title: Differential effects of Akt isoforms on somatic cell reprogramming.
abstract: Akt plays an important role in cell growth, proliferation and survival. The specific roles of the three Akt isoforms in somatic cell reprogramming have not been investigated. Here we report that, during iPSC generation, enhanced Akt1 activity promotes complete reprogramming mainly through increased activation of Stat3 in concert with leukemia inhibitory factor (LIF) and, to a lesser extent, through promotion of colony formation. Akt1 augments Stat3 activity through activation of mTOR and upregulation of LIF receptor expression. Similarly, enhanced Akt2 or Akt3 activation also promotes reprogramming and coordinates with LIF to activate Stat3. Blocking Akt1 or Akt3 but not Akt2 expression prohibits cell proliferation and reprogramming. Furthermore, the halt in cell proliferation and reprogramming caused by mTOR and Akt inhibitors can be reversed by inhibition of GSK3. Finally, we found that expressing the GSK3β target Esrrb overrides inhibition of Akt and restores reprogramming. Our data demonstrated that during reprogramming, Akt promotes establishment of pluripotency through co-stimulation of Stat3 activity with LIF. Akt1 and Akt3 are essential for the proliferation of reprogrammed cells, and Esrrb supports cell proliferation and complete reprogramming during Akt signaling.
authors.affiliation: Center for Regenerative Biology, Department of Animal Science, University of Connecticut, Storrs, CT 06269, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Tang
authors.affiliation: Center for Regenerative Biology, Department of Animal Science, University of Connecticut, Storrs, CT 06269, USA.
authors.forename: Zongliang
authors.initials: Z
authors.lastname: Jiang
authors.affiliation: Center for Regenerative Biology, Department of Animal Science, University of Connecticut, Storrs, CT 06269, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Luo
authors.affiliation: Center for Regenerative Biology, Department of Animal Science, University of Connecticut, Storrs, CT 06269, USA.
authors.forename: Xueming
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Center for Regenerative Biology, Department of Animal Science, University of Connecticut, Storrs, CT 06269, USA.
authors.forename: Ling
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Molecular and Cellular Biology/Biotechnology and Bioservices Center, University of Connecticut, Storrs, CT 06269, USA.
authors.forename: Carol
authors.initials: C
authors.lastname: Norris
authors.affiliation: Center for Regenerative Biology, Department of Animal Science, University of Connecticut, Storrs, CT 06269, USA xiuchun.tian@uconn.edu.
authors.forename: Xiuchun Cindy
authors.initials: XC
authors.lastname: Tian
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D065150:Cellular Reprogramming; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000201:enzymology*; D053605:Leukemia Inhibitory Factor / Q000235:genetics / Q000378:metabolism; D051379:Mice; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism
chemical_list: D053605:Leukemia Inhibitory Factor; C507838:Lif protein, mouse; D050796:STAT3 Transcription Factor; C514862:Akt1 protein, mouse; C494922:Akt2 protein, mouse; C491753:Akt3 protein, mouse; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3
keywords: Akt; GSK3; Isoform; Reprogramming; Stat3; iPSC