βTrCP controls the lysosome-mediated degradation of CDK1, whose accumulation correlates with tumor malignancy.
βTrCP controls the lysosome-mediated degradation of CDK1, whose accumulation correlates with tumor malignancy.
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DOI：
10.18632/oncotarget.2274
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发表时间：
2014-09-15
期刊：
影响因子：
--
通讯作者：
Romero F
中科院分区：
文献类型：
--
作者：
Herrero-Ruiz J;Mora-Santos M;Giráldez S;Sáez C;Japón MA;Tortolero M;Romero F
在哺乳动物中，细胞周期进程由细胞周期蛋白依赖性激酶控制，其中CDK 1在G2/M转换、G1进程和G1/S转换的调节中起重要作用。CDK 1通过其与细胞周期蛋白的结合、磷酸化和去磷酸化、亚细胞定位的变化以及通过CDK抑制剂蛋白的直接结合而高度调节。CDK 1稳态蛋白水平通过蛋白合成和降解的协调调节在整个细胞周期中保持恒定。我们发现CDK 1被E3泛素连接酶SCFβTrCP泛素化，并被溶酶体降解。此外，我们还发现DNA损伤不仅可以触发CDK 1抑制性磷酸化位点的稳定和CDK 1基因表达的抑制，而且还可以以细胞类型依赖的方式调节β TrCP诱导的CDK 1降解。具体而言，在某些细胞系中用化疗剂阿霉素治疗引起CDK 1降解并诱导细胞凋亡，而在其他细胞系中，它抑制蛋白质的破坏。这些观察结果提出了一种可能性，即不同的肿瘤类型，根据其致病谱突变，可能对DNA损伤后β TrCP诱导的CDK 1降解表现出不同的敏感性。最后，我们发现CDK 1在患者肿瘤中的积累与βTrCP呈负相关，与肿瘤恶性程度呈正相关。
In mammals, cell cycle progression is controlled by cyclin-dependent kinases, among which CDK1 plays important roles in the regulation of the G2/M transition, G1 progression and G1/S transition. CDK1 is highly regulated by its association to cyclins, phosphorylation and dephosphorylation, changes in subcellular localization, and by direct binding of CDK inhibitor proteins. CDK1 steady-state protein levels are held constant throughout the cell cycle by a coordinated regulation of protein synthesis and degradation. We show that CDK1 is ubiquitinated by the E3 ubiquitin ligase SCFβTrCP and degraded by the lysosome. Furthermore, we found that DNA damage not only triggers the stabilization of inhibitory phosphorylation sites on CDK1 and repression of CDK1 gene expression, but also regulates βTrCP-induced CDK1 degradation in a cell type-dependent manner. Specifically, treatment with the chemotherapeutic agent doxorubicin in certain cell lines provokes CDK1 degradation and induces apoptosis, whereas in others it inhibits destruction of the protein. These observations raise the possibility that different tumor types, depending on their pathogenic spectrum mutations, may display different sensitivity to βTrCP-induced CDK1 degradation after DNA damage. Finally, we found that CDK1 accumulation in patients’ tumors shows a negative correlation with βTrCP and a positive correlation with the degree of tumor malignancy.
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