title: Cytokine receptor signaling activates an IKK-dependent phosphorylation of PUMA to prevent cell death.
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.
authors: Centre for Cancer Biology, Division of Human Immunology, SA Pathology, Adelaide, South Australia 5000, Australia.
authors: J J
authors: JJ
authors: Sandow
authors: A M
authors: AM
authors: Jabbour
authors: M R
authors: MR
authors: Condina
authors: C P
authors: CP
authors: Daunt
authors: F C
authors: FC
authors: Stomski
authors: B D
authors: BD
authors: Green
authors: C D
authors: CD
authors: Riffkin
authors: P
authors: P
authors: Hoffmann
authors: M A
authors: MA
authors: Guthridge
authors: J
authors: J
authors: Silke
authors: A F
authors: AF
authors: Lopez
authors: P G
authors: PG
authors: Ekert
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D016923:Cell Death / Q000502:physiology; D002460:Cell Line; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism*; D007377:Interleukin-3 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000502:physiology; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000502:physiology*; D059748:Proteolysis; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D016185:Receptors, Interleukin-3 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; C508596:IL3 protein, human; D007377:Interleukin-3; D016328:NF-kappa B; C488588:PUMA protein, mouse; D011518:Proto-Oncogene Proteins; D016185:Receptors, Interleukin-3; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D051550:I-kappa B Kinase; D046988:Proteasome Endopeptidase Complex