Vasudevan Krishna Murthi, Burikhanov Ravshan, Goswami Anindya, Rangnekar Vivek M
Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky, Lexington, KY 40536, USA.
Cancer Res. 2007 Nov 1;67(21):10343-50. doi: 10.1158/0008-5472.CAN-07-1827.
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.
Ras是人类癌症中最常见的突变致癌基因之一。然而，Ras诱导细胞转化的机制尚未完全阐明。我们在此提供证据表明，致癌性Ras抑制10号染色体缺失的肿瘤抑制磷酸酶和张力蛋白同源物（PTEN）的表达，致癌性Ras的这一作用是由Raf-丝裂原活化蛋白激酶/细胞外信号调节激酶（ERK）激酶（MEK）-ERK途径通过上调c-Jun介导的。Jun(+/+)细胞通过致癌性Ras发生细胞转化，野生型PTEN的恢复而非PTEN的磷酸化缺陷突变体可诱导这些细胞凋亡。相反，在Jun(-/-)细胞中，致癌性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表达可预防Jun(-/-)细胞中对致癌性Ras的凋亡反应。这些发现表明，致癌性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，我们的发现确定了致癌途径和肿瘤抑制途径之间一个新的分子界面，该界面调节细胞转化和存活。
