Pdx1 Level Defines Pancreatic Gene Expression Pattern and Cell Lineage Differentiation
| Autor: | Haiyan Wang, Beate Ritz-Laser, Claes B. Wollheim, Hisamitsu Ishihara, Kerstin A. Hagenfeldt, Jacques Philippe, Pierre Maechler |
|---|---|
| Rok vydání: | 2001 |
| Předmět: |
Cytoplasm
endocrine system medicine.medical_specialty Pancreas/cytology Insulinoma/chemistry Cellular differentiation Enteroendocrine cell Biology Biochemistry Glucagon Trans-Activators/genetics Cell Line Islets of Langerhans Transactivation Internal medicine Gene expression Tumor Cells Cultured medicine Animals ddc:612 Pancreas Molecular Biology ddc:616 Pancreatic Neoplasms/chemistry Cell Nucleus Homeodomain Proteins Regulation of gene expression Cell Differentiation Cell Biology Cytoplasm/metabolism Rats Cell biology Molecular Weight Pancreatic Neoplasms Glucagon/biosynthesis Endocrinology Gene Expression Regulation Cell culture Cell Nucleus/metabolism Trans-Activators PDX1 Insulinoma Islets of Langerhans/metabolism |
| Zdroj: | Journal of Biological Chemistry, Vol. 276, No 27 (2001) pp. 25279-86 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m101233200 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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