The mechanisms by which p53 prevents development of cancer are much more complicated than previously thought. Under normal conditions, p53 is involved in cell-cycle arrest, Q1apoptosis, DNA repair, and inhibition of angiogenesis; it also promotes degradation of proteins through transcriptional regulation of certain target genes. Here we report the isolation of a novel transcriptional target of p53, designated p53RFP (p53-inducible RING-finger protein), whose product has E3 ubiquitin ligase activity. Its expression was negatively correlated to that of p21(WAF1) protein; p53RFP is likely to play a role in the regulation of this protein, probably through interaction with, and ubiquitination of, p21(WAF1). p53RFP appears to represent the second known example, the first being MDM2, of an E3 ubiquitin ligase as a p53 target. Our results further suggest that p53 might regulate the stability of p21(WAF1) through transcriptional regulation of p53RFP, and this feature may represent a novel mechanism for a p53-dependent cell-cycle checkpoint.