TY - JOUR
T1 - Cytokine receptor signaling activates an IKK-dependent phosphorylation of PUMA to prevent cell death
AU - Sandow, J J
AU - Jabbour, Anissa
AU - Condina, M R
AU - Daunt, Carmel
AU - Stomski, Frank
AU - Green, Benjamin
AU - Riffkin, C
AU - Hoffmann, Peter
AU - Guthridge, Mark
AU - Silke, John
AU - Lopez, A F
AU - Ekert, Paul
PY - 2012
Y1 - 2012
N2 - P53-upregulated modifier of apoptosis (PUMA), a pro-apoptotic member of the Bcl-2 family, is transcriptionally activated by p53 and is a key effector of p53-dependent apoptosis. We show that PUMA protein is subject to rapid post-translational regulation by phosphorylation at a conserved residue, serine 10, following serum or interleukin-3 (IL-3) stimulation. Serine 10 is not within the Bcl-2 homology (BH3) domain, and PUMA phosphorylated at serine 10 retained the ability to co-immunoprecipitate with antiapoptotic Bcl-2 family members. However, phosphorylated PUMA was targeted for proteasomal degradation indicating that it is less stable than unphosphorylated PUMA. Importantly, we identified IKK1/IKK2/Nemo as the kinase complex that interacts with and phosphorylates PUMA, thereby also demonstrating that IL-3 activates NFB signaling. The identification and characterization of this novel survival pathway has important implications for IL-3 signaling and hematopoietic cell development. A? 2012 Macmillan Publishers Limited All rights reserved.
AB - P53-upregulated modifier of apoptosis (PUMA), a pro-apoptotic member of the Bcl-2 family, is transcriptionally activated by p53 and is a key effector of p53-dependent apoptosis. We show that PUMA protein is subject to rapid post-translational regulation by phosphorylation at a conserved residue, serine 10, following serum or interleukin-3 (IL-3) stimulation. Serine 10 is not within the Bcl-2 homology (BH3) domain, and PUMA phosphorylated at serine 10 retained the ability to co-immunoprecipitate with antiapoptotic Bcl-2 family members. However, phosphorylated PUMA was targeted for proteasomal degradation indicating that it is less stable than unphosphorylated PUMA. Importantly, we identified IKK1/IKK2/Nemo as the kinase complex that interacts with and phosphorylates PUMA, thereby also demonstrating that IL-3 activates NFB signaling. The identification and characterization of this novel survival pathway has important implications for IL-3 signaling and hematopoietic cell development. A? 2012 Macmillan Publishers Limited All rights reserved.
UR - http://www.nature.com/cdd/journal/v19/n4/pdf/cdd2011131a.pdf
U2 - 10.1038/cdd.2011.131
DO - 10.1038/cdd.2011.131
M3 - Article
VL - 19
SP - 633
EP - 641
JO - Cell Death and Differentiation
JF - Cell Death and Differentiation
SN - 1350-9047
IS - 4
ER -