Cytokine mediated suppression of TF-1 apoptosis requires PI3K activation and inhibition of Bim expression.
Phosphatidylinositol 3-kinase (PI3K) and its effector protein kinase B (PKB/c-akt) have been implicated as critical mediators of cytokine-induced survival signals. In this study, we have utilized an IL-5 dependent hematopoietic cell line (TF-1) to investigate the signaling events involved in cytokine-dependent erythroblast survival. We demonstrate that IL-5 rescues TF-1 cells from apoptosis through a PI3K/PKB-dependent signaling pathway. Cytokine-withdrawal leads to activation of the Forkhead transcription factor FOXO3a and subsequent expression of the pro-apoptotic Bcl-2 family member Bim. Bim is itself sufficient to induce apoptosis in these cells. Importantly, activation of an inducible active FOXO3a mutant is alone sufficient for upregulation of Bim expression and induction of apoptosis. These data define a mechanism by which survival factors inhibit the default apoptotic pathway and can regulate TF-1 erythroblast survival.
Rosas
Marcela
M
Department of Pulmonary Diseases H02.128, University Medical Center, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.
Birkenkamp
Kim U
KU
Lammers
Jan-Willem J
JW
Koenderman
Leo
L
Coffer
Paul J
PJ
D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; D002352:Carrier Proteins / Q000378:metabolism*; D053148:Caspase 3; D053179:Caspase 7; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004900:Erythroblasts / Q000378:metabolism*; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D038362:Glycogen Synthase Kinase 3 / Q000502:physiology; D006801:Humans; D015848:Interleukin-5 / Q000502:physiology*; D008565:Membrane Proteins / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D015848:Interleukin-5; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; D019869:Phosphatidylinositol 3-Kinases; D038362:Glycogen Synthase Kinase 3; C505407:CASP3 protein, human; C505520:CASP7 protein, human; D053148:Caspase 3; D053179:Caspase 7; D020169:Caspases