemical compounds

  • The restoration of PAX4 gene expression after treatment with the demethylating agent 5-aza-2'-deoxycitidine, as well as bisulfite sequencing analysis, indicated that gene overexpression was caused by DNA demethylation at the promoter region [5].
  • A similarly bimodal induction of FLIP, pancreatic duodenal homeobox (PDX)-1, and Pax4 mRNA expression, as well as glucose-stimulated insulin secretion, was observed [12].
  • In patients X, Y, and Z with homozygous mutation in Pax4, CS was 0.418, 0.208, and 1.279 ng/mL/min, respectively, and Si was 1.11, 2.88, and 0.00 x 10(-4)/min/(microU/mL), respectively [13].
  • Four diabetic patients carried the homozygous mutation (Thr/Thr) in the NeuroD1 gene and 3 patients carried the homozygous mutation (Trp/Trp) in the Pax4 gene, while both homozygous mutations were not detected in the control subjects [13].

Regulatory relationships of PAX4

  • Together, these results suggest a model in which PAX4 expression is activated during pancreatic development by a combination of pancreas-specific factors but is then switched off once PAX4 protein reaches sufficient levels [11].
  • In addition, suppression of E47/E12 expression in AR42J-B13 cells using siRNA oligonucleotides results in the significant decrease in the intrinsic activin A-induced PAX4 expression [14].

Other interactions of PAX4

  • The transcription factor PAX4 is located at 7q32 and participates downstream of ISL1 in the transcription factor cascade critical to beta-cell development [9].
  • This cis-activating NRSE element also confers NRSF-dependent modulation in the context of the native pax4 gene promoter [2].
  • Furthermore, this insulinoma associated expression of PAX4 mRNA was accompanied with expression of its novel variant form (PAX4v) [4].
  • We screened a cosmid library of human genomic DNA using polymerase chain reaction products for PAX4 as a probe and isolated three positive cosmid clones [15].
  • Phylogenetic analyses demonstrate that the Trichoplax PaxB gene, TriPaxB, is basal not only to all other known PaxB genes but also to PaxA and PaxC genes and their relatives in triploblasts (namely Pax2/5/8, Pax4/6, and Poxneuro) [16].

Analytical, diagnostic and therapeutic context of PAX4


  1. No evidence of linkage or diabetes-associated mutations in the transcription factors BETA2/NEUROD1 and PAX4 in Type II diabetes in France. Dupont, S., Vionnet, N., Chèvre, J.C., Gallina, S., Dina, C., Seino, Y., Yamada, Y., Froguel, P. Diabetologia (1999) [Pubmed]
  2. Regulation of Pax4 paired homeodomain gene by neuron-restrictive silencer factor. Kemp, D.M., Lin, J.C., Habener, J.F. J. Biol. Chem. (2003) [Pubmed]
  3. Association of childhood type 1 diabetes mellitus with a variant of PAX4: possible link to beta cell regenerative capacity. Biason-Lauber, A., Boehm, B., Lang-Muritano, M., Gauthier, B.R., Brun, T., Wollheim, C.B., Schoenle, E.J. Diabetologia (2005) [Pubmed]
  4. Expression of dominant negative form of PAX4 in human insulinoma. Miyamoto, T., Kakizawa, T., Ichikawa, K., Nishio, S., Kajikawa, S., Hashizume, K. Biochem. Biophys. Res. Commun. (2001) [Pubmed]
  5. Aberrant DNA demethylation in promoter region and aberrant expression of mRNA of PAX4 gene in hematologic malignancies. Li, Y., Nagai, H., Ohno, T., Ohashi, H., Murohara, T., Saito, H., Kinoshita, T. Leuk. Res. (2006) [Pubmed]
  6. Chromosomal localization of seven PAX genes and cloning of a novel family member, PAX-9. Stapleton, P., Weith, A., Urbánek, P., Kozmik, Z., Busslinger, M. Nat. Genet. (1993) [Pubmed]
  7. The diabetes-linked transcription factor PAX4 promotes {beta}-cell proliferation and survival in rat and human islets. Brun, T., Franklin, I., St-Onge, L., Biason-Lauber, A., Schoenle, E.J., Wollheim, C.B., Gauthier, B.R. J. Cell Biol. (2004) [Pubmed]
  8. PAX4 gene variations predispose to ketosis-prone diabetes. Mauvais-Jarvis, F., Smith, S.B., Le May, C., Leal, S.M., Gautier, J.F., Molokhia, M., Riveline, J.P., Rajan, A.S., Kevorkian, J.P., Zhang, S., Vexiau, P., German, M.S., Vaisse, C. Hum. Mol. Genet. (2004) [Pubmed]
  9. Interaction and association analysis of a type 1 diabetes susceptibility locus on chromosome 5q11-q13 and the 7q32 chromosomal region in Scandinavian families. Holm, P., Rydlander, B., Luthman, H., Kockum, I. Diabetes (2004) [Pubmed]
  10. 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]
  11. Autoregulation and maturity onset diabetes of the young transcription factors control the human PAX4 promoter. Smith, S.B., Watada, H., Scheel, D.W., Mrejen, C., German, M.S. J. Biol. Chem. (2000) [Pubmed]
  12. Low Concentration of Interleukin-1{beta} Induces FLICE-Inhibitory Protein-Mediated {beta}-Cell Proliferation in Human Pancreatic Islets. Maedler, K., Schumann, D.M., Sauter, N., Ellingsgaard, H., Bosco, D., Baertschiger, R., Iwakura, Y., Oberholzer, J., Wollheim, C.B., Gauthier, B.R., Donath, M.Y. Diabetes (2006) [Pubmed]
  13. Beta-cell dysfunction in late-onset diabetic subjects carrying homozygous mutation in transcription factors NeuroD1 and Pax4. Kanatsuka, A., Tokuyama, Y., Nozaki, O., Matsui, K., Egashira, T. Metab. Clin. Exp. (2002) [Pubmed]
  14. Activin A-induced expression of PAX4 in AR42J-B13 cells involves the increase in transactivation of E47/E12. Kanno, R., Ogihara, T., Igarashi, Y., Tanaka, Y., Smith, S.B., Kojima, I., German, M.S., Kawamori, R., Watada, H. Biochim. Biophys. Acta (2006) [Pubmed]
  15. Assignment of the human PAX4 gene to chromosome band 7q32 by fluorescence in situ hybridization. Tamura, T., Izumikawa, Y., Kishino, T., Soejima, H., Jinno, Y., Niikawa, N. Cytogenet. Cell Genet. (1994) [Pubmed]
  16. The Trichoplax PaxB gene: a putative Proto-PaxA/B/C gene predating the origin of nerve and sensory cells. Hadrys, T., DeSalle, R., Sagasser, S., Fischer, N., Schierwater, B. Mol. Biol. Evol. (2005) [Pubmed]
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