As4S4 targets RING-type E3 ligase c-CBL to induce degradation of BCR-ABL in chronic myelogenous leukemia
As4S4 targets RING-type E3 ligase c-CBL to induce degradation of BCR-ABL in chronic myelogenous leukemia
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DOI：
10.1073/pnas.1016311108
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发表时间：
2010-12-14
影响因子：
11.1
通讯作者：
Chen, Sai-Juan
中科院分区：
文献类型：
--
作者：
Mao, Jian-Hua;Sun, Xiao-Yan;Chen, Sai-Juan
砷是一种治疗急性早幼粒细胞白血病的药物，可诱导慢性粒细胞白血病(CML)细胞凋亡和bcr-abl降解。我们证明bcr-abl的泛素化和降解是由c-cbl介导的，c-cbl是一种环型E3连接酶，也被证明参与了许多其他受体/蛋白酪氨酸激酶的泛素化。我们的数据显示，硫化砷(As4S4)显著上调了c-CBL蛋白的表达。有趣的是，砷直接结合c-CBL的环指结构域来抑制其自身泛素化/降解，而不干扰其底物BCR-ABL的泛素化增强和随后的蛋白分解。在CML小鼠体内，也观察到砷处理后c-CBL诱导的bcr-abl降解。这些发现提供了对砷分子机制的洞察，并进一步支持了砷与酪氨酸激酶抑制剂联合应用于慢性粒细胞白血病的治疗应用，以及潜在地也用于涉及异常受体/蛋白酪氨酸激酶信号转导的其他恶性肿瘤。
Arsenic, a curative agent for acute promyelocytic leukemia, induces cell apoptosis and degradation of BCR-ABL in chronic myelogenous leukemia (CML). We demonstrated that ubiquitination and degradation of BCR-ABL was mediated by c-CBL, a RING-type E3 ligase that was also shown to be involved in ubiquitination for many other receptor/protein tyrosine kinases. Our data showed that c-CBL protein was considerably up-regulated by arsenic sulfide (As4S4). Interestingly, arsenic directly bound the RING finger domain of c-CBL to inhibit its self-ubiquitination/degradation without interfering with the enhancement of ubiquitination and subsequent proteolysis of its substrate BCR-ABL. Degradation of BCR-ABL due to c-CBL induction as a result of arsenic treatment was also observed in vivo in CML mice. These findings provide insight into the molecular mechanisms of arsenic and further support its therapeutic applications in CML in combination with tyrosine kinase inhibitors and potentially also in other malignancies involving aberrant receptor/protein tyrosine kinase signaling.