Li Yunqing, Guessous Fadila, Kwon Sherwin, Kumar Manish, Ibidapo Opeyemi, Fuller Lauren, Johnson Elizabeth, Lal Bachchu, Hussaini Isa, Bao Yongde, Laterra John, Schiff David, Abounader Roger
Department of Neurology, University of Virginia, Charlottesville, Virginia 22908, USA.
Cancer Res. 2008 Mar 15;68(6):1723-31. doi: 10.1158/0008-5472.CAN-07-1963.
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.
我们首次证明，肿瘤抑制因子PTEN可具有促肿瘤特性。我们发现，PTEN通过提高功能获得性突变型p53（mut-p53）蛋白水平而获得这些意外特性。我们发现，将PTEN恢复至含有mut-p53的细胞会导致G(1)-S期细胞周期进程和细胞增殖的诱导，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会导致细胞增殖受到抑制以及体内肿瘤生长受到抑制。我们通过证明敲低mut-p53表达可抑制或逆转PTEN的促肿瘤作用，展示了PTEN促肿瘤作用对mut-p53的依赖性。从机制上讲，我们表明PTEN表达通过抑制Mdm2介导的mut-p53降解以及可能还通过直接蛋白质结合来提高mut-p53蛋白水平。这些发现描述了PTEN的一种新功能，并且对于旨在在人类肿瘤中操控PTEN或p53的实验和治疗策略具有重要意义。它们表明，应考虑PTEN和p53的突变状态以实现良好的治疗效果。这些发现还为人类癌症中PTEN和p53同时发生突变的低频率提供了解释。
