Activation of p53 by roscovitine-mediated suppression of MDM2 expression
Activation of p53 by roscovitine-mediated suppression of MDM2 expression
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DOI：
10.1038/sj.onc.1204412
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发表时间：
2001-05-31
期刊：
影响因子：
8
通讯作者：
Chen, JD
中科院分区：
文献类型：
--
作者：
Lu, WG;Chen, LH;Chen, JD
抑癌基因P53受MDM2癌蛋白调控。MDM2的过表达使P53维持在低水平，并导致部分肿瘤中P53的功能失活。我们发现，最初被开发为细胞周期蛋白依赖激酶(CDK)抑制剂的罗可维汀和奥洛莫星治疗可以有效地稳定和激活MDM2扩增或细胞质p53扩增的肿瘤细胞中的核P53。这些抑制剂在不影响P53-MDM2结合以及P53和MDM2的核穿梭功能的情况下阻止P53的降解。罗索维汀也能稳定突变体p53Ala-315，表明它不是通过调节丝氨酸315的CDK磷酸化起作用，而是诱导MDM2在蛋白和mRNA水平上的表达下调。MDM2的异位表达可阻断罗可维汀诱导p53稳定的能力。低浓度的罗索维汀与DNA损伤剂喜树碱协同激活P53，这些结果表明小分子CDK抑制剂可以通过对MDM2表达的有效抑制来激活P53，并可作为其他DNA损伤药物的增敏剂。
The p53 tumor suppressor is regulated by the MDM2 oncoprotein. Overexpression of MDM2 maintains p53 at low levels and contributes to the functional inactivation of p53 in a subset of tumors. We found that treatment with roscovitine and olomoucin, which were originally developed as cyclin-dependent kinase (CDK) inhibitors, can efficiently stabilize and activate nuclear p53 in tumor cells with MDM2 amplification or cytoplasmic p53. These inhibitors block the degradation of p53 without affecting p53-MDM2 binding and the nuclear shuttling function of p53 and MDM2. Roscovitine also induces stabilization of the p53 Ala-315 mutant, indicating that it does not act by regulating the CDK phosphorylation of serine 315, Roscovitine induces down-regulation of MDM2 expression at both protein and mRNA levels. Ectopic expression of MDM2 can abrogate the ability of roscovitine to induce p53 stabilization. Low concentrations of roscovitine cooperate with the DNA-damaging agent camptothecin to activate p53 in a synergistic fashion, These results show that the small molecule CDK inhibitors can be used to activate p53 through their potent inhibitory effect on MDM2 expression and may be useful as sensitizing agents for other DNA-damaging drugs.