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Liu, J, Wang, Y, Birnbaum, MJ and Stoffers, DA (2010) Three-amino-acid-loop-extension homeodomain factor Meis3 regulates cell survival via PDK1. Proc. Natl. Acad. Sci. U.S.A. 107:20494-9
Three-amino-acid-loop-extension (TALE) homeodomain proteins including Meis and Pbx families are generally recognized for their roles in growth and differentiation during vertebrate embryogenesis and tumorigenesis. Whereas genetic studies indicate that Pbx1 regulates the development and function of insulin-producing pancreatic β-cells, the role of Meis family members in β-cells is still unknown. Here we show that Meis3 is abundantly expressed in pancreatic islets and β-cells and that it regulates β-cell survival. We further identify the 3-phosphoinositide-dependent protein kinase 1 (PDK1), a well-known kinase involved in the PI3K-Akt signaling pathway, as a direct Meis3 target, which mediates its role in β-cell survival. This regulatory module appears to function broadly as we also identify Meis3 regulation of cell survival and PDK1 expression in ovarian carcinoma cells, suggesting a unique function for Meis3 beyond the traditional roles for TALE homeodomain factors during embryogenesis.
Animals; Apoptosis/genetics; Apoptosis/physiology; Blotting, Western; Cell Line, Tumor; Cell Survival/genetics; Cell Survival/physiology; Chromatin Immunoprecipitation; DNA Primers/genetics; Homeodomain Proteins/genetics; Homeodomain Proteins/metabolism; In Situ Nick-End Labeling; Islets of Langerhans/metabolism; Male; Mice; Mice, Inbred C57BL; Microarray Analysis; Protein-Serine-Threonine Kinases/genetics; Protein-Serine-Threonine Kinases/metabolism; RNA, Small Interfering/genetics; Reverse Transcriptase Polymerase Chain Reaction; Transcription Factors/genetics; Transcription Factors/metabolism