INVOLVEMENT OF THE HOMEODOMAIN-CONTAINING TRANSCRIPTION FACTOR PDX-1 IN ISLET AMYLOID POLYPEPTIDE GENE-TRANSCRIPTION

The AT-rich eis-motif A elements of the insulin gene promoter contribu te to directing the gene's expression to pancreatic beta-cells, bound by a homeodomin-containing transcription factor, PDX-1/IPF1/STF-1/IDX- 1. The islet amyloid polypeptide (IAPP; amylin) gene, which is also ex pressed in limited tissues such as pancreatic beta- and delta-cells, c ontained similar AT-rich sequences in its regulatory sequences. To und erstand the molecular basis of IAPP gene regulation, we evaluated the possible physiological significance of the motif in human IAPP gene re gulation. All of the three typical A element-like sequences that match ed the CT-box consensus (AT-1, -207/-202; AT-2, -154/-142; and AT-3, - 88/-83) were shown to bind specifically to a nuclear factor in the bet a-cell-derived MIN6 cells, which was subsequently identified immunolog ically as the insulin gene transcription factor PDX-1. When the promot er activity was examined in MIN6 cells, the disruption of AT-1 or AT-3 but not of AT-2 caused a marked reduction in the IAPP gene promoter. Thus, despite the observation that ll the three A element-like regions could bind to PDX-1, the AT-2 site may not be involved in mediating t he PDX-1 action in vivo. These observations suggest the involvement of PDX-1 in human IAPP gene regulation, which seems to be mediated throu gh at least two A element-like cis-motifs in the gene promoter. (C) 19 96 Acamdemic Press