p73, a p53 family protein, shares significant sequence homolog and functional similarity with p53. However, unlike p53, p73 has at least seven alternatively spliced isoforms with different carboxyl termini (p73alpha-eta). Moreover, the p73 gene can be transcribed from a cryptic promoter located in intron 3, producing seven more proteins (DeltaNp73alpha-eta). DeltaNp73, which does not contain the N-terminal activation domain in p73, has been thought to be transcriptionally inactive and dominant negative over p53 or p73. To systemically analyze the activity of the DeltaN variant, we generated stable cell lines, which inducibly express DeltaNp73alpha, DeltaNp73beta, and various DeltaNp73beta mutants by using the tetracycline-inducible expression system. Surprisingly, we found that DeltaNp73beta is indeed active in inducing cell cycle arrest and apoptosis. Importantly, we found that, when DeltaNp73beta is expressed at a physiologically relevant level, it is capable of suppressing cell growth. We then demonstrated that these DeltaNp73beta activities are not cell type specific. We showed that the 13 unique residues at the N terminus are required for DeltaNp73beta to suppress cell growth. We also found that, among the 13 residues, residues 6 to 10 are critical to DeltaNp73beta function. Furthermore, we found that DeltaNp73beta is capable of inducing some p53 target genes, albeit to a lesser extent than does p73beta. Finally, we found that the 13 unique residues, together with the N-terminal PXXP motifs, constitute a novel activation domain. Like DeltaNp73beta, DeltaNp73gamma is active in transactivation. However, unlike DeltaNp73beta, DeltaNp73alpha is inactive in suppressing cell growth. Our data, together with others' previous findings, suggest that DeltaNp73beta may have distinct functions under certain cellular circumstances.