Physical and Functional Interaction between Ribosomal Protein L11 and the Tumor Suppressor ARF
Physical and Functional Interaction between Ribosomal Protein L11 and the Tumor Suppressor ARF
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DOI：
10.1074/jbc.m111.311902
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发表时间：
2012-05-18
影响因子：
4.8
通讯作者：
Lu, Hua
中科院分区：
文献类型：
--
作者：
Dai, Mu-Shui;Challagundla, Kishore B.;Lu, Hua
肿瘤抑制蛋白ARF在致癌应激下激活p53，而核糖体蛋白L11在核糖体应激后诱导p53。这两种蛋白结合MDM2的中心区域，尽管不重叠，并抑制MDM2对p53的活性。然而，目前尚不清楚这两种通路是否在功能上相连。本研究表明，在体外和细胞中，ARF直接与L11结合，然后与MDM2和p53形成复合物。L11协同增强arf诱导的p53转录活性和细胞周期阻滞。支持这些结果，敲除L11可减少arf介导的p53积累并减轻arf诱导的细胞周期阻滞。有趣的是，ARF的过表达会增加无核糖体L11的水平，并增强L11与MDM2和p53的相互作用。这些结果表明，ARF激活p53，至少部分是通过诱导核糖体应激，导致L11抑制MDM2，并提示ARF-MDM2-p53和L11-MDM2-p53通路在功能上相互联系。
The ARF tumor suppressor protein activates p53 in response to oncogenic stress, whereas ribosomal protein L11 induces p53 following ribosomal stress. Both proteins bind to central, albeit non-overlapping, regions of MDM2 and suppress MDM2 activity toward p53. However, it is not known whether the two pathways are functionally connected. Here we show that ARF directly binds to L11 in vitro and in cells, which then forms a complex with MDM2 and p53. L11 collaboratively enhances ARF-induced p53 transcriptional activity and cell cycle arrest. Supporting these results, knocking down L11 reduces ARF-mediated p53 accumulation and alleviates ARF-induced cell cycle arrest. Interestingly, overexpression of ARF increases the levels of ribosome-free L11 and enhances the interaction of L11 with MDM2 and p53. These results demonstrate that ARF activates p53, at least partly by induction of ribosomal stress, which results in L11 suppression of MDM2, and suggest that the ARF-MDM2-p53 and the L11-MDM2-p53 pathways are functionally connected.