Similarity of the DNA-damage responsiveness and growth-suppressive properties of waf1/cip1 and gadd45.


Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Zhan, Q; Eldeiry, W; Bae, I; Alamo, I; Kastan, M; Vogelstein, B; Fornace, A

Published Date

  • May 1995

Published In

Volume / Issue

  • 6 / 5

Start / End Page

  • 937 - 946

PubMed ID

  • 21556622

Pubmed Central ID

  • 21556622

International Standard Serial Number (ISSN)

  • 1019-6439

Digital Object Identifier (DOI)

  • 10.3892/ijo.6.5.937


  • eng

Conference Location

  • Greece