The caudal homeobox protein cdx-2/3 activates endogenous proglucagon gene expression in InR1-G9 islet cells.

The proglucagon gene is expressed in a highly cell-specific manner in islet and enteroendocrine cells. DNA sequences within the proximal proglucagon G1 promoter region bind the homeobox protein cdx-2/3, and cdx-2/3 activates the proglucagon promoter in fibroblasts. We show here that cdx-2/3 activates the proglucagon promoter in both islet (InR1-G9) and enteroendocrine (STC-1 and GLUTag) cell lines. Furthermore, transfected cdx-2/3 increased the levels of endogenous proglucagon mRNA transcripts in both transient and stable transfections of InR1-G9 islet cells. The cdx-2/3-dependent induction of endogenous proglucagon mRNA transcripts in stable islet lines was associated with a corresponding increase in the transcriptional activity of proglucagon promoter-luciferase plasmids. An amino-terminally truncated cdx-2/3 derivative containing the homeodomain and carboxy-terminal region of the molecule inhibited both the cdx-2/3 activation of the proglucagon promoter and the induction of endogenous proglucagon mRNA transcripts. These observations demonstrate that cdx-2/3, acting through the proximal G1 element, is a major transcriptional determinant of cell-specific proglucagon gene expression in pancreatic islet cells.