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Constitutive Activation of Cyclin B1-associated cdc2 Kinase Overrides p53-mediated G₂-M Arrest¹

Bioscience Research Division, Korea Research Institute of Bioscience & Biotechnology, Yusung, Taejeon 305-333, Korea

Recent studies have suggested that p53 regulates the G₂ checkpoint in the cell cycle and that this function is required for the maintenance of genomic integrity. In this study, we investigated a regulatory role of p53 specifically in G₂-M transition. Human bladder carcinoma cells lacking functional p53 were synchronized at G₁-S, which is preceded by p53-mediated G₁ arrest. p53 expression in the synchronized cells was induced by infection with a recombinant adenovirus that encodes p53. After release from the G₁-S arrest, the cells progressed to S-phase and G₂ but failed to enter mitosis. Biochemical analysis showed that p53 inhibits cell cycle-dependent expression of cdc2 and cyclin B1 and consequently inhibits cdc2 kinase. The role of cyclin B1-associated cdc2 kinase in p53-mediated G₂-M arrest was further investigated by expression of both cyclin B1 and cdc2AF, in which inhibitory phosphorylation sites were substituted. The cells expressing both cdc2AF and cyclin B1 showed a constitutive activation of cdc2 kinase during cell cycle progression and passed through G₂-M regardless of p53 expression. Therefore, inactivation of cdc2 kinase through cdc2 and cyclin B1 repression is an essential step in p53-mediated G₂-M arrest.

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