Par-4 inhibits Akt and suppresses Ras-induced lung tumorigenesis
Par-4 inhibits Akt and suppresses Ras-induced lung tumorigenesis
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DOI：
10.1038/emboj.2008.149
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发表时间：
2008-08-20
期刊：
影响因子：
11.4
通讯作者：
Diaz-Meco, Maria T.
中科院分区：
文献类型：
--
作者：
Joshi, Jayashree;Fernandez-Marcos, Pablo J.;Diaz-Meco, Maria T.
非典型PKC相互作用蛋白Par-4在体外抑制细胞存活和肿瘤发生，其在小鼠中的遗传失活导致寿命缩短、良性肿瘤发展增强和低频率致癌。在这里，我们证明了Par-4在正常肺中高度表达，但在人肺癌样本中表达减少。我们发现，在小鼠肺肿瘤模型中，Par-4的缺乏显着增强Ras诱导的肺癌形成在体内，作为一个负调节Akt激活。我们还证明，在细胞培养，在体内，和在生化实验中，Akt的调节Par-4介导的PKC ζ，建立一个新的范例Akt的调节，并可能，Ras诱导的肺癌，其中Par-4是一种新的肿瘤抑制因子。
The atypical PKC-interacting protein, Par-4, inhibits cell survival and tumorigenesis in vitro, and its genetic inactivation in mice leads to reduced lifespan, enhanced benign tumour development and low-frequency carcinogenesis. Here, we demonstrate that Par-4 is highly expressed in normal lung but reduced in human lung cancer samples. We show, in a mouse model of lung tumours, that the lack of Par-4 dramatically enhances Ras-induced lung carcinoma formation in vivo, acting as a negative regulator of Akt activation. We also demonstrate in cell culture, in vivo, and in biochemical experiments that Akt regulation by Par-4 is mediated by PKC zeta, establishing a new paradigm for Akt regulation and, likely, for Ras-induced lung carcinogenesis, wherein Par-4 is a novel tumour suppressor.