Depression of oncogenecity by dephosphorylating and degrading BCR-ABL.
Depression of oncogenecity by dephosphorylating and degrading BCR-ABL.
复制标题
通过去磷酸化和降解 BCR-ABL 抑制致癌性
DOI：
10.18632/oncotarget.13754
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发表时间：
2017-01-10
期刊：
影响因子：
--
通讯作者：
Feng WL
中科院分区：
文献类型：
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作者：
Gao M;Huang ZL;Tao K;Xiao Q;Wang X;Cao WX;Xu M;Hu J;Feng WL
BCR-ABL融合蛋白的异常磷酸化和过度表达是慢性粒细胞白血病（CML）的主要发病机制。磷酸化BCR-ABL Y177募集GRB 2衔接子并触发白血病RAS-MAPK和PI 3 K-AKT信号。在这项研究中，我们设计了一个SPOA系统，通过靶向BCR-ABL Y177去磷酸化和降解BCR-ABL。我们检测了其对CML细胞中BCR-ABL磷酸化和表达以及细胞增殖和凋亡的影响。我们发现，SPOA显著地使BCR-ABL Y177去磷酸化，阻止GRB 2募集，并使RAS-MAPK和PI 3 K-AKT信号解偶联。同时，SPOA以泛素非依赖性方式降解BCR-ABL癌蛋白，抑制BCR-ABL介导的STAT 5和CRKL信号转导，抑制CML细胞增殖和诱导凋亡，抑制K562细胞的致瘤性。这些结果提供了证据表明，去磷酸化和降解致癌BCR-ABL提供了一种替代的CML治疗。
Aberrant phosphorylation and overexpression of BCR-ABL fusion protein are responsible for the main pathogenesis in chronic myeloid leukemia (CML). Phosphorylated BCR-ABL Y177 recruits GRB2 adaptor and triggers leukemic RAS-MAPK and PI3K-AKT signals. In this study, we engineered a SPOA system to dephosphorylate and degrade BCR-ABL by targeting BCR-ABL Y177. We tested its effect on BCR-ABL phosphorylation and expression, as well as cell proliferation and apoptosis in CML cells. We found that SPOA remarkably dephosphorylated BCR-ABL Y177, prevented GRB2 recruitment, and uncoupled RAS-MAPK and PI3K-AKT signals. Meanwhile, SPOA degraded BCR-ABL oncoprotein in ubiquitin-independent manner and depressed the signal transduction of STAT5 and CRKL by BCR-ABL. Furthermore, SPOA inhibited proliferation and induced apoptosis in CML cells and depressed the oncogenecity of K562 cells in mice. These results provide evidence that dephosphorylating and degrading oncogenic BCR-ABL offer an alternative CML therapy.