NEGATIVE REGULATION OF WEE1 EXPRESSION AND CDC2 PHOSPHORYLATION DURING P53-MEDIATED GROWTH ARREST AND APOPTOSIS

The G(2) cell cycle checkpoint protects cells from potentially lethal mitotic entry after DNA damage. This checkpoint involves inhibitory ph osphorylation of Cdc2 at the tyrosine-15 (Y15) position, mediated in p art by the Wee1 protein kinase, Recent evidence suggests that p53 may accelerate mitotic entry after DNA damage and that the override of the G(2) checkpoint may play a role in the induction of apoptosis by p53. To determine the biochemical mechanism by which p53 inactivates the G (2), checkpoint, the effects of p53 activation on Wee1 expression, Cdc 2-Y15 phosphorylation, and cyclin B1-associated Cdc2 kinase activity w ere examined. Under conditions of either growth arrest or apoptosis, p 53 activation resulted in the down-regulation of Wee1 expression and d ephosphorylation of Cdc2, A parallel increase in cyclin B1/Cdc2 kinase activity was observed during p53-mediated apoptosis, Negative regulat ion of the Wee1 expression and Cdc2 phosphorylation by p53 was also ev ident in thymus tissue from p53(+/+) mice but not from p53(-/-) mice. Inactivation of the G(2) checkpoint may contribute to the tumor suppre ssor activity of p53.