生物
甲戊酸途径
癌变
下调和上调
RNA干扰
甲戊酸
心理压抑
ABCA1
癌症研究
细胞生物学
甾醇调节元件结合蛋白
信号转导
刺猬信号通路
基因
基因表达
运输机
遗传学
生物合成
核糖核酸
作者
Sung-Hwan Moon,Chun‐Hao Huang,Shauna L. Houlihan,Kausik Regunath,William A. Freed-Pastor,John P. Morris,Darjus F. Tschaharganeh,Edward R. Kastenhuber,Anthony M. Barsotti,Rachel Culp‐Hill,Wen Xue,Yu-Jui Ho,Timour Baslan,Xiang Li,Allison Mayle,Elisa de Stanchina,Lars Zender,David Tong,Angelo D’Alessandro,Scott W. Lowe,Carol Prives
出处
期刊:Cell
[Elsevier]
日期:2019-01-01
卷期号:176 (3): 564-580.e19
被引量:271
标识
DOI:10.1016/j.cell.2018.11.011
摘要
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.
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