Negative regulation of c-Myc transcription by pancreas duodenum homeobox-1

Abstract

The pancreatic and duodenal homeobox factor-1 (Pdx1) is essential for pancreatic development and insulin gene transcription, whereas c-Myc has a deleterious effect on islet function. However, the relationship between c-Myc and Pdx1 is poorly concerned. Here we demonstrated that Pdx1 could suppress c-Myc promoter activity, which relied on T cell factor (Tcf) binding elements harbored in c-Myc promoter. Furthermore, the transcription activity of β-catenin/Tcf was markedly decreased on Pdx1 expression, but cotransfection of Pdx1 short hairpin RNA abrogated this effect. Pdx1 expression did not induce β-catenin degradation nor did it alter their subcellular distribution. The mutation analysis showed that the amino acids (1-209) of Pdx1 harboring an inhibitory domain, which might lead to the reduction of β-catenin/Tcf/p300 complex levels and attenuate their binding activity with c-Myc promoter sequences. Moreover, adenovirus-mediated Pdx1 interference caused cell proliferation and cytokine-induced apoptosis via the dysregulation of c-Myc transcription. These results indicated that the Pdx1 functioned as a key regulator for maintenance of β-cell function, at least in part, through controlling c-Myc expression and the loss of its regulatory function may be an alternative mechanism for β-cell neogenesis and apoptosis found in diabetes. Copyright © 2007 by The Endocrine Society.