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Akt1 is the principal Akt isoform regulating apoptosis in limiting cytokine concentrations

B D Green1, A M Jabbour, J J Sandow

  • 1Cell Signalling and Cell Death Division, Walter and Eliza Hall Institute of Medical Research, Royal Parade, Parkville, Victoria 3052, Australia.

Cell Death and Differentiation
|June 22, 2013
PubMed

Insights

The Akt1 protein is crucial for cell survival during interleukin-3 (IL-3) signaling by repressing p53-dependent apoptosis pathways, particularly those involving Puma. Akt1 is essential for preventing programmed cell death in myeloid cells.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Immunology

Background:

  • Cytokine receptor signaling activates Akt, promoting cell growth and survival.
  • Interleukin-3 (IL-3) is a key cytokine for myeloid cell development and survival.
  • The role of specific Akt isoforms in IL-3 signaling and apoptosis remains incompletely understood.

Purpose of the Study:

  • To elucidate the specific functions of Akt1, Akt2, and Akt3 in IL-3-dependent myeloid cell signaling.
  • To investigate the mechanisms by which Akt1 regulates apoptosis in response to IL-3 withdrawal.
  • To determine the role of Akt1 in controlling p53-dependent apoptosis pathways.

Main Methods:

  • Generation of IL-3-dependent myeloid cell lines from mice lacking Akt1, Akt2, or Akt3.
  • Assessment of apoptosis rates at varying IL-3 concentrations.
  • Analysis of cell proliferation and survival upon expression of constitutively active Akt1.
  • Investigation of Akt1's effect on apoptosis in cells deficient for Bim, Bad, or Puma.

Main Results:

  • Akt1 deletion accelerated apoptosis, especially at low IL-3 concentrations.
  • Constitutively active Akt1 delayed apoptosis upon IL-3 withdrawal but did not induce proliferation without IL-3.
  • Akt1-dependent cell survival was partially dependent on Puma but independent of Bim or Bad.
  • Akt1 was found to repress p53-dependent apoptosis, including Puma transcriptional upregulation.

Conclusions:

  • Akt1 plays a critical role in IL-3 signaling by repressing p53-dependent apoptosis pathways.
  • The repression of Puma by Akt1 is a key mechanism for promoting cell survival.
  • Regulation of BH3-only proteins by Akt is not essential for Akt-dependent cell survival in this context.

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