PTEN has tumor-promoting properties in the setting of gain-of-function p53 mutations
PTEN has tumor-promoting properties in the setting of gain-of-function p53 mutations
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DOI：
10.1158/0008-5472.can-07-1963
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发表时间：
2008-03-15
期刊：
影响因子：
11.2
通讯作者：
Abounader, Roger
中科院分区：
文献类型：
--
作者：
Li, Yunqing;Guessous, Fadila;Abounader, Roger
我们第一次证明了抑癌基因PTEN可以具有促癌特性。我们表明，PTEN获得这些意想不到的性能，通过提高功能获得性突变p53（mut-p53）蛋白水平。我们发现，PTEN恢复到携带mut-p53的细胞导致诱导G（1）-S细胞周期进展和细胞增殖，并抑制细胞死亡。相反，在表达野生型PTEN和mut-p53的细胞中抑制PTEN导致抑制细胞增殖和抑制体内肿瘤生长。我们通过敲低mut-p53表达抑制或逆转PTEN的促肿瘤作用，显示了PTEN促肿瘤作用对mut-p53的依赖性。从机制上讲，我们表明，PTEN表达增强mut-p53蛋白水平通过抑制mut-p53降解Mdm 2，也可能通过直接的蛋白结合。这些发现描述了PTEN的一种新功能，并对旨在操纵人类肿瘤中的PTEN或p53的实验和治疗策略具有重要意义。他们认为，应考虑PTEN和p53的突变状态以获得有利的治疗结果。这些发现也为人类癌症中PTEN和p53同时突变的低频率提供了解释。
We show, for the first time, that the tumor suppressor PTEN can have tumor-promoting properties. We show that PTEN acquires these unexpected properties by enhancing gain-of-function mutant p53 (mut-p53) protein levels. We find that PTEN restoration to cells harboring mut-p53 leads to induction of G(1)-S cell cycle progression and cell proliferation and to inhibition of cell death. Conversely, PTEN inhibition in cells expressing wild-type PTEN and mut-p53 leads to inhibition of cell proliferation and inhibition of in vivo tumor growth. We show the dependency of the tumor-promoting effects of PTEN on mut-p53 by showing that knockdown of mut-p53 expression inhibits or reverses the tumor-promoting effects of PTEN. Mechanistically, we show that PTEN expression enhances mut-p53 protein levels via inhibition of mut-p53 degradation by Mdm2 and possibly also via direct protein binding. These findings describe a novel function of PTEN and have important implications for experimental and therapeutic strategies that aim at manipulating PTEN or p53 in human tumors. They suggest that the mutational status of PTEN and p53 should be considered to achieve favorable therapeutic outcomes. The findings also provide an explanation for the low frequency of simultaneous mutations of PTEN and p53 in human cancer.