The in vivo role of the RP-Mdm2-p53 pathway in signaling oncogenic stress induced by pRb inactivation and Ras overexpression.
The in vivo role of the RP-Mdm2-p53 pathway in signaling oncogenic stress induced by pRb inactivation and Ras overexpression.
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DOI：
10.1371/journal.pone.0021625
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Zhang Y
中科院分区：
文献类型：
--
作者：
Pan W;Issaq S;Zhang Y
Mdm 2-p53肿瘤抑制途径通过整合各种应激源并引发对细胞生长和增殖的影响，在调节细胞稳态中起着至关重要的作用。最近的研究表明，在体内的信号转导途径介导的核糖体蛋白（RP）-Mdm 2的相互作用，响应核糖体生物应激和唤起保护性p53反应。已经显示，在Mdm 2的锌指中具有特异性破坏RP L11-Mdm 2结合的Cys至Phe突变的小鼠在伯基特淋巴瘤的致癌c-Myc驱动的小鼠模型中倾向于加速淋巴瘤形成。由于大多数癌基因在上调时同时促进细胞生长和增殖，因此有理由认为RP-Mdm 2-p53途径也可能是响应于c-Myc以外的癌基因所必需的。使用基因工程小鼠，我们现在表明，破坏RP-Mdm 2-p53通路的Mdm 2C 305 F突变不会加速前列腺肿瘤的发生诱导的pRb家族蛋白（pRb/p107/p130）的失活。相反，p19 Arf的缺失大大加速了由pRb家族蛋白的抑制诱导的前列腺癌的进展。此外，使用异位表达的致癌H-Ras，我们证明了在Mdm 2C 305 F突变MEF细胞中p53反应保持完整。因此，与被认为是一般致癌反应途径的p19 Arf-Mdm 2-p53途径不同，RP-Mdm 2-p53途径似乎特异性抑制致癌c-Myc诱导的肿瘤发生。
The Mdm2-p53 tumor suppression pathway plays a vital role in regulating cellular homeostasis by integrating a variety of stressors and eliciting effects on cell growth and proliferation. Recent studies have demonstrated an in vivo signaling pathway mediated by ribosomal protein (RP)-Mdm2 interaction that responds to ribosome biogenesis stress and evokes a protective p53 reaction. It has been shown that mice harboring a Cys-to-Phe mutation in the zinc finger of Mdm2 that specifically disrupts RP L11-Mdm2 binding are prone to accelerated lymphomagenesis in an oncogenic c-Myc driven mouse model of Burkitt's lymphoma. Because most oncogenes when upregulated simultaneously promote both cellular growth and proliferation, it therefore stands to reason that the RP-Mdm2-p53 pathway might also be essential in response to oncogenes other than c-Myc. Using genetically engineered mice, we now show that disruption of the RP-Mdm2-p53 pathway by an Mdm2C305F mutation does not accelerate prostatic tumorigenesis induced by inactivation of the pRb family proteins (pRb/p107/p130). In contrast, loss of p19Arf greatly accelerates the progression of prostate cancer induced by inhibition of pRb family proteins. Moreover, using ectopically expressed oncogenic H-Ras we demonstrate that p53 response remains intact in the Mdm2C305F mutant MEF cells. Thus, unlike the p19Arf-Mdm2-p53 pathway, which is considered a general oncogenic response pathway, the RP-Mdm2-p53 pathway appears to specifically suppress tumorigenesis induced by oncogenic c-Myc.
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