Abstract
The activation of the Akt signalling in response to cytokine receptor signalling promotes protein synthesis, cellular growth and proliferation. To determine the role of Akt in interleukin-3 (IL-3) signalling, we generated IL-3-dependent myeloid cell lines from mice lacking Akt1, Akt2 or Akt3. Akt1 deletion resulted in accelerated apoptosis at low concentrations of IL-3. Expression of constitutively active Akt1 was sufficient to delay apoptosis in response to IL-3 withdrawal, but not sufficient to induce proliferation in the absence of IL-3. Akt1 prolonged survival of Bim- or Bad-deficient cells, but not cells lacking Puma, indicating that Akt1-dependent repression of apoptosis was in part dependent on Puma and independent of Bim or Bad. Our data show that a key role of Akt1 during IL-3 signalling is to repress p53-dependent apoptosis pathways, including transcriptional upregulation of Puma. Moreover, our data indicate that regulation of BH3-only proteins by Akt is dispensable for Akt-dependent cell survival.
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Abbreviations
- 4-OHT:
-
4-hydroxytamoxifen
- PI3K:
-
phosphoinositide-3 kinase
- IL-3R:
-
interleukin-3 receptor
- IL-3:
-
interleukin-3
- FDM cells:
-
factor-dependent myeloid cells
- WT:
-
wild type
- iAkt1:
-
4-OHT inducible Akt14-OHT
- ieGFP:
-
inducible enhanced Green Fluorescent Protein
- GSK-3:
-
glycogen synthase kinase-3
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Acknowledgements
We thank Professor Andreas Strasser and Dr. Philippe Bouillet for the provision of mice and advise. We thank Dr. Matthew Burton for help with flow cytometry. This work is supported by project grants from the National Health and Medical Research Council of Australia (NHMRC). PGE is supported by the Viertel Senior Medical Research Fellowship. This work was made possible through Victorian State Government Operational Infrastructure Support and Australian Government NHMRC IRIISS.
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Green, B., Jabbour, A., Sandow, J. et al. Akt1 is the principal Akt isoform regulating apoptosis in limiting cytokine concentrations. Cell Death Differ 20, 1341–1349 (2013). https://doi.org/10.1038/cdd.2013.63
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DOI: https://doi.org/10.1038/cdd.2013.63
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