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A DNA Damage Signal Is Required for p53 to Activate gadd45¹

The Institute for Biomolecular Structure and Function and Department of Biological Sciences, Hunter College and Graduate School, City University of New York, New York, New York 10021 [G. X., A. C., M. O., J. B.]; National Cancer Center Research Institute, Tokyo 104, Japan [Y. T.]; and Department of Molecular Genetics, The Public Health Research Institute, New York, New York 10016 [S. T., F. R. K.]

We provide direct evidence that overexpression of p53 is not sufficient for robust p53-dependent activation of the endogenous gadd45 gene. When p53 was induced in TR9-7 cells in the absence of DNA damage, waf1/p21 and mdm2 mRNA levels were increased, but a change in gadd45 mRNA was barely detectable. Activation of the gadd45 gene was observed when camptothecin was added to cells containing p53 in the absence of a further increase in the p53 level. Phosphorylation of p53 at serine 15 and acetylation at lysine 382 were detected after drug treatment. It has been suggested that p53 posttranslational modification is critical during activation. However, inhibition of these modifications by wortmannin was not sufficient to block the transactivation of gadd45. Interestingly, after camptothecin treatment, increased DNase I sensitivity was detected at the gadd45 promoter, suggesting that an undetermined DNA damage signal is involved in inducing chromatin remodeling at the gadd45 promoter while cooperating with p53 to activate gadd45 transcription.

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