Cell growth dilutes the cell cycle inhibitor Rb to trigger cell division

Cell size is fundamental to cell physiology. For example, cell size determines the spatial scale of organelles and intracellular transport and thereby affects biosynthesis. Although some genes that affect mammalian cell size have been identified, the molecular mechanisms through which cell growth drives cell division have remained elusive. We show that cell growth during the G(1) phase of the cell division cycle dilutes the cell cycle inhibitor Retinoblastoma protein (Rb) to trigger division in human cells. RB overexpression increased cell size and G(1) duration, whereas RB deletion decreased cell size and removed the inverse correlation between cell size at birth and the duration of the G(1) phase. Thus, Rb dilution through cell growth in G(1) provides one of the long-sought molecular mechanisms that promotes cell size homeostasis.