Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P51532 (transcriptional activator)
 6,546 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The paired-homeodomain transcription factor PAX4 is expressed in the developing pancreas and along with PAX6 is required for normal development of the endocrine cells. In the absence of PAX4, the numbers of insulin-producing beta cells and somatostatin-producing delta cells are drastically reduced, while the numbers of glucagon-producing alpha cells are increased. 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. The paired half of this consensus sequence has similarities to the PAX6 paired domain consensus binding site, and the two proteins bind to common sequences in several islet genes, although with different relative affinities. When expressed in an alpha-cell line, PAX4 represses transcription through the glucagon or insulin promoters or through an isolated PAX4 binding site. This repression is not simply due to competition with the PAX6 transcriptional activator for the same binding site, since PAX4 fused to the unrelated yeast GAL4 DNA binding domain also represses transcription through the GAL4 binding site in the alpha-cell line and to a lesser degree in beta-cell lines and NIH 3T3 cells. Repressor activity maps to more than one domain within the molecule, although the homeodomain and carboxyl terminus give the strongest repression. PAX4 transcriptional regulation apparently plays a role only early in islet development, since Pax4 mRNA as determined by reverse transcriptase PCR peaks at embryonic day 13.5 in the fetal mouse pancreas and is undetectable in adult islets. In summary, PAX4 can function as a transcriptional repressor and is expressed early in pancreatic development, which may allow it to suppress alpha-cell differentiation and permit beta-cell differentiation.
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PMID:Paired-homeodomain transcription factor PAX4 acts as a transcriptional repressor in early pancreatic development. 1056 52

Expression of the proendocrine factor Neurogenin3 determines which progenitor cells in the developing pancreas will differentiate into the endocrine cells of the islets of Langerhans. To better understand how Neurogenin3 directs endocrine differentiation, we examined the mechanisms by which Neurogenin3 regulates the promoters of three transcription factor genes expressed in endocrine precursor cells: the nkx2.2 gene, the PAX4 gene, and the NEUROG3 gene, the human gene encoding Neurogenin3 itself. The function of all three promoters depends on at least one critical E box, a common DNA sequence that forms a binding site for basic helix-loop-helix proteins like Neurogenin3. Neurogenin3 bound to and effectively activated transcription through the nkx2.2 and PAX4 E boxes. In contrast, Neurogenin3 strongly repressed the NEUROG3 promoter, although a proximal E box was required for activity in the absence of Neurogenin3, suggesting that a ubiquitous transcriptional activator may bind to this site, and that Neurogenin3 could act as a competitive inhibitor of this activator. This hypothesis was supported by the lack of evidence for significant intrinsic transcriptional repression capacity in the Neurogenin3 protein, and by the ability of isolated DNA-binding basic helix-loop-helix domains to repress the NEUROG3 promoter. Neurogenin3 produced additional repression, however, when the protein included an intact transcriptional activation domain, suggesting that it may also induce the expression of a downstream transcriptional repressor. In summary, while Neurogenin3 orchestrates islet cell differentiation by activating islet cell transcription factor genes, it simultaneously represses its own promoter.
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PMID:Neurogenin3 activates the islet differentiation program while repressing its own expression. 1457 36