Pten regulates Aurora-A and cooperates with Fbxw7 in modulating radiation-induced tumor development.
Pten regulates Aurora-A and cooperates with Fbxw7 in modulating radiation-induced tumor development.
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DOI：
10.1158/1541-7786.mcr-12-0025
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发表时间：
2012-06
期刊：
影响因子：
--
通讯作者：
Mao JH
中科院分区：
文献类型：
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作者：
Kwon YW;Kim IJ;Wu D;Lu J;Stock WA Jr;Liu Y;Huang Y;Kang HC;DelRosario R;Jen KY;Perez-Losada J;Wei G;Balmain A;Mao JH
Aurora-A激酶基因在多种人类癌症中经常被扩增和/或过度表达，这导致了针对该途径开发治疗药物的重大努力。在这里，我们证明了Aurora-A是F-box蛋白FBXW7泛素化和随后降解的靶标，该过程由GSK3β调节。利用一系列截断的Aurora-A蛋白和位点定向诱变，我们在Aurora-A中发现了不同的FBXW7和GSK3β结合位点。任何一个位点的关键残基突变都会严重破坏Aurora-A的降解。此外，我们发现Pten的缺失通过AKT/GSK3β通路减弱fbxw7依赖性的Aurora-A降解，从而导致Aurora-A的稳定。此外，与Fbxw7+/ -或Pten+/ -小鼠相比，辐射诱导的肿瘤潜伏期在Fbxw7+/ -或Pten+/ -小鼠中显著缩短，这表明Fbxw7和Pten似乎在抑制肿瘤发生方面协同作用。我们的研究结果建立了一个新的翻译后调控网络，其中Pten和Fbxw7通路似乎汇聚在Aurora-A水平的调控上。
The Aurora-A kinase gene is frequently amplified and/or over-expressed in a variety of human cancers, leading to major efforts to develop therapeutic agents targeting this pathway. Here we demonstrate that Aurora-A is targeted for ubiquitination and subsequent degradation by the F-box protein FBXW7 in a process that is regulated by GSK3β. Using a series of truncated Aurora-A proteins and site directed mutagenesis, we identified distinct FBXW7 and GSK3β binding sites in Aurora-A. Mutation of critical residues in either site substantially disrupts degradation of Aurora-A. Furthermore, we show that loss of Pten results in the stabilization of Aurora-A by attenuating FBXW7-dependent degradation of Aurora-A through the AKT/GSK3β pathway. Moreover, radiation-induced tumor latency is significantly shortened in Fbxw7+/− Pten+/− mice as compared to either Fbxw7+/− or Pten+/− mice, indicating that Fbxw7 and Pten appear to cooperate in suppressing tumorigenesis. Our results establish a novel posttranslational regulatory network in which the Pten and Fbxw7 pathways appear to converge on the regulation of Aurora-A level.