The downregulation of the pro-apoptotic protein Par-4 is critical for Ras-induced survival and tumor progression
The downregulation of the pro-apoptotic protein Par-4 is critical for Ras-induced survival and tumor progression
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DOI：
10.1093/emboj/18.22.6362
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发表时间：
1999-11-15
期刊：
影响因子：
11.4
通讯作者：
Moscat, J
中科院分区：
文献类型：
--
作者：
Barradas, M;Monjas, A;Moscat, J
细胞凋亡的抑制是癌基因转化的重要特征。Par-4基因产物最近已被证明在经历凋亡性细胞死亡的细胞中被上调，并且其异位表达被证明在凋亡中是关键的。我们证明致癌Pas的表达通过MEK依赖性途径促进Par-4蛋白和mRNA水平的有效降低。此外，MEK、Raf-I或ζ蛋白激酶C但不表达磷脂酰肌醇3-激酶（PI 3-激酶）的永久活性突变体的表达足以降低Par-4水平。这些影响是独立的p53，p16和p19，并检测到不仅在成纤维细胞原代培养，但也在NIH 3 T3和HeLa细胞，表明它们不是次要的Pas细胞周期调控的行动。重要的是，Ras转化细胞中Par-4水平恢复到正常水平使这些细胞在PI 3-激酶被抑制的条件下对肿瘤坏死因子-α的促凋亡作用敏感，并且还严重损害软琼脂中的集落形成和裸鼠中的肿瘤发展，以及增加这些肿瘤对喜树碱的敏感性，这表明致癌性Pas下调Par-4是肿瘤进展中的关键事件。
Inhibition of apoptosis is an important characteristic of oncogenic transformation. The Par-4 gene product has recently been shown to be upregulated in cells undergoing apoptotic cell death, and its ectopic expression was shown to be critical in apoptosis, We demonstrate that expression of oncogenic Pas promotes a potent reduction of Par-4 protein and mRNA levels through a MEK-dependent pathway. In addition, the expression of permanently active mutants of MEK, Raf-l or zeta protein kinase C but not of phosphatidylinositol 3-kinase (PI 3-kinase) is sufficient to decrease Par-4 levels. These effects are independent of p53, p16 and p19, and were detected not only in fibroblast primary cultures but also in NIH 3T3 and HeLa cells, indicating that they are not secondary to Pas actions on cell cycle regulation. Importantly, restoration of Par-4 levels to normal in Ras-transformed cells makes these cells sensitive to the pro-apoptotic actions of tumor necrosis factor-alpha under conditions in which PI 3-kinase is inhibited and also severely impairs colony formation in soft agar and tumor development in nude mice, as well as increases the sensitivity of these tumors to camptothecin, This indicates that the downregulation of Par-4 by oncogenic Pas is a critical event in tumor progression.