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Pdx1 level defines pancreatic gene expression pattern and cell lineage differentiation

Ritz-Laser, B
Published in Journal of Biological Chemistry. 2001, vol. 276, no. 27, p. 25279-86
Abstract The absence of Pdx1 and the expression of brain-4 distinguish alpha-cells from other pancreatic endocrine cell lineages. To define the transcription factor responsible for pancreatic cell differentiation, we employed the reverse tetracycline-dependent transactivator system in INS-I cell-derived subclones INSralphabeta and INSrbeta to achieve tightly controlled and conditional expression of wild type Pdx1 or its dominant-negative mutant, as well as brain-4. INSralphabeta cells express not only insulin but also glucagon and brain-4, while INSrbeta cells express only insulin. Overexpression of Pdx1 eliminated glucagon mRNA and protein in INSralphabeta cells and promoted the expression of beta-cell-specific genes in INSrbeta cells. Induction of dominant-negative Pdx1 in INSralphabeta cells resulted in differentiation of insulin-producing beta-cells into glucagon-containing alpha-cells without altering brain4 expression. Loss of Pdx1 function alone in INSrbeta cells, which do not express endogenous brain-4 and glucagon, was also sufficient to abolish the expression of genes restricted to beta-cells and to cause alpha-cell differentiation. In contrast, induction of brain-4 in INSrbeta cells initiated detectable expression of glucagon but did not affect beta-cell-specific gene expression. In conclusion, Pdx1 confers the expression of pancreatic beta-cell-specific genes, such as genes encoding insulin, islet amyloid polypeptide, Glut2, and Nkx6.1. Pdx1 defines pancreatic cell lineage differentiation. Loss of Pdx1 function rather than expression of brain4 is a prerequisite for alpha-cell differentiation.
Keywords AnimalsCell DifferentiationCell LineCell Nucleus/metabolismCytoplasm/metabolismGene Expression RegulationGlucagon/biosynthesisHomeodomain ProteinsInsulinoma/chemistryIslets of Langerhans/metabolismMolecular WeightPancreas/cytologyPancreatic Neoplasms/chemistryRatsTrans-Activators/geneticsTumor Cells, Cultured
PMID: 11309388
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WANG, Haiyan et al. Pdx1 level defines pancreatic gene expression pattern and cell lineage differentiation. In: The Journal of biological chemistry, 2001, vol. 276, n° 27, p. 25279-86. doi: 10.1074/jbc.M101233200 https://archive-ouverte.unige.ch/unige:35182

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Deposited on : 2014-04-01

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