Degradation of HER2 by cbl-based chimeric ubiquitin Ligases
Degradation of HER2 by cbl-based chimeric ubiquitin Ligases
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DOI：
10.1158/0008-5472.can-06-3731
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发表时间：
2007-09-15
期刊：
影响因子：
11.2
通讯作者：
Yao, Libo
中科院分区：
文献类型：
--
作者：
Li, Xia;Shen, Liangliang;Yao, Libo
靶向致病蛋白的泛素化和嵌合分子降解是一种很有前途的癌症治疗替代策略。本研究通过重组几种基于ccl的嵌合泛素连接酶来实现HER2的有效下调。这些嵌合分子由Cbl nh2末端酪氨酸激酶结合域、连接体和RING结构域组成，其中Src同源2结构域被生长因子受体结合蛋白2 （Grb2）、Grb7、p85或Src的结构域取代。嵌合蛋白不仅与HER2相互作用，而且增强了内源性过表达HER2的下调。将嵌合蛋白导入过表达HER2的乳腺癌SK-BR-3细胞或卵巢癌SK-OV-3细胞后，它们以环指结构域依赖的方式有效地促进了HER2的泛素化和降解。因此，这些嵌合分子的表达导致了集落形成的抑制，增加了细胞在G周期中的比例，并抑制了致瘤性。总之，我们的研究结果表明，本研究设计的基于ccl的嵌合泛素连接酶可能代表了一种靶向治疗her2过表达癌症的新方法。
Targeting disease-causing proteins for ubiquitination and degradation by chimeric molecules represents a promising alternative therapeutic strategy in cancer. Here, several Cbl-based chimeric ubiquitin ligases were recombined to achieve effective down-regulation of HER2. These chimeric molecules consisted of the Cbl NH2-terminal tyrosine kinase binding domain, linker, and RING domain, with the Src homology 2 domain replaced with that from growth factor receptor binding protein 2 (Grb2), Grb7, p85, or Src. The chimeric proteins not only interacted with HER2 but also enhanced the down-regulation of endogenous overexpressed HER2. After the chimeric proteins were introduced into HER2-overexpressing breast cancer SK-BR-3 cells or ovarian cancer SK-OV-3 cells, they effectively promoted HER2 ubiquitination and degradation in a RING finger domain-dependent manner. Consequently, expression of these chimeric molecules led to an inhibition of colony formation, increased the proportion of cells in the G, cycle, and suppressed tumorigenicity. Collectively, our findings suggest that the Cbl-based chimeric ubiquitin ligases designed in the present study may represent a novel approach for the targeted therapy of HER2-overexpressing cancers.