Regulation of the G2/M transition by p53

p53 protects mammals from neoplasia by inducing apoptosis, DNA repair and c ell cycle arrest in response to a variety of stresses. p53-dependent arrest of cells in the G1 phase of the cell cycle is an important component of th e cellular response to stress. Here we review recent evidence that implicat es p53 in controlling entry into mitosis when cells enter G2 with damaged D NA or when they are arrested in S phase due to depletion of the substrates required for DNA synthesis, Part of the mechanism by which p53 blocks cells at the G2 checkpoint involves inhibition of Cdc2, the cyclin-dependent kin ase required to enter mitosis. Cdc2 is inhibited simultaneously by three tr anscriptional targets of p53, Gadd45, p21, and 14-3-3 sigma. Binding of Cdc 2 to Cyclin B1 is required for its activity, and repression of the cyclin B I gene by p53 also contributes to blocking entry into mitosis, p53 also rep resses the cdc2 gene, to help ensure that cells do not escape the initial b lock. Genotoxic stress also activates p53-independent pathways that inhibit Cdc2 activity, activation of the protein kinases Chk1 and Chk2 by the prot ein kinases Atm and Atr, Chk1 and Chk2 inhibit Cdc2 by inactivating Cdc25, the phosphatase that normally activates Cdc2. Chk1, Chk2, Atm and Atr also contribute to the activation of p53 in response to genotoxic stress and the refore play multiple roles, p53 induces transcription of the reprimo, B99, and mcg10 genes, all of which contribute to the arrest of cells in G2, but the mechanisms of cell cycle arrest by these genes is not known. Repression of the topoisomer ase II gene by p53 helps to block entry into mitosis and strengthens the G2 arrest. In summary, multiple overlapping p53-dependent and p53-independent pathways regulate the G2/M transition in response to ge notoxic stress.