Cytokines and BCR-ABL mediate suppression of TRAIL-induced apoptosis through inhibition of forkhead FOX03a transcription factor
Cytokines and BCR-ABL mediate suppression of TRAIL-induced apoptosis through inhibition of forkhead FOX03a transcription factor
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DOI：
10.1073/pnas.0731871100
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发表时间：
2003-05-27
影响因子：
11.1
通讯作者：
Khosravi-Far, R
中科院分区：
文献类型：
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作者：
Ghaffari, S;Jagani, Z;Khosravi-Far, R
众所周知，细胞因子提供的生存信号通过抑制涉及Bcl-2家族成员的线粒体途径来抑制细胞凋亡。在这里，我们表明，在造血细胞中，细胞因子也调节死亡受体介导的途径。我们证明，正常细胞中的造血细胞因子如IL-3和促红细胞生成素，以及转化细胞中的bcr-abl癌蛋白，可以抑制肿瘤坏死因子相关的凋亡诱导配体(TRAIL)的转录。利用小干扰RNA，我们证明了TRAIL功能的抑制足以部分挽救被剥夺细胞因子的细胞免于凋亡。最后，我们证明了细胞因子和BCR-ABL对TRAIL转录的抑制是通过磷酸化和抑制叉头FOXO3a转录因子来介导的。Bcr-abl诱导的TRAIL转录抑制可能为慢性粒细胞白血病的致瘤性提供了新的机制。
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.