mTOR inhibitors blunt the p53 response to nucleolar stress by regulating RPL11 and MDM2 levels
mTOR inhibitors blunt the p53 response to nucleolar stress by regulating RPL11 and MDM2 levels
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DOI：
10.4161/15384047.2014.955743
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发表时间：
2014-01-01
影响因子：
3.6
通讯作者：
Lindstrom, Mikael S.
中科院分区：
文献类型：
--
作者：
Goudarzi, Kaveh M.;Nister, Monica;Lindstrom, Mikael S.
雷帕霉素的机械靶点（mTOR）是通过其刺激核糖体生物合成和mRNA翻译的能力来调节细胞生长的主要调节剂。相比之下，p53肿瘤抑制因子负控制细胞生长，并通过对细胞的广泛损伤而被激活。mTOR和p53信号通路通过许多不同的机制连接。抑制核糖体生物合成的化疗药物通常诱导核仁应激和p53的活化。在这里，我们已经调查了p53对核仁压力的反应是如何受到骨肉瘤和神经胶质瘤细胞系中mTOR同时抑制的影响。我们发现mTOR通路的抑制剂包括雷帕霉素、渥曼青霉素和咖啡因可以减弱p53对放线菌素D诱导的核仁应激的反应。mTOR的合成抑制剂（替西罗莫司，LY294.002和PP 242）也损害放线菌素D触发的p53稳定和p21诱导。已知核糖体蛋白（RPL 11）是核仁应激后p53蛋白稳定所必需的。用mTOR抑制剂处理细胞可能导致RPL 11的合成减少，从而使p53不稳定。我们发现，雷帕霉素在钝化p53对核仁应激的反应方面模仿了RPL 11耗竭的作用。然而，雷帕霉素降低p53和RPL 11水平的程度在细胞系之间存在差异。雷帕霉素减弱p53对核仁应激反应的其他机制可能也参与其中。事实上，雷帕霉素增加了内源性MDM 2的水平，尽管抑制了其在Ser-166的磷酸化。我们的研究结果可能对mTOR通路抑制剂组合癌症治疗的设计具有影响。
Mechanistic target of rapamycin (mTOR) is a master regulator of cell growth through its ability to stimulate ribosome biogenesis and mRNA translation. In contrast, the p53 tumor suppressor negatively controls cell growth and is activated by a wide range of insults to the cell. The mTOR and p53 signaling pathways are connected by a number of different mechanisms. Chemotherapeutics that inhibit ribosome biogenesis often induce nucleolar stress and activation of p53. Here we have investigated how the p53 response to nucleolar stress is affected by simultaneous mTOR inhibition in osteosarcoma and glioma cell lines. We found that inhibitors of the mTOR pathway including rapamycin, wortmannin, and caffeine blunted the p53 response to nucleolar stress induced by actinomycin D. Synthetic inhibitors of mTOR (temsirolimus, LY294.002 and PP242) also impaired actinomycin D triggered p53 stabilization and induction of p21. Ribosomal protein (RPL11) is known to be required for p53 protein stabilization following nucleolar stress. Treatment of cells with mTOR inhibitors may lead to reduced synthesis of RPL11 and thereby destabilize p53. We found that rapamycin mimicked the effect of RPL11 depletion in terms of blunting the p53 response to nucleolar stress. However, the extent to which the levels of p53 and RPL11 were reduced by rapamycin varied between cell lines. Additional mechanisms whereby rapamycin blunts the p53 response to nucleolar stress are likely to be involved. Indeed, rapamycin increased the levels of endogenous MDM2 despite inhibition of its phosphorylation at Ser-166. Our findings may have implications for the design of combinatorial cancer treatments with mTOR pathway inhibitors.