| The activation of the rat insulin gene II by BETA2 and PDX-1 in rat insulinoma cells is repressed by Pax6. | |
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MedLine Citation:
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PMID: 20943817 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The transcriptional transactivator Pax6 binds the pancreatic islet cell-specific enhancer sequence (PISCES) of the rat insulin I gene. However the human, mouse, and rat insulin gene II promoters do not contain a PISCES element. To analyze the role of Pax6 in those PISCES-less promoters, we investigated its influence on rat insulin gene II expression and included in our studies the main activators: pancreatic and duodenal homeobox protein-1 (PDX-1) and BETA2/E47. Luciferase assays, Northern blots, and RIA were used to study effects of Pax6 overexpression, gel shift and chromatin precipitation assays to study its binding to the DNA, and yeast two-hybrid assays and glutathione S transferase capture assays to investigate its interactions with PDX-1 and BETA2. Finally, glucose-dependent intracellular transport of Pax6 was demonstrated by fluorescence microscopy. Overexpression of Pax6 prevents activation of the rat insulin II gene by BETA2 and PDX-1 and hence suppresses insulin synthesis and secretion. In vitro, Pax6 binds to the A-boxes, thereby blocking binding of PDX-1, and at the same time, its paired domain interacts with BETA2. Fluorescence microscopy demonstrated that the nuclear-cytoplasmic localization of Pax6 and PDX-1 are oppositely regulated by glucose. From the results, it is suggested that at low concentrations of glucose, Pax6 is localized in the nucleus and prevents the activation of the insulin gene by occupying the PDX-1 binding site and by interacting with BETA2. |
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Authors:
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Gabriele Wolf; Behnam Hessabi; Anke Karkour; Ulrike Henrion; Meike Dahlhaus; Annett Ostmann; Bernd Giese; Martin Fraunholz; Piotr Grabarczyk; Robert Jack; Reinhard Walther |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-10-13 |
Journal Detail:
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Title: Molecular endocrinology (Baltimore, Md.) Volume: 24 ISSN: 1944-9917 ISO Abbreviation: Mol. Endocrinol. Publication Date: 2010 Dec |
Date Detail:
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Created Date: 2010-11-25 Completed Date: 2011-03-10 Revised Date: 2011-06-01 |
Medline Journal Info:
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Nlm Unique ID: 8801431 Medline TA: Mol Endocrinol Country: United States |
Other Details:
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Languages: eng Pagination: 2331-42 Citation Subset: IM |
Affiliation:
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Department of Medical Biochemistry and Molecular Biology, University of Greifswald, Klinikum, Greifswald, Germany. |
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| MeSH Terms | |
Descriptor/Qualifier:
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Active Transport, Cell Nucleus Animals Basic Helix-Loop-Helix Transcription Factors / genetics, metabolism* Down-Regulation Eye Proteins / biosynthesis, genetics*, metabolism Gene Expression Regulation, Neoplastic* Glucose / pharmacology Homeodomain Proteins / antagonists & inhibitors, biosynthesis, genetics*, metabolism* Humans Insulin / biosynthesis, genetics*, metabolism, secretion Insulinoma / genetics*, metabolism Mice Paired Box Transcription Factors / biosynthesis, genetics*, metabolism Pancreatic Neoplasms / genetics*, metabolism Promoter Regions, Genetic Protein Binding Protein Transport Rats Repressor Proteins / biosynthesis, genetics*, metabolism Trans-Activators / antagonists & inhibitors, genetics, metabolism* |
| Chemical | |
Reg. No./Substance:
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0/Basic Helix-Loop-Helix Transcription Factors; 0/Eye Proteins; 0/Homeodomain Proteins; 0/Neurod1 protein, rat; 0/PAX6 protein; 0/Paired Box Transcription Factors; 0/Repressor Proteins; 0/Trans-Activators; 0/pancreatic and duodenal homeobox 1 protein; 11061-68-0/Insulin; 50-99-7/Glucose |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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