The p53 tumor suppressor protein is the most intensively studied member of a family of three related transcription factors in mammals. The protein and its homologues, p63 and p73, share a common domain structure, with particularly high sequence homology in the DNA-binding domain. Most of the DNA-contacting residues in p53 are conserved in p63 and p73, and all three proteins have been shown to bind to similar DNA sequences. However, the phenotypes of mutant mice carrying inactivated alleles of p53, p63 or p73 indicate that these genes carry out highly distinct functions: p63- and p73-null mice exhibit pleiotropic defects in embryonic development, whereas p53 deficiency results in tumorigenesis in early adult life. The basis for this specificity of action is unclear. We are conducting a series of experiments to determine the spectrum of genes regulated by each of the p53 family members. We have generated cell lines carrying inducible constructs for expression of each of these transcription factors, and we are assaying them with oligonucleotide chip arrays. In addition, we are measuring changes in gene expression in cells derived from mutant mice. Better understanding of the transcriptional targets of the p53-related genes may indicate which downstream genes are specific to the tumor-suppressing activity of p53 and provide insights into the structural basis for target gene specificity.