title: Akt1 is the principal Akt isoform regulating apoptosis in limiting cytokine concentrations.
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.
authors.affiliation: Cell Signalling and Cell Death Division, Walter and Eliza Hall Institute of Medical Research, Royal Parade, Parkville, Victoria 3052, Australia.
authors.forename: B D
authors.initials: BD
authors.lastname: Green
authors.forename: A M
authors.initials: AM
authors.lastname: Jabbour
authors.forename: J J
authors.initials: JJ
authors.lastname: Sandow
authors.forename: C D
authors.initials: CD
authors.lastname: Riffkin
authors.forename: D
authors.initials: D
authors.lastname: Masouras
authors.forename: C P
authors.initials: CP
authors.lastname: Daunt
authors.forename: M
authors.initials: M
authors.lastname: Salmanidis
authors.forename: G
authors.initials: G
authors.lastname: Brumatti
authors.forename: B A
authors.initials: BA
authors.lastname: Hemmings
authors.forename: M A
authors.initials: MA
authors.lastname: Guthridge
authors.forename: R B
authors.initials: RB
authors.lastname: Pearson
authors.forename: P G
authors.initials: PG
authors.lastname: Ekert
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D048708:Cell Growth Processes / Q000502:physiology; D016207:Cytokines / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D007377:Interleukin-3 / Q000378:metabolism; D007527:Isoenzymes; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000166:cytology / Q000201:enzymology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D016185:Receptors, Interleukin-3 / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D016207:Cytokines; D007377:Interleukin-3; D007527:Isoenzymes; D016185:Receptors, Interleukin-3; C514862:Akt1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt