p53 Represses the Mevalonate Pathway to Mediate Tumor Suppression
p53 Represses the Mevalonate Pathway to Mediate Tumor Suppression
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DOI：
10.1016/j.cell.2018.11.011
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发表时间：
2019-01-24
期刊：
影响因子：
64.5
通讯作者：
Prives, Carol
中科院分区：
文献类型：
--
作者：
Moon, Sung-Hwan;Huang, Chun-Hao;Prives, Carol
我们对 p53 抑制肿瘤发生的复杂过程的理解仍然存在差距。在这里，我们描述了 p53 在抑制甲羟戊酸途径中的新作用，甲羟戊酸途径负责胆固醇和非甾醇类异戊二烯的生物合成。 p53 通过转录诱导 ABCA1 胆固醇转运蛋白基因来阻断 SREBP-2（该途径的主要转录调节因子）的激活。肝癌小鼠模型表明，当需要 p53 来主动抑制肿瘤发生时，p53 会下调甲羟戊酸途径基因表达，从而发生在癌前肝细胞中。此外，甲羟戊酸途径的药理学或 RNAi 抑制限制了由 p53 缺失驱动的小鼠肝细胞癌的发展。与 p53 丢失一样，ABCA1 的消融会促进小鼠肝脏肿瘤的发生，并与 SREBP-2 成熟的增加相关。我们的研究结果表明，甲羟戊酸途径的抑制是 p53 介导的肝脏肿瘤抑制的重要组成部分，并概述了这种情况发生的机制。
There are still gaps in our understanding of the complex processes by which p53 suppresses tumorigenesis. Here we describe a novel role for p53 in suppressing the mevalonate pathway, which is responsible for biosynthesis of cholesterol and nonsterol isoprenoids. p53 blocks activation of SREBP-2, the master transcriptional regulator of this pathway, by transcriptionally inducing the ABCA1 cholesterol transporter gene. A mouse model of liver cancer reveals that downregulation of mevalonate pathway gene expression by p53 occurs in premalignant hepatocytes, when p53 is needed to actively suppress tumorigenesis. Furthermore, pharmacological or RNAi inhibition of the mevalonate pathway restricts the development of murine hepatocellular carcinomas driven by p53 loss. Like p53 loss, ablation of ABCA1 promotes murine liver tumorigenesis and is associated with increased SREBP-2 maturation. Our findings demonstrate that repression of the mevalonate pathway is a crucial component of p53-mediated liver tumor suppression and outline the mechanism by which this occurs.