Upregulation of p27 and its inhibition of CDK2/cyclin E activity following DNA damage by a novel platinum agent are dependent on the expression of p21.
Upregulation of p27 and its inhibition of CDK2/cyclin E activity following DNA damage by a novel platinum agent are dependent on the expression of p21.
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DOI：
10.1038/sj.bjc.6603448
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发表时间：
2006-12-04
影响因子：
8.8
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中科院分区：
文献类型：
--
作者：
顺铂类似物1R， 2r -二氨基环己烷（反式双乙酰托）（二氯）铂iv （DAP）是一种dna损伤剂，将进入临床试验，因为它对顺铂耐药肿瘤细胞具有强大的细胞毒性作用。这种细胞毒性可能存在于其通过p53/p21途径抑制CDKs选择性激活g1期检查点反应的能力中。我们现在评估了另一种CDK抑制剂p27在dap介导的g1期CDK2活性抑制中的作用。我们在卵巢A2780肿瘤细胞中的研究表明，DAP诱导的p27水平与p21相当或更高。p27的诱导不是通过转录机制，而是由于通过依赖于p21的机制，蛋白质稳定性增加了四倍。此外，dap诱导的p21促进了CDK2复合物中p27的选择性增加，而不是CDK4复合物，这种选择性增加有助于抑制CDK2激酶活性。被抑制的复合物含有p27或p21，但不是两者都含有，与p27和p21相关的周期蛋白E的相对水平表明，大约25%的CDK2活性抑制是由p27引起的，75%是由p21引起的。本研究首次证明p27上调可直接归因于dna损伤剂激活p53/p21通路，并揭示p53/p21/p27轴是检查点应答的重要组成部分。
The cisplatin analogue 1R,2R-diaminocyclohexane(trans-diacetato)(dichloro)platinumIV (DAP) is a DNA-damaging agent that will be entering clinical trials for its potent cytotoxic effects against cisplatin-resistant tumour cells. This cytotoxicity may reside in its ability to selectively activate G1-phase checkpoint response by inhibiting CDKs via the p53/p21 pathway. We have now evaluated the role of another CDK inhibitor p27 as a contributor to DAP-mediated inhibition of G1-phase CDK2 activity. Our studies in ovarian A2780 tumour cells demonstrate that p27 levels induced by DAP are comparable to or greater than those seen for p21. The induction of p27 is not through a transcriptional mechanism, but rather is due to a four-fold increase in protein stabilisation through a mechanism dependent on p21. Moreover, DAP-induced p21 promoted the selective increase of p27 in the CDK2 complex, but not in CDK4 complex, and this selective increase contributed to inhibition of the CDK2 kinase activity. The inhibited complex contained either p27 or p21, but not both, with the relative levels of cyclin E associated with p27 and p21 indicating that about 25% of the inhibition of CDK2 activity was due to p27 and 75% due to p21. This study provides the first evidence that p27 upregulation is directly attributable to activation of the p53/p21 pathway by a DNA-damaging agent, and promulgates p53/p21/p27 axis as a significant component of checkpoint response.
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