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Ras signalling linked to the cell-cycle machinery by the retinoblastoma protein

An Erratum to this article was published on 03 April 1997

Abstract

The Ras proto-oncogene is a central component of mitogenic signal-transduction pathways, and is essential for cells both to leave a quiescent state (G0) and to pass through the G1/S transition of the cell cycle1–6. The mechanism by which Ras signalling regulates cell-cycle progression is unclear, however. Here we report that the retinoblastoma tumour-suppressor protein (Rb), a regulator of G1 exit7, functionally links Ras to passage through the G1 phase. Inactivation of Ras in cycling cells caused a decline in cyclin D1 protein levels, accumulation of the hypophosphorylated, growth-suppressive form of Rb, and G1 arrest. When Rb was disrupted either genetically or biochemically, cells failed to arrest in G1 following Ras inactivation. In contrast, inactivation of Ras in quiescent cells prevented growth-factor induction of both immediate-early gene transcription and exit from G0 in an Rb-independent manner. These data suggest that Rb is an essential G1-specific mediator that links Ras-dependent mitogenic signalling to cell-cycle regulation.

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References

  1. 1

    Pardee, A. B. Gl events and regulation of cell proliferation. Science 246, 603–608 (1989).

    ADS  CAS  Article  Google Scholar 

  2. 2

    Pronk. G. J. & Bos, J. L. The role of p21ras in receptor tyrosine kinase signalling. Biochim. Biophys.Acta 1198, 131–147 (1994).

    PubMed  Google Scholar 

  3. 3

    Marshall, C. J. Specificity of receptor tyrosine kinase signalling: transient versus sustained extracellular signal-regulated kinase activation. Cell 8O, 179–185 (1995).

    Article  Google Scholar 

  4. 4

    Dobrowolski, S., Harter, M. & Stacey, D. W. Cellular ras activity is required for passage through multiple points of the G0/G1 phase in Balb/c 3T3 cells. Mol. Cell. Biol. 14, 5441–5449 (1994).

    CAS  Article  Google Scholar 

  5. 5

    Feramisco, J. R., Gross, M., Kamata, T., Rosenberg, M. & Sweet, R. W. Microinjection of the oncogene form of the human H-ras (T-24) protein results in rapid proliferation of quiescent cells. Cell 38, 109–117 (1984).

    CAS  Article  Google Scholar 

  6. 6

    Stacey, D. W. & Kung, H. F. Transformation of NIH 3T3 cells by microinjection of Ha-ras protein. Nature 310, 508–511 (1984).

    ADS  CAS  Article  Google Scholar 

  7. 7

    Weinberg, R. A. The retinoblastoma protein and cell cycle control. Cell 81, 323–330 (1995).

    CAS  Article  Google Scholar 

  8. 8

    Mulcahy, L. S., Smith, M. R. & Stacey, D. W. Requirement for ras proto-oncogene function during serum-stimulated growth of NIH 3T3 cells. Nature 313, 241–243 (1985).

    ADS  CAS  Article  Google Scholar 

  9. 9

    Lukas, J. et al. Retinoblastoma-protein-dependent cell-cycle inhibition by the tumour suppressor p16. Nature 375, 503–506 (1995).

    ADS  CAS  Article  Google Scholar 

  10. 10

    Koh, J., Enders, G. H., Dynlacht, B. D. & Harlow, E. Tumour-derived p16 alleles encoding proteins defective in cell-cycle inhibition. Nature 375, 506–510 (1995).

    ADS  CAS  Article  Google Scholar 

  11. 11

    Feig, L. A. & Cooper, G. M. Inhibition of NIH 3T3 cell proliferation by a mutant ras protein with preferential affinity for GDP. Mol. Cell. Biol. 8, 3235–3243 (1988).

    CAS  Article  Google Scholar 

  12. 12

    Cai, H., Szeberenyi, J. & Cooper, G. M. Effect of a dominant inhibitory Ha-ras mutation on mitogenic signal transduction. Mol. Cell. Biol. 10, 5314–5323 (1990).

    CAS  Article  Google Scholar 

  13. 13

    Medema, R. H., Herrera, R. E., Lam, F. & Weinberg, R. A. Growth suppression by p16ink4 requires functional retinoblastoma protein. Proc. Natl Acad. Sci. USA 92, 6289–6293 (1995).

    ADS  CAS  Article  Google Scholar 

  14. 14

    Guan, K.-L. et al. Growth suppression by p18, a p16INK4/MTSl- and p14INK4B/MTS2-related CDK6 inhibitor, correlates with wild-type pRb function. Genes Dev. 8, 2939–2952 (1994).

    CAS  Article  Google Scholar 

  15. 15

    Sherr, C. J. & Roberts, J. M. Inhibitors of mammalian Gl cyclin-dependent kinases. Genes Dev. 9, 1149–1163 (1995).

    CAS  Article  Google Scholar 

  16. 16

    Herrera, R. E. et al. Altered cell cycle kinetics, gene expression, and Gl restriction point regulation in Rb-deficient fibroblasts. Mol. Cell. Biol 16, 2402–2407 (1996).

    CAS  Article  Google Scholar 

  17. 17

    Lukas, J., Bartkova, J., Rohde, M., Strauss, M. & Bartek, J. Cyclin D1 is dispensable for G1 control in retinoblastoma gene-deficient cells independently of cdk4 activity. Mol. Cell. Biol. 15, 2600–2611 (1995).

    CAS  Article  Google Scholar 

  18. 18

    Sherr, C. J. Mammalian G1 cyclins. Cell 73, 1059–1065 (1993).

    CAS  Article  Google Scholar 

  19. 19

    Lavoie, J. N., L'Allemain, G., Brunet, A., Muller, R. & Pouysségur, J. Cyclin D1 expression is regulated positively by the p42/p44MAPK and negatively by the p38/HOGMAPK pathway. J. Biol. Chem. 271, 20608–20616 (1966).

    Article  Google Scholar 

  20. 20

    Albanese, C. et al. Transforming p21ras mutants and c-Ets-2 activate the cyclin D1 promoter through distinguishable regions. J. Biol. Chem. 270, 23589–23597 (1995).

    CAS  Article  Google Scholar 

  21. 21

    Filmus, J. et al. Induction of cyclin D1 overexpression by activated ras. Oncogene 9, 3627–3633 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22

    Liu, J.-J. et al. Ras transformation results in an elevated level of cyclin D1 and acceleration of G1 progression in NIH 3T3 cells. Mol. Cell. Biol. 15, 3654–3663 (1995).

    CAS  Article  Google Scholar 

  23. 23

    Winston, J. T., Coats, S. R., Wang, Y.-Z. & Pledger, W. J. Regulation of the cell cycle machinery by oncogenic Ras. Oncogene 12, 127–134 (1996).

    CAS  PubMed  Google Scholar 

  24. 24

    Serrano, M., Gomez-Lohoz, E., DePinho, R. A., Beach, D. & Bar-Sagi, D. Inhibition of Ras-induced proliferation and transformation by p16INK4. Science 267, 249–252 (1995).

    ADS  CAS  Article  Google Scholar 

  25. 25

    Hatakeyama, M., Brill, J. A., Fink, G. R. & Weinberg, R. A. Collaboration of G1 cyclins in the functional inactivation of the retinoblastoma protein. Genes Dev. 8, 1759–1771 (1994).

    CAS  Article  Google Scholar 

  26. 26

    Zalvide, J. & DeCaprio, J. A. Role of pRb-related proteins in simian virus 40 large-T-antigen-mediated transformation. Mol. Cell. Biol 15, 5800–5810 (1995).

    CAS  Article  Google Scholar 

  27. 27

    Schneider, J. W., Gu, W., Zhu, L., Mahdavi, V. & Nadal-Ginard, B. Reversal of terminal differentiation mediated by p107 in Rb-/- muscle cells. Science 264, 1467–1471 (1994).

    ADS  CAS  Article  Google Scholar 

  28. 28

    Ewen, M. E. et al. Functional interactions of the retinoblastoma protein with mammalian D-type cyclins. Cell 73, 487–497 (1993).

    CAS  Article  Google Scholar 

  29. 29

    Serrano, M., Hannon, G. J. & Beach, D. A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/cdk4. Nature 366, 704–707 (1993).

    ADS  CAS  Article  Google Scholar 

  30. 30

    Ewen, M. E., Oliver, C. J., Sluss, H. K., Miller, S. J. & Peeper, D. S. p53-dependent repression of CDK4 translation in TGF-β-induced cell-cycle arrest. Genes Dev. 9, 204–217 (1995).

    CAS  Article  Google Scholar 

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Peeper, D., Upton, T., Ladha, M. et al. Ras signalling linked to the cell-cycle machinery by the retinoblastoma protein. Nature 386, 177–181 (1997). https://doi.org/10.1038/386177a0

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