Cytokines and BCR-ABL mediate suppression of TRAIL-induced apoptosis through inhibition of forkhead FOX03a transcription factor

被引:119
作者
Ghaffari, S
Jagani, Z
Kitidis, C
Lodish, HF
Khosravi-Far, R
机构
[1] Whitehead Inst Biomed Res, Cambridge, MA 02142 USA
[2] Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA 02215 USA
[3] Harvard Univ, Sch Med, Biol & Biomed Sci Program, Boston, MA 02215 USA
[4] MIT, Cambridge, MA 02139 USA
关键词
D O I
10.1073/pnas.0731871100
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
收藏
页码:6523 / 6528
页数:6
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