Joshi Jayashree, Fernandez-Marcos Pablo J, Galvez Anita, Amanchy Ramars, Linares Juan F, Duran Angeles, Pathrose Peterson, Leitges Michael, Cañamero Marta, Collado Manuel, Salas Clara, Serrano Manuel, Moscat Jorge, Diaz-Meco Maria T
Department of Cancer and Cell Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
EMBO J. 2008 Aug 20;27(16):2181-93. doi: 10.1038/emboj.2008.149. Epub 2008 Jul 24.
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 PKCzeta, establishing a new paradigm for Akt regulation and, likely, for Ras-induced lung carcinogenesis, wherein Par-4 is a novel tumour suppressor.
非典型蛋白激酶C相互作用蛋白Par-4在体外可抑制细胞存活和肿瘤发生，在小鼠中其基因失活会导致寿命缩短、良性肿瘤发展增强以及低频致癌。在此，我们证明Par-4在正常肺组织中高表达，但在人类肺癌样本中表达降低。我们在肺肿瘤小鼠模型中表明，缺乏Par-4会在体内显著增强Ras诱导的肺癌形成，它作为Akt激活的负调节因子发挥作用。我们还在细胞培养、体内及生化实验中证明，Par-4对Akt的调节由PKCzeta介导，为Akt调节以及可能为Ras诱导的肺癌发生建立了新的模式，其中Par-4是一种新的肿瘤抑制因子。
