Cyclin E and its binding partner Cdk2 control the G1/S transition in mammalian cells. Increased levels of cyclin E are found in some cancers. Additionally, proteolytic removal of the cyclin E N-terminus occurs in some cancers and is associated with increased cyclin E-Cdk2 activity and poor clinical prognosis. Cyclin E levels are tightly regulated and controlled in part through ubiquitin-mediated degradation initiated by one of two E3 ligases, Cul1 and Cul3. Cul1 ubiquitylates phosphorylated cyclin E, but the mechanism through which Cul3 ubiquitylates cyclin E is poorly understood. In experiments to ascertain how Cul3 mediates cyclin E destruction, we identified a degron on cyclin E that Cul3 targets for ubiquitylation. Recognition of the degron and binding of Cul3 does not require a BTB domain-containing adaptor protein. Additionally, this degron is lacking in N-terminally truncated cyclin E. Our results describe a mechanism whereby N-terminally truncated cyclin E can avoid the Cul3-mediated degradation pathway. This mechanism helps to explain the increased activity that is associated with the truncated cyclin E variants that occurs in some cancers.

中文翻译：

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Cul3 通过位于细胞周期蛋白 E N 末端区域内的降解决定子调节细胞周期蛋白 E1 蛋白丰度。


细胞周期蛋白 E 及其结合伙伴 Cdk2 控制哺乳动物细胞中的 G1/S 转变。在某些癌症中发现细胞周期蛋白 E 水平升高。此外，某些癌症中会发生细胞周期蛋白 E N 末端的蛋白水解去除，并且与细胞周期蛋白 E-Cdk2 活性增加和不良临床预后相关。细胞周期蛋白 E 水平部分通过由两种 E3 连接酶 Cul1 和 Cul3 之一引发的泛素介导的降解受到严格调节和控制。 Cul1 泛素化磷酸化细胞周期蛋白 E，但 Cul3 泛素化细胞周期蛋白 E 的机制尚不清楚。在确定 Cul3 如何介导细胞周期蛋白 E 破坏的实验中，我们鉴定了细胞周期蛋白 E 上的一个降解决定子，Cul3 的目标是泛素化。降解决定子的识别和 Cul3 的结合不需要包含 BTB 结构域的接头蛋白。此外，N 端截短的细胞周期蛋白 E 中缺乏该降解决定子。我们的结果描述了 N 端截短的细胞周期蛋白 E 可以避免 Cul3 介导的降解途径的机制。这种机制有助于解释某些癌症中与截短的细胞周期蛋白 E 变体相关的活性增加。