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

Author

Listed:
  • Daniel S. Peeper

    (The Dana-Farber Cancer Institute and the Harvard Medical School
    The Netherlands Cancer Institute)

  • Todd M. Upton

    (The Dana-Farber Cancer Institute and the Harvard Medical School)

  • Mohamed H. Ladha

    (The Dana-Farber Cancer Institute and the Harvard Medical School)

  • Elizabeth Neuman

    (The Dana-Farber Cancer Institute and the Harvard Medical School)

  • Juan Zalvide

    (The Dana-Farber Cancer Institute and the Harvard Medical School)

  • René Bernards

    (The Netherlands Cancer Institute)

  • James A. DeCaprio

    (The Dana-Farber Cancer Institute and the Harvard Medical School)

  • Mark E. Ewen

    (The Dana-Farber Cancer Institute and the Harvard Medical School)

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.

Suggested Citation

  • Daniel S. Peeper & Todd M. Upton & Mohamed H. Ladha & Elizabeth Neuman & Juan Zalvide & René Bernards & James A. DeCaprio & Mark E. Ewen, 1997. "Ras signalling linked to the cell-cycle machinery by the retinoblastoma protein," Nature, Nature, vol. 386(6621), pages 177-181, March.
    • Handle: RePEc:nat:nature:v:386:y:1997:i:6621:d:10.1038_386177a0
    DOI: 10.1038/386177a0
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