Escape from premature senescence is not sufficient for oncogenic transformation by Ras

• Published in: Nature cell biology Vol. 3; no. 2; pp. 198 - 203
• Main Authors: Bernards, René, Peeper, Daniel S, Dannenberg, Jan-Hermen, Douma, Sirith, Riele, Hein te
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.02.2001
• Subjects: Aging; Animals; Blotting, Western; Cell Division; Cell Transformation, Neoplastic; Cells, Cultured; Cellular Senescence - genetics; Cellular Senescence - physiology; Cloning; Fibroblasts; G proteins; Gene Expression Regulation; Genes; Genes, ras; Genes, Retinoblastoma; Genetic aspects; Growth Inhibitors - genetics; Growth Inhibitors - metabolism; Humans; Mice; Mutation; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; p107 protein; Physiological aspects; Proteins; Proteins - genetics; Proteins - metabolism; RB gene; Retinoblastoma; Retinoblastoma-Like Protein p107; Retroviridae - genetics; Retroviridae - metabolism; Senescence; Signal Transduction; Tumor suppressor genes; Tumor Suppressor Protein p14ARF; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Netherlands
• ISSN: 1465-7392; 1476-4679; 1476-4679
• DOI: 10.1038/35055110

Resistance of primary cells to transformation by oncogenic Ras has been attributed to the induction of replicative growth arrest. This irreversible 'fail-safe mechanism' resembles senescence and requires induction by Ras of p19ARF and p53 (refs 3-5). Mutation of either p19ARF or p53 alleviates Ras-induced senescence and facilitates oncogenic transformation by Ras. Here we report that, whereas Rb and p107 are each dispensable for Ras-induced replicative arrest, simultaneous ablation of both genes disrupts Ras-induced senescence and results in unrestrained proliferation. This occurs despite activation by Ras of the p19ARF /p53 pathway, identifying pRb and p107 as essential mediators of Ras-induced antiproliferative p19ARF/p53 signalling. Unexpectedly, in contrast to p19ARF or p53 deficiency, loss of Rb/p107 function does not result in oncogenic transformation by Ras, as Ras-expressing Rb−/−/p107−/− fibroblasts fail to grow anchorage-independently in vitro and are not tumorigenic in vivo. These results demonstrate that in the absence of both Rb and p107 cells are resistant to p19ARF/p53-dependent protection against Ras-induced proliferation, and uncouple escape from Ras-induced premature senescence from oncogenic transformation.