Activation of the phosphatidylinositol 3-kinase/Akt pathway protects against interleukin-3 starvation but not DNA damage-induced apoptosis.
Baf-3 cells are dependent on interleukin-3 (IL-3) for their survival and proliferation in culture. To identify anti-apoptotic pathways, we performed a retroviral-insertion mutagenesis on Baf-3 cells and selected mutants that have acquired a long term survival capacity. The phenotype of one mutant, which does not overexpress bcl-x and proliferates in the absence of IL-3, is described. We show that, in this mutant, Akt is constitutively activated leading to FKHRL1 phosphorylation and constitutive glycolytic activity. This pathway is necessary for the mutant to survive following IL-3 starvation but is not sufficient or necessary to protect cells from DNA damage-induced cell death. Indeed, inhibition of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway in Baf-3 cells does not prevent the ability of IL-3 to protect cells against gamma-irradiation-induced DNA damage. This protective effect of IL-3 rather correlates with the expression of the anti-apoptotic Bcl-x protein. Taken together, these data demonstrate that the PI3K/Akt pathway is sufficient to protect cells from growth factor starvation-induced apoptosis but is not required for IL-3 inhibition of DNA damage-induced cell death.
Mathieu
A L
AL
Immuno-apoptose, U503 INSERM CERVI, 21 avenue Tony Garnier, 69007 Lyon, France.
Gonin
S
S
Leverrier
Y
Y
Blanquier
B
B
Thomas
J
J
Dantin
C
C
Martin
G
G
Baverel
G
G
Marvel
J
J
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002455:Cell Division / Q000235:genetics; D002460:Cell Line; D002470:Cell Survival / Q000235:genetics; D004249:DNA Damage; D004789:Enzyme Activation; D006801:Humans; D007377:Interleukin-3 / Q000172:deficiency / Q000235:genetics; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D015398:Signal Transduction
D007377:Interleukin-3; D019869:Phosphatidylinositol 3-Kinases