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

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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 35). 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.

References

  1. 1

    Newbold, R. F. & Overell, R. W. Nature 304, 648–651 (1983).

  2. 2

    Franza, B. R., Maruyama, K., Garrels, J. I. & Ruley, H. E. Cell 44, 409–418 ( 1986).

  3. 3

    Serrano, M., Lin, A. W., McCurrach, M. E., Beach, D. & Lowe, S. W. Cell 88, 593–602 (1997).

  4. 4

    Palmero, I., Pantoja, C. & Serrano, M. Nature 395, 125– 126 (1998).

  5. 5

    Sherr, C. J. Genes Dev. 12, 2984–2991 (1998).

  6. 6

    Kamijo, T. et al. Cell 91, 649–659 (1997).

  7. 7

    Tanaka, N. et al. Cell 77, 829–839 (1994).

  8. 8

    Weinberg, R. A. Cell 88, 573–575 ( 1997).

  9. 9

    Chin, L. et al. Genes Dev. 11, 2822–2834 (1997).

  10. 10

    Land, H., Parada, L. F. & Weinberg, R. A. Nature 304, 596– 602 (1983).

  11. 11

    Ruley, H. E. Nature 304, 602–606 ( 1983).

  12. 12

    Weinberg, R. A. Cancer Res. 49, 3713–3721 (1989).

  13. 13

    Peeper, D. S. et al. Nature 386, 177–181 (1997).

  14. 14

    Serrano, M. et al. Cell 85, 27–37 (1996).

  15. 15

    Noda, A., Ning, Y., Venable, S. F., Pereira-Smith, O. M. & Smith, J. R. Exp. Cell Res. 211, 90– 98 (1994).

  16. 16

    Hara, E. et al. Mol. Cell. Biol. 16, 859– 867 (1996).

  17. 17

    Herrera, R. E. et al. Mol. Cell. Biol. 16, 2402– 2407 (1996).

  18. 18

    Lu, X., Park, S. H., Thompson, T. C. & Lane, D. P. Cell 70, 153–161 ( 1992).

  19. 19

    Robanus-Maandag, E. et al. Genes Dev. 12, 1599– 1609 (1998).

  20. 20

    Bates, S. et al. Nature 395, 124–125 (1998).

  21. 21

    Carnero, A., Hudson, J. D., Price, C. M. & Beach, D. H. Nature Cell Biol. 2, 148–155 (2000).

  22. 22

    te Riele, H., Maandag, E. R. & Berns, A. Proc. Natl Acad. Sci. USA 89, 5128–5132 (1992).

  23. 23

    Dannenberg, J. H., van Rossum, A., Schuijff, L. & te Riele, H. Genes Dev. 14, 3051–3064 (2000).

  24. 24

    Morgenstern, J. P. & Land, H. Nucleic Acids Res. 18, 3587–3596 ( 1990).

  25. 25

    Kanda, T., Sullivan, K. F. & Wahl, G. M. Curr. Biol. 8, 377– 385 (1998).

  26. 26

    van den Heuvel, S. & Harlow, E. Science 262, 2050–2054 (1993).

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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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Correspondence to René Bernards.

Supplementary information

Figure S1 RasV12-expressing, Rb-family-deficient MEFs are unable to grow anchorage-independently. (PDF 125 kb)

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