title: Similarity of the DNA-damage responsiveness and growth-suppressive properties of waf1/cip1 and gadd45.
abstract: The cellular responses to genotoxic stress are complex involving both p53-dependent and independent mechanisms. In the case of the GADD genes, many stresses eliciting growth arrest have been shown to induce these genes in a coordinate fashion regardless of p53 status, while the ionizing radiation response (IR) of GADD45 has been found to be strictly p53-dependent. In the current study, the response of GADD45 was compared 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 where one or both alleles of p53 had been deleted. After IR, all 3 genes showed very similar transcriptional responses as measured by rapid increases in mRNA. in a p53-dependent manner. Like GADD45, the WAF1/CIP1 induction by IR can be enhanced by the radiosensitizer iododeoxyuridine, and provides further evidence that DNA strand breaks can act as a signal for activation of the p53 pathway. In addition, caffeine, which blocks IR cell-cycle checkpoint activation, reduced IR induction for both genes. Unlike the case for IR, only WAF1/CIP1 showed a consistent similarity to GADD45 to DNA base-damaging agents, where appreciable induction occurred in cells regardless of p53 status. The similarity between WAF1/CIP1 and GADD45 also extended to their growth suppressive properties, and a combination of expression vectors for these genes suppressed growth appreciably more than either alone. A reasonable interpretation of these results is that growth suppression after DNA damage by either p53-dependent or independent pathways is mediated by the combined action of multiple downstream effecters including WAF1/CIP1 and GADD45.
authors.affiliation: JOHNS HOPKINS UNIV,JOHNS HOPKINS ONCOL CTR,BALTIMORE,MD 21287.
authors.forename: Q
authors.initials: Q
authors.lastname: Zhan
authors.forename: W
authors.initials: W
authors.lastname: Eldeiry
authors.forename: I
authors.initials: I
authors.lastname: Bae
authors.forename: I
authors.initials: I
authors.lastname: Alamo
authors.forename: M
authors.initials: M
authors.lastname: Kastan
authors.forename: B
authors.initials: B
authors.lastname: Vogelstein
authors.forename: A
authors.initials: A
authors.lastname: Fornace