Cytokines and BCR-ABL mediate suppression of TRAIL-induced apoptosis through inhibition of forkhead FOXO3a transcription factor.
Cytokine-provided survival signals are known to suppress apoptosis through inhibition of mitochondrial pathways that involve Bcl-2 family members. Here we show that in hematopoietic cells, cytokines also regulate death receptor-mediated pathways. We demonstrate that hematopoietic cytokines such as IL-3 and erythropoietin in normal cells, as well as BCR-ABL oncoprotein in transformed cells, inhibit transcription of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Using small interfering RNAs, we show that the inhibition of TRAIL function is sufficient to partially rescue cytokine-deprived cells from apoptosis. Finally, we demonstrate that cytokine and BCR-ABL suppression of TRAIL transcription is mediated through phosphorylation and inhibition of the forkhead FOXO3a transcription factor. BCR-ABL-induced inhibition of TRAIL transcription in hematopoietic cells may provide a novel mechanism for tumorigenicity in chronic myeloid leukemia.
Ghaffari
Saghi
S
Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
Jagani
Zainab
Z
Kitidis
Claire
C
Lodish
Harvey F
HF
Khosravi-Far
Roya
R
D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D001483:Base Sequence; D002460:Cell Line; D016207:Cytokines / Q000502:physiology*; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors*; D024202:Electrophoretic Mobility Shift Assay; D016044:Fusion Proteins, bcr-abl / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053221:TNF-Related Apoptosis-Inducing Ligand; D014157:Transcription Factors / Q000037:antagonists & inhibitors*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D051017:Apoptosis Regulatory Proteins; D016207:Cytokines; D017931:DNA Primers; D004268:DNA-Binding Proteins; D008562:Membrane Glycoproteins; D053221:TNF-Related Apoptosis-Inducing Ligand; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D016044:Fusion Proteins, bcr-abl