title: Activation of Akt signaling is sufficient to maintain pluripotency in mouse and primate embryonic stem cells.
abstract: Embryonic stem (ES) cells can self-renew indefinitely without losing their differentiation ability to any cell types. Phosphoinositide-3 kinase (PI3K)/Akt signaling plays a pivotal role in various stem cell systems, including the formation of embryonic germ (EG) cells from primordial germ cells and self-renewal of neural stem cells. Here, we show that myristoylated, active form of Akt (myr-Akt) maintained the undifferentiated phenotypes in mouse ES cells without the addition of leukemia inhibitory factor (LIF). The effects of myr-Akt were reversible, because LIF dependence and pluripotent differentiation activity were restored by the deletion of myr-Akt. In addition, myr-Akt-Mer fusion protein, whose enzymatic activity is controlled by 4-hydroxy-tamoxifen, also maintained the pluripotency of not only mouse but also cynomolgus monkey ES cells. These results clearly demonstrate that Akt signaling sufficiently maintains pluripotency in mouse and primate ES cells, and support the notion that PI3K/Akt signaling axis regulates 'stemness' in a broad spectrum of stem cell systems.
authors.affiliation: Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Watanabe
authors.forename: H
authors.initials: H
authors.lastname: Umehara
authors.forename: K
authors.initials: K
authors.lastname: Murayama
authors.forename: M
authors.initials: M
authors.lastname: Okabe
authors.forename: T
authors.initials: T
authors.lastname: Kimura
authors.forename: T
authors.initials: T
authors.lastname: Nakano
mesh_terms: D000818:Animals; D018929:Cell Culture Techniques; D002454:Cell Differentiation; D049109:Cell Proliferation / Q000187:drug effects*; D004622:Embryo, Mammalian / Q000166:cytology* / Q000378:metabolism; D004789:Enzyme Activation; D004965:Estrogen Antagonists / Q000494:pharmacology; D015850:Interleukin-6 / Q000378:metabolism; D053605:Leukemia Inhibitory Factor; D008252:Macaca fascicularis; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D019814:Myristic Acid / Q000378:metabolism; D010641:Phenotype; D039904:Pluripotent Stem Cells / Q000187:drug effects / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics*; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000494:pharmacology; D051176:beta Catenin / Q000378:metabolism
chemical_list: D004965:Estrogen Antagonists; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; C507838:Lif protein, mouse; D011993:Recombinant Fusion Proteins; D050796:STAT3 Transcription Factor; D051176:beta Catenin; D013629:Tamoxifen; D019814:Myristic Acid; C016601:afimoxifene; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3