Die Interaktion zwischen dem Transkriptionsfaktor FoxO1a und der Proteinkinase DYRK1 und ihre Bedeutung bei der Regulation des Glucose-6-Phosphatasegens

In this work the functional interaction between the kinase DYRK1 and the transcription factor FoxO1a was characterized. The role of DYRK1 in insulin-dependent regulation of hepatic glucose-production was investigated. In different independent studies in liver cells a stimulatory effect of DYRK1 on glucose-6-phosphatase (g6pase) promoter activity was shown. An increased amount of endogenous g6pase-mRNA was found in stabilly transfected hepatoma cells overexpressing DYRK1. In luciferase reportergene assays a synergistic effect of DYRK1A and FoxO1a was found. A phosphorylation of FoxO1a by DYRK1A had been described before. This phosphorylation is not responsible fort he effect. In further studies it was shown that the effect requires intact FoxO1a binding sites in the g6pase promoter. These findings suggest that the effect is a FoxO1a-dependent effect. Different DYRK-isoforms showed different effects on g6pase promoter activity, probably due to different subcellular localization. Thus this work presents the first report of the functional relevance of the interaction between the protein kinase DYRK1 and the transcription factor FoxO1a. Besides that the influence on glucose-6-phosphatase gene expression was described.