Poster Presentation 25th Lorne Cancer Conference 2013

Interleukin-3 signalling responses in myeloid cells     (#217)

Anissa Jabbour 1 , Carmel Daunt 1 , Dimitra Masouras 1 , Chung Kok 2 , Richard D'Andrea 2 , Paul Ekert 1
  1. Walter + Eliza Hall Institute, Parkville, VIC, Australia
  2. The Centre for Stem Cell Biology, University of Adelaide, Adelaide, Australia

Apoptosis induced by Interleukin-3 (IL-3) deprivation is inhibited by Bcl-2 and Bcl-xL. Of the pro-apoptotic BH3-only proteins, Puma is essential for apoptosis in IL-3 dependent myeloid cell lines subjected to IL-3 deprivation. We have found that the regulation of Puma in response to IL-3 loss in myeloid cells is predominantly transcriptionally regulated by p53. p53-/- cells were protected against IL-3 withdrawal and after IL-3 deprivation Puma protein levels in p53-/- cells were substantially lower than in wildtype cells. Additionally, increased p53 transcriptional activity was associated with a loss of the p53 regulator, MDM2. Thus, we have shown that p53 protein is activated after IL-3 deprivation by loss of MDM2, which allows activated p53 to transcriptionally upregulate Puma, which initiates apoptosis. Using array data comparing wildtype and p53-/- transcriptional responses to IL-3, we show that p53-/- cells have a deregulated intracellular signalling environment and display a more rapid and sustained response to IL-3. This was accompanied by an increase in active ERK1/2 and a dependence on an intact MAP kinase-signalling pathway. Contrastingly, we find that p53-/- cells are independent on AKT for their survival. Thus, loss of p53 in myeloid cells results in an altered transcriptional/kinase-signalling environment that favours enhanced cytokine signalling.