SIMILARITY OF THE DNA-DAMAGE RESPONSIVENESS AND GROWTH-SUPPRESSIVE PROPERTIES OF WAF1 CIP1 AND GADD45/

The cellular responses to genotoxic stress are complex involving both p53-dependent and independent mechanisms. In the case of the GADD gene s, many stresses eliciting growth arrest have been shown to induce the se genes in a coordinate fashion regardless of p53 status, while the i onizing radiation response (IR) of GADD45 has been found to be strictl y p53-dependent. In the current study, the response of GADD45 was comp ared to the p53-regulated genes WAF1/CIP1 and MDM2 in a panel of human lines with known p53 status and also in mouse embryo fibroblasts wher e one or both alleles of p53 had been deleted. After IR, all 3 genes s howed very similar transcriptional responses as measured by rapid incr eases in mRNA. in a p53-dependent manner. Like GADD45, the WAF1/CIP1 i nduction by IR can be enhanced by the radiosensitizer iododeoxyuridine , and provides further evidence that DNA strand breaks can act as a si gnal for activation of the p53 pathway. In addition, caffeine, which b locks IR cell-cycle checkpoint activation, reduced IR induction for bo th genes. Unlike the case for IR, only WAF1/CIP1 showed a consistent s imilarity to GADD45 to DNA base-damaging agents, where appreciable ind uction occurred in cells regardless of p53 status. The similarity betw een WAF1/CIP1 and GADD45 also extended to their growth suppressive pro perties, and a combination of expression vectors for these genes suppr essed growth appreciably more than either alone. A reasonable interpre tation of these results is that growth suppression after DNA damage by either p53-dependent or independent pathways is mediated by the combi ned action of multiple downstream effecters including WAF1/CIP1 and GA DD45.