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Critical reanalysis of the methods that discriminate the activity of CDK2 from CDK1

机译：对区分CDK2和CDK1活性的方法的重新分析

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摘要

Cyclin dependent kinases 1 and 2 (CDK1 and CDK2) play crucial roles in regulating cell cycle progression from G1 to S, through S, and G2 to M phase. Both inhibition and aberrant activation of CDK1/2 can be detrimental to cancer cell growth. However, the tools routinely employed to discriminate between the activities of these 2 kinases do not have the selectivity commonly attributed to them. Activation of these kinases is often assayed as a decrease of the inhibitory tyrosine-15 phosphorylation, yet the antibodies used cannot discriminate between phosphorylated CDK1 and CDK2. Inhibitors of these kinases, while partially selective against purified kinases, may lack selectivity when applied to intact cells. High levels of cyclin E are often considered a marker of increased CDK2 activity, yet active CDK2 targets cyclin E for degradation, hence high levels usually reflect inactive CDK2. Finally, inhibition of CDK2 does not arrest cells in S phase suggesting CDK2 is not required for S phase progression. Furthermore, activation of CDK2 in S phase can rapidly induce DNA double-strand breaks in some cell lines. The misunderstandings associated with the use of these tools has led to misinterpretation of results. In this review, we highlight these challenges in the field.
机译：细胞周期蛋白依赖性激酶1和2（CDK1和CDK2）在调节细胞周期从G1到S，通过S和G2到M的过程中起着至关重要的作用。 CDK1 / 2的抑制和异常激活都可能对癌细胞的生长有害。然而，通常用来区分这两种激酶的活性的工具没有通常归因于它们的选择性。这些激酶的激活通常被分析为抑制性酪氨酸15磷酸化的减少，但是使用的抗体无法区分磷酸化的CDK1和CDK2。这些激酶的抑制剂虽然对纯化的激酶具有部分选择性，但在应用于完整细胞时可能缺乏选择性。高水平的细胞周期蛋白E通常被认为是增加的CDK2活性的标志物，而活性CDK2靶向细胞周期蛋白E进行降解，因此高水平的细胞周期蛋白E通常反映出无活性的CDK2。最后，抑制CDK2不会使细胞停滞在S期，这表明CDK2对于S期进程不是必需的。此外，在S期激活CDK2可以在某些细胞系中快速诱导DNA双链断裂。与这些工具的使用有关的误解导致对结果的误解。在本文中，我们重点介绍了这些挑战。

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