Oncogenic Stress Responses

Publisher Summary Cancer is a major cause of death in older mammals. Primary human and murine cells have proven essential in the analysis of oncogene-induced cell cycle arrest and in the identification of underlying molecular mechanisms. Expression of activated oncogenes triggers an irreversible growth arrest state with many similarities to the cellular senescence seen in late-passage primary fibroblasts. This premature senescence response is considered to be protective, since it removes cells with aberrant oncogene expression from the pool of growing cells. Both Rb and p53 are critical regulators of oncogene-induced senescence (OIS) downstream of Ink4a/Arf. The activities of Rb and p53 are significantly increased during OIS. Inactivation of either protein results in the reversal of the senescence phenotype in mouse embryo fibroblasts with subsequent re-entry into the cell cycle. This result suggests that Rb and p53 together play an important role in both initiating and maintaining senescence. Rb-and p53-independent cell cycle block, which seems to be more specific in human cells, likely acts as a second barrier to cellular immortalization, and may help explain the remarkable stability of the senescent cell cycle arrest in human cells. The phosphorylation of p38MAPK favors cancer cell proliferation under certain conditions; this may reflect the activation of signaling pathways that are engaged to restrain aberrant cell cycle progression in the presence of activated oncogenes. The ability of p38MAPK to target different components of the Ink4a/cyclin D/Rb and Arf/p53 pathways further supports its potential role in regulating OIS.