The duodenal homeobox-1 protein Pdx-1 is one of the regulators for the transcription of the insulin gene. Pdx-1 is a phosphoprotein, and there is increasing evidence for the regulation of some of its functions by phosphorylation. Here, we asked whether protein kinase CK2 might phosphorylate Pdx-1 and how this phosphorylation could be implicated in the functional regulation of Pdx-1. We used fragments of Pdx-1 as well as phosphorylation mutants for experiments with protein kinase CK2. Transactivation was measured by reporter assays using the insulin promoter. Our data showed that Pdx-1 is phosphorylated by protein kinase CK2 at amino acids thr(231) and ser(232), and this phosphorylation was implicated in the regulation of the transcription factor activity of Pdx-1. Furthermore, inhibition of protein kinase CK2 by specific inhibitors led to an elevated release of insulin from pancreatic beta-cells. Thus, these findings identify CK2 as a novel mediator of the insulin metabolism.
Abstract. The homeobox domain transcription factor PDX-1 is essential for pancreatic development and for the maintenance of ß-cell function. The participation of pancreatic duodenal homeobox factor-1 (PDX-1) in the transcription of several genes which are essential for glucose sensing and insulin synthesis underlines its key role in ß-cells of the pancreas. PDX-1 binds to the promoter of insulin, glucose transporter 2, and glucokinase and regulates their expression. By proteinprotein interaction, PDX-1 acts in concert with other transcription factors or coactivators at the level of the insulin promoter. Ectopic expression of PDX-1 together with other cofactors can re-program cells to behave like ß-cells and produce insulin. This property of PDX-1 opens new strategies for the treatment of diabetes. Little is known about its regulation at the posttranslational level. Here, we report on its DNA-binding activity, the nuclear import and on posttranslational modifications such as phosphorylation, glycosylation and sumoylation. Modulation of these posttranslational modifications may be an alternate strategy for treating diabetes.
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