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

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 (GO) and to pass through the GI/S transition of the cell cycle. 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 GI exit, functionally links Ras to passage through the Gl 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 Gl arrest. When Rb was disrupted either genetically or biochemically, cells failed to arrest in Gl following Ras inactivation. In contrast, inactivation of Ras in quiescent cells prevented growth-factor induction of both immediate-early gene transcription and exit from GO in an Rb-independent manner. These data suggest that Rb is an essential GI-specific mediator that links Ras-dependent mitogenic signalling to cell-cycle regulation.