Cytokine receptor signaling activates an IKK-dependent phosphorylation of PUMA to prevent cell death
Date
2012
Authors
Sandow, J.
Jabbour, A.
Condina, M.
Daunt, C.
Stomski, F.
Green, B.
Riffkin, C.
Hoffmann, P.
Guthridge, M.
Silke, J.
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Journal article
Citation
Cell Death and Differentiation, 2012; 19(4):633-641
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JJ Sandow, AM Jabbour, MR Condina, CP Daunt, FC Stomski, BD Green, CD Riffkin, P Hoffmann, MA Guthridge, J Silke, AF Lopez and PG Ekert
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Abstract
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 NFκB signaling. The identification and characterization of this novel survival pathway has important implications for IL-3 signaling and hematopoietic cell development.
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Copyright 2011 Macmillan Publishers Limited