The ability of~ 53 to activate transcription from specific sequences suggests that genes induced by p53 may mediate its biological role as a tumor suppressor. Using a subtractive hybridization approach, we identified a gene, named WAR, whose induction was associated with wild-type but not mutant~ 53 gene expression in a human brain tumor cell line. The WAR gene was localized to chromosome 6~ 21.2, and its sequence, structure, and activation by~ 53 was conserved in rodents. Introduction of WAR cDNA suppressed the growth of human brain, lung, and colon tumor cells in culture. Using a yeast enhancer trap, a p53-binding site was identified 2.4 kb upstream of WAFf coding sequences. The WAFf promoter, including this p53-binding site, conferred p53-dependent inducibility upon a heterologous reporter gene. These studies define a gene whose expression is directly induced by~ 53 and that could be an important mediator of p53-dependent tumor growth suppression.