Suppression of PTEN expression is essential for antiapoptosis and cellular transformation by oncogenic ras
Suppression of PTEN expression is essential for antiapoptosis and cellular transformation by oncogenic ras
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DOI：
10.1158/0008-5472.can-07-1827
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发表时间：
2007-11-01
期刊：
影响因子：
11.2
通讯作者：
Rangnekar, Vivek M.
中科院分区：
文献类型：
--
作者：
Vasudevan, Krishna Murthi;Burikhanov, Ravshan;Rangnekar, Vivek M.
Ras是一系列人类癌症中最常见的突变癌基因之一。然而，Ras诱导细胞转化的机制尚未完全阐明。我们在此提供的证据表明，致癌Ras抑制肿瘤抑制性磷酸酶和张力蛋白同源物10号染色体缺失（PTEN）的表达，并且致癌Ras的这种作用是由Raf-mitogen-activated protein kinase/extracellular signal-regulated kinase（ERK）kinase（MEK）-ERK途径通过上调c-Jun. Jun（+）/（+）介导的。细胞通过致癌Ras进行细胞转化，野生型PTEN的恢复而不是磷酸缺陷型突变体的恢复诱导这些细胞的凋亡。相反，在Jun（-）/（-）细胞中，致癌Ras既不抑制PTEN也不引起转化，而是诱导PTEN依赖性凋亡。通过抑制PTEN的表达可以防止Jun（-）/（-）细胞对致癌Ras的凋亡反应。这些结果表明，致癌Ras通过Raf-MEK-ERK-c-Jun途径抑制凋亡基因PTEN，从而诱导抗凋亡和细胞转化。总之，我们的研究结果确定了一个新的致癌和肿瘤抑制途径之间的分子界面，调节细胞转化和生存。
Ras is one of the most commonly mutated oncogenes in the array of human cancers. The mechanism by which Ras induces cellular transformation is, however, not fully elucidated. We present here evidence that oncogenic Ras suppresses the expression of the tumor suppressor phosphatase and tensin homologue deleted from chromosome 10 (PTEN), and this action of oncogenic Ras is mediated by the Raf-mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase (MEK)-ERK pathway via up-regulation of c-Jun. Jun(+)/(+). cells undergo cellular transformation by oncogenic Ras, and restoration of wild-type PTEN, but not a phosphate-defective mutant of PTEN, induces apoptosis in these cells. Conversely, in Jun(-)/(-) cells, oncogenic Ras neither suppresses PTEN nor causes transformation, but rather it induces PTEN-dependent apoptosis. An apoptotic response to oncogenic Ras in Jun(-)/(-) cells can be prevented by suppressing PTEN expression. These findings imply that oncogenic Ras suppresses the apoptotic gene PTEN via the Raf-MEK-ERK-c-Jun pathway to induce antiapoptosis and cellular transformation. Together, our findings identify a novel molecular interface between the oncogenic and tumor suppressor pathways that regulates cellular transformation and survival.