p53 displacement from centrosomes and p53-mediated G(1) arrest following transient inhibition of the mitotic spindle

Growing evidence indicates a central role for p53 in mediating cell cycle a rrest in response to mitotic spindle defects so as to prevent rereplication in cells in which the mitotic division has failed. Here we report that a t ransient inhibition of spindle assembly induced by nocodazole, a tubulin-de polymerizing drug, triggers a stable activation of p53, which can transduce a cell cycle inhibitory signal even when the spindle-damaging agent is rem oved and the spindle is allowed to reassemble. Cells transiently exposed to nocodazole continue to express high levels of p53 and p21 in the cell cycl e that follows the transient exposure to nocodazole and become arrested in G,, regardless of whether they carry a diploid or polyploid genome after mi totic exit. We also show that p53 normally associates with centrosomes in m itotic cells, whereas nocodazole disrupts this association. Together these results suggest that the induction of spindle damage, albeit transient, int erferes with the subcellular localization of p53 at specific mitotic locati ons, which in turn dictates cell cycle arrest in the offspring of such defe ctive mitoses.