p27Kip1 alters the response of cells to mitogen and is part of a cell-intrinsic timer that arrests the cell cycle and initiates differentiation.

In many vertebrate cell lineages, precursor cells divide a limited number of times before they arrest and terminally differentiate into postmitotic cells. It is not known what causes them to stop dividing. We have been studying the 'stopping' mechanism in the proliferating precursor cells that give rise to oligodendrocytes, the cells that make myelin in the central nervous system. We showed previously that the cyclin-dependent kinase inhibitor p27Kip1 (p27) progressively accumulates in cultured precursor cells as they proliferate and that the time course of the increase is consistent with the possibility that p27 accumulation is part of a cell-intrinsic timer that arrests the cell cycle and initiates differentiation at the appropriate time. We now provide direct evidence that p27 is part of the intrinsic timer. We show that although p27-/- precursor cells stop dividing and differentiate almost as fast as wild-type cells when deprived of mitogen, when stimulated by saturating amounts of mitogen they have a normal cell-cycle time but tend to go through one or two more divisions than wild-type cells before they stop and differentiate. Cells that are p27+/- behave in an intermediate way, going through at most one extra division, indicating that the levels of p27 matter in the way the timer works. We also show that p27-/- precursor cells are more sensitive than wild-type cells to the mitogenic effect of platelet-derived growth factor. These findings demonstrate that p27 is part of the normal timer that determines when oligodendrocyte precursor cells stop dividing and differentiate, at least in vitro. It seems likely that p27 plays a similar role in many other cell lineages, which could explain the phenotypes of the p27-/- and p27+/- mice.