Activation of p53/p21(waf1) pathway is associated with senescence during v-Ha-ras transformation of immortal C2C12 myoblasts

It has recently been shown that tumor cells can retain the ability to undergo senescence, while the capacity of by-passing senescence has been associated with tumor progression. In this report, we showed that v-Ha-ras-mediated transformation of already immortal C2C12 myoblasts can be associated with senescence, in a low amount during in vitro passages and, to a higher extent, affer cellular stress (cell culture alkalinkation), or DNA damage (doxorubicin treatment). The capacity to undergo replicative senescence is associated with a strong increase of wtp53 transcriptional activity and p21(WAF1) up-regulation. These biochemical activities are down-modulated in the cells that evade the massive replicative senescence after stressing stimuli. Altogether, these findings show that active ras can cause senescence during the transformation of already immortal cells in association with p53/p21(WAF1) pathway activation and support the hypothesis that p53/p21(WAF1) functional activity is important in maintaining the integrity of the senescence pathway during cellular transformation.