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PMID:11309388

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Citation

Wang, H, Maechler, P, Ritz-Laser, B, Hagenfeldt, KA, Ishihara, H, Philippe, J and Wollheim, CB (2001) Pdx1 level defines pancreatic gene expression pattern and cell lineage differentiation. J. Biol. Chem. 276:25279-86

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.

Links

PubMed Online version:10.1074/jbc.M101233200

Keywords

Animals; Cell Differentiation; Cell Line; Cell Nucleus/metabolism; Cytoplasm/metabolism; Gene Expression Regulation; Glucagon/biosynthesis; Homeodomain Proteins; Insulinoma/chemistry; Islets of Langerhans/metabolism; Molecular Weight; Pancreas/cytology; Pancreatic Neoplasms/chemistry; Rats; Trans-Activators/genetics; Tumor Cells, Cultured

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

RAT:PDX1

involved_in

GO:0030154: cell differentiation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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