Suppression of PTEN expression is essential for antiapoptosis and cellular transformation by oncogenic Ras.
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.
Vasudevan
Krishna Murthi
KM
Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky, Lexington, KY 40536, USA.
Burikhanov
Ravshan
R
Goswami
Anindya
A
Rangnekar
Vivek M
VM
D000818:Animals; D017209:Apoptosis; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic; D015536:Down-Regulation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D011905:Genes, ras; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D011401:Promoter Regions, Genetic; D016755:Proto-Oncogene Proteins c-jun / Q000502:physiology; D015398:Signal Transduction; D051996:Transcription Factor RelA / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000502:physiology; D048490:raf Kinases / Q000502:physiology; D018631:ras Proteins / Q000378:metabolism*
D016755:Proto-Oncogene Proteins c-jun; D051996:Transcription Factor RelA; D016159:Tumor Suppressor Protein p53; D019869:Phosphatidylinositol 3-Kinases; D048490:raf Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; C487757:Pten protein, mouse; D018631:ras Proteins