title: Gene Expression Profiling in Mouse Embryonic Stem Cells Reveals Glycogen Synthase Kinase-3-Dependent Targets of Phosphatidylinositol 3-Kinase and Wnt/β-Catenin Signaling Pathways.
abstract: Glycogen synthase kinase-3 (Gsk-3) activity is an important regulator of numerous signal transduction pathways. Gsk-3 activity is the sum of two largely redundant proteins, Gsk-3α and Gsk-3β, and in general, Gsk-3 is a negative regulator of cellular signaling. Genetic deletion of both Gsk-3α and Gsk-3β in mouse embryonic stem cells (ESCs) has previously been shown to lead to the constitutive activation of the Wnt/β-catenin signaling pathway. However, in addition to Wnt signaling, all Gsk-3-regulated pathways, such as insulin signaling, are also affected simultaneously in Gsk-3α(-) (/) (-); Gsk-3β(-) (/) (-)ESCs. In an effort to better understand how specific signaling pathways contribute to the global pattern of gene expression in Gsk-3α(-) (/) (-); Gsk-3β(-) (/) (-)ESCs, we compared the gene expression profiles in Gsk-3α(-) (/) (-); Gsk-3β(-) (/) (-) ESCs to mouse ESCs in which either Wnt/β-catenin signaling or phosphatidylinositol 3-kinase (PI3K)-dependent insulin signaling are constitutively active. Our results show that Wnt signaling has a greater effect on up-regulated genes in the Gsk-3α(-) (/) (-); Gsk-3β(-) (/) (-)ESCs, whereas PI3K-dependent insulin signaling is more responsible for the down-regulation of genes in the same cells. These data show the importance of Gsk-3 activity on gene expression in mouse ESCs, and that these effects are due to the combined effects of multiple signaling pathways.
authors.affiliation: Department of Integrative Biology, University of Colorado Denver , Denver, CO , USA.
authors.forename: Colleen M
authors.initials: CM
authors.lastname: Bartman
authors.affiliation: Department of Integrative Biology, University of Colorado Denver , Denver, CO , USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Egelston
authors.affiliation: Department of Integrative Biology, University of Colorado Denver , Denver, CO , USA.
authors.forename: Sravya
authors.initials: S
authors.lastname: Kattula
authors.affiliation: Center for Human and Molecular Genetics, Research Institute at Nationwide Children's Hospital , Columbus, OH , USA.
authors.forename: Leigh C
authors.initials: LC
authors.lastname: Zeidner
authors.affiliation: Center for Human and Molecular Genetics, Research Institute at Nationwide Children's Hospital , Columbus, OH , USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: D'Ippolito
authors.affiliation: Stem Cell and Cancer Research Institute, Department of Biochemistry and Biomedical Sciences, McMaster University , Hamilton, ON , Canada.
authors.forename: Bradley W
authors.initials: BW
authors.lastname: Doble
authors.affiliation: Department of Integrative Biology, University of Colorado Denver , Denver, CO , USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Phiel
keywords: Wnt; embryonic stem cells; gene expression; glycogen synthase kinase-3; microarray; phosphatidylinositol 3-kinase; quantitative PCR; signal transduction