Akt3 is responsible for the survival and proliferation of embryonic stem cells

The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB/Akt) pathway plays an important role in regulating cell proliferation, metabolism, and survival. However, the distinct roles of Akt isoforms (Akt1, Akt2, and Akt3) in pluripotent stem cell maintenance are not fully defined. Using mouse e...

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Bibliographic Details
Published in:Biology open 2017-06, Vol.6 (6), p.850-861
Main Authors: Wang, Ling, Huang, Delun, Jiang, Zongliang, Luo, Yan, Norris, Carol, Zhang, Ming, Tian, Xiuchun, Tang, Young
Format: Article
Language:English
Subjects:
1-Phosphatidylinositol 3-kinase
AKT protein
AKT1 protein
AKT2 protein
Akt3
Apoptosis
Cell cycle
Cell proliferation
Cell survival
Depletion
Downstream effects
Embryo cells
Embryonic stem cells
Embryos
G1 phase
Isoforms
Kinases
MDM2 protein
Metabolism
p53
p53 Protein
Pluripotency
Stem cell transplantation
Stem cells
Survival
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Summary:The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB/Akt) pathway plays an important role in regulating cell proliferation, metabolism, and survival. However, the distinct roles of Akt isoforms (Akt1, Akt2, and Akt3) in pluripotent stem cell maintenance are not fully defined. Using mouse embryonic stem cells (ESCs), we show that direct inhibition of Akt activity leads to ESC apoptosis. The Akt3, but not Akt1 or Akt2, activity specifically regulates this effect. Inhibiting Akt3 also leads to a cell cycle arrest at G1 phase. These regulatory roles of Akt3 are dependent on its kinase activity. Blocking the expression of Akt1 plus Akt2 in ESCs does not affect cell survival or proliferation, although blocking Akt1 aggravates the apoptotic effect induced by depletion of Akt3. We further show that blocking Akt3 in ESCs results in significant nuclear accumulation of p53, as well as the activation of its downstream targets, such as Mdm2, p21, and Fas. Inhibiting p53 and its downstream targets partially rescued the effects caused by Akt3-depletion. Our results revealed an Akt3 isoform-specific mechanism for ESC survival and proliferation involving the control of p53 activity.
ISSN:2046-6390
2046-6390
DOI:10.1242/bio.024505