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

Nature Cell Biology volume 3, pages 198–203 (2001)Cite this article

Abstract

Resistance of primary cells to transformation by oncogenic Ras has been attributed to the induction of replicative growth arrest1,2,3. 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 Ras3,6,7. 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.

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Figure 1: Primary Rb−/−/p107−/− fibroblasts fail to undergo RasV12-induced premature senescence.
Figure 2: Continued proliferation of parental and RasV12-expressing primary Rb−/−/p107−/− fibroblasts.
Figure 3: Signalling from RasV12 to the p16INK4a and p19ARF/p53 pathways is intact in primary Rb−/−/p107−/− fibroblasts.
Figure 4: Rb−/−/p107−/− MEFs are under no selective pressure to lose expression of RasV12 or mutate p53 during prolonged culture.

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Acknowledgements

We thank M. Dekker-Vlaar, K. van't Wout and the animal facility (Netherlands Cancer Institute) for help with generating chimaeric mice, isolating and preparing mouse embryos and tumour-induction experiments, J. Jonkers for providing p53−/− MEFs, R. A. DePinho, P. Krimpenfort and J. Jacobs for INK4a−/− MEFs, C. J. Sherr for ARF−/− MEFs, J-W. Voncken, E. Wientjes and E. Verhoeven for Ras and Myc retroviral vectors, G. Nolan for retroviral packaging cells, our colleagues for helpful discussions, and A. Berns for critically reading the manuscript. D.S.P., J-H.D. and S.D. were supported by grants from the Dutch Cancer Society (KWF).

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Author notes

  1. Daniel S. Peeper and Jan-Hermen Dannenberg: These authors contributed equally to this work

Authors and Affiliations

  1. Division of Molecular Carcinogenesis and Center for Biomedical Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, 1066 CX, The Netherlands

    Daniel S. Peeper, Jan-Hermen Dannenberg, Sirith Douma, Hein te Riele & René Bernards

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  1. Daniel S. Peeper
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Correspondence to René Bernards.

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Peeper, D., Dannenberg, JH., Douma, S. et al. Escape from premature senescence is not sufficient for oncogenic transformation by Ras. Nat Cell Biol 3, 198–203 (2001). https://doi.org/10.1038/35055110

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