Activation of p53/p21waf1 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 bypassing 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 senesence, 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 wt-p53 transcriptional activity and p21WAF1 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 associaton with p53/p21WAF1 pathway activation and support the hypothesis that p53/p21WAF1 functional activity is important in maintaining the integrity of the senescence pathway during cellular transformation.
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Molecular Oncogenesis Laboratory, C.R.S., Regina Elena Cancer Institute, via delle Messi d'Oro 156, 00158 Rome, Italy. dorazi@crs.ifo.it
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D000818:Animals; D002455:Cell Division / Q000235:genetics; D002461:Cell Line, Transformed; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism; D016922:Cellular Senescence / Q000235:genetics*; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology*; D016158:Genes, p53; D011905:Genes, ras; D051379:Mice; D009132:Muscles / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics; D013312:Stress, Physiological / Q000235:genetics / Q000473:pathology; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D015854:Up-Regulation
C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D016159:Tumor Suppressor Protein p53