RAS SIGNALING LINKED TO THE CELL-CYCLE MACHINERY BY THE RETINOBLASTOMA PROTEIN

The Ras proto-oncogene is a central component of mitogenic signal-tran sduction pathways, and is essential for cells both to leave a quiescen t state (G0) and to pass through the G1/S transition of the cell cycle (1-6). The mechanism by which Ras signalling regulates cell-cycle prog ression is unclear, however. Here we report that the retinoblastoma tu mour-suppressor protein (Rb), a regulator of G1 exit(7), functionally Links pas to passage through the G1 phase. Inactivation of Ras in cycl ing cells-caused a decline in cyclin D1 protein levels, accumulation o f the hypophosphorylated, growth-suppressive form of Rb, and G1 arrest . When Rb was disrupted either genetically or biochemically, cells fai led to arrest in G1 following Ras inactivation. In contrast, inactivat ion of Ras in quiescent cells prevented growth-factor induction of bot h immediate-early gene transcription and exit from G0 in an Rb-indepen dent manner. These data suggest that Rb is an essential G1-specific me diator that links Ras-dependent mitogenic signalling to cell-cycle reg ulation.