Inhibitory effect of Bcl-2 on p53-mediated transactivation following genotoxic stress

In the cellular response to genotoxic stress, cell cycle checkpoint and apo ptosis are considered to be two of the major biological events in maintaini ng genomic stability. The tumor suppressor p53 has been shown to play criti cal roles in these stress-induced cellular responses at least in part throu gh the activation of its down-stream genes, such as p21(ClPl/WAFl), GADD45 and BAX. In addition, p53 has been found to down-regulate the expression of BCL-2, which is able to block apoptosis induced by both p53-dependent and independent signaling events. In this report,,ve have found that increased expression of Bcl-2 protein in the human Burkitt's lymphoma WMN cell line s uppressed apoptosis induced by different DNA-damaging agents. The induction of p53-regulated genes including GADDIS, p21(ClPl/WAFl) and BAX by genotox ic stress was substantially reduced in cells expressing high levels of Bcl- 2 protein. Furthermore, Bcl-2 protein was shown to specifically suppress th e p53-mediated transactivation of p21(ClPl/WAFl) and PG13-CAT, which is a t ypical p53-binding-site reporter construct, Similarly, the inhibitory effec t of Bcl-2 protein was seen in a GADD45 promoter reporter construct after t reatment with methylmethane sulfonate or UV-radiation, These results indica te that in addition to its apoptosis-suppressing activity, Bcl-2 protein is able to inhibit transactivation of p53-regulated genes, which function in multiple important cellular responses to genotoxic stress, including the co ntrol of cell cycle checkpoints, cell growth suppression and DNA repair.