TRANSCRIPTION FACTORS CONTRIBUTING TO THE PANCREATIC BETA-CELL PHENOTYPE

Insulin promoter factor-1 (IPF1) (renamed to pancreatic-duodenal homeo box factor-1, PDX1) was originally cloned and characterized as an isle t beta-cell specific insulin gene transcription factor(1) and later sh own to be essential for the formation of the mature pancreas (2, 3). i n the adult normal pancreas PDX1 is almost exclusively expressed in th e beta-cell compartment and generally absent from the alpha-cell while it is widely expressed in the pancreatic epithelium during developmen t. Using pluripotent rat islet tumor cultures and derived insulinomas and glucagonomas we have analyzed differential expression of a large n umber 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 maintai ned in the insulinoma, while Nkx6.1 was selectively co-induced with in sulin during insulinoma formation. Both factors were not detectable in the glucagonoma. Nkx6.1 proved to have a highly beta-cell restricted expression in the adult rat. Forced expression of recombinant PDX1 in the glucagonoma resulted in efficient transcriptional activation of th e endogenous insulin and IAPP genes, but did not affect glucagon gene activity. In this hybrid alpha/beta-cell phenotype the endogenous Nkx6 .1 gene remained silent. We conclude that PDX1 in synergy with NeuroD specifies part of the beta-cell phenotype including transcriptional ac tivation of insulin and IAPP genes, but that other factors such as Nkx 6.1 and Pax6 are required for additional features of the fully mature beta-cell phenotype.