As a general rule, mammalian cells will multiply only if they are stimulated to do so by extracellular signals, called mitogens, produced by other cells. If deprived of such signals, the cell cycle arrests in G 1 ; if the cell is deprived of mitogens for long enough, it will withdraw from the cell cycle and enter a nonproliferating state, in which the cell can remain for days or weeks, months, or even for the lifetime of the organism, as we discuss shortly.

Escape from cell-cycle arrest—or from certain nonproliferating states—requires the accumulation of cyclins. Mitogens act by switching on cell signaling pathways that stimulate the synthesis of G 1 cyclins, G 1 /S cyclins, and other proteins involved in DNA synthesis and chromosome duplication. The buildup of these cyclins triggers a wave of G 1 /S-Cdk activity, which ultimately relieves the negative controls that otherwise block progression from G 1 to S phase.

One crucial negative control is provided by the Retinoblastoma (Rb) protein. Rb was initially identified from studies of a rare childhood eye tumor called retinoblastoma, in which the Rb protein is missing or defective. Rb is abundant in the nuclei of all vertebrate cells, where it binds to particular transcription regulators and prevents them from turning on the genes required for cell proliferation.

Mitogens release the Rb brake by triggering the activation of G 1 -Cdks and G 1 /S-Cdks. These complexes phosphorylate the Rb protein, altering its conformation so that it releases its bound transcription regulators, which are then free to activate the genes required for entry into S phase.