Transcription Factors Contributing to the Pancreatic β-Cell Phenotype

 

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Abstract

Insulin promoter factor-1 (IPF1) (renamed to pancreaticduodenal homeobox factor-1, PDX1) was originally cloned and characterized as an islet β-cell specific insulin gene transcription factor (1) and later shown to be essential for the formation of the mature pancreas (2,3). In the adult normal pancreas PDX1 is almost exclusively expressed in the β-cell compartment and generally absent from the α-cell while it is widely expressed in the pancreatic epithelium during development. Using pluripotent rat islet tumor cultures and derived insulinomas and glucagonomas we have analyzed differential expression of a large number of genes including the transcription factors PDX1, Nkx6.1, Pax6, and NeuroD. While NeuroD and Pax6 expression was detectable among all phenotypes, PDX1 was expressed in the pluripotent culture and maintained in the insulinoma, while Nkx6.1 was selectively co-induced with insulin during insulinoma formation. Both factors were not detectable in the glucagonoma. Nkx6.1 proved to have a highly β-cell restricted expression in the adult rat. Forced expression of recombinant PDX1 in the glucagonoma resulted in efficient transcriptional activation of the endogenous insulin and IAPP genes, but did not affect glucagon gene activity. In this hybrid α/β-cell phenotype the endogenous NkxG.1 gene remained silent. We conclude that PDX1 in synergy with NeuroD specifies part of the β-cell phenotype including transcriptional activation of insulin and IAPP genes, but that other factors such as Nkx6.1 and Pax6 are required for additional features of the fully mature β-cell phenotype.