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

• We have now isolated cosmids for six additional human PAX genes (PAX-1,-2,-5,-7,-8,-9) and a polymerase chain reaction fragment for PAX-4 [6].
• The chromosomal location of all cloned PAX genes was determined by analysis of somatic cell hybrids and (except PAX-4) by fluorescence in situ hybridization to metaphase chromosomes [6].
• The mechanism by which the beta-cell transcription factor Pax4 influences cell function/mass was studied in rat and human islets of Langerhans [7].
• Infection of human islets with an inducible adenoviral Pax4 construct caused proliferation and protection against cytokine-evoked apoptosis, whereas the mutant was less effective [7].
• Recently, a missense mutation (Arg121Trp) of PAX4 has been implicated in early and insulin deficient type 2 diabetes in Japanese subjects [8].

Biological context of PAX4

• Association with type 1 diabetes was also observed using the transmission disequilibrium test for two haplotypes at the PAX4 locus (P < 0.05) [9].
• Mutation screening showed single nucleotide polymorphisms, several of which resulted in amino acid substitutions: NEUROD1, Ala45Thr; PAX4, Pro321His and Pro334Ala [1].
• To gain insight into PAX4 function, we cloned a full-length Pax4 cDNA from a beta-cell cDNA library and identified a bipartite consensus DNA binding sequence consisting of a homeodomain binding site separated from a paired domain binding site by 15 nucleotides [10].
• Autoregulation and maturity onset diabetes of the young transcription factors control the human PAX4 promoter [11].
• We compared the transrepression potential of the PAX4 variants in betaTC3 cells and analysed their influence on beta cell growth [3].

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

• Assignment of the human PAX4 gene to chromosome band 7q32 by fluorescence in situ hybridization [15].
• We observed the aberrant expression of PAX4 mRNA in 10 of 15 hematologic cell lines analyzed by RT-PCR [5].

References