Ras Proteins Induce Senescence by Altering the Intracellular Levels of Reactive Oxygen Species

摘要: Human diploid fibroblasts eventually lose the capacity to replicate in culture and enter a viable but nonproliferative state of senescence. Recently, it has been demonstrated that retroviral-mediated gene transfer into primary an activated ras (V12ras) rapidly accelerates development senescent phenotype. Using this vitro system, we have sought define mediators Ras-induced We demonstrate expression V12Ras results increase intracellular particular, mitochondrial reactive oxygen species. The ability induce growth arrest senescence is shown be partially inhibited by coexpression rac1 gene. A more dramatic rescue V12Ras-expressing cells when are placed low environment, condition which species production inhibited. In addition, 1% Ras unable trigger level cyclin-dependent kinase inhibitor p21 or activate program. Under normoxic (20% O2) conditions, phenotype unaffected scavengers superoxide rescued hydrogen peroxide. These suggest normal cells, proteins regulate oxidant rise H2O2 represents critical signal mediating replicative