The unique NH2-terminally deleted (DeltaN) residues, the PXXP motif, and the PPXY motif are required for the transcriptional activity of the DeltaN variant of p63.

p63, a member of the p53 family of transcription factors, is known to be involved in epithelial development. However, its role in tumorigenesis is unclear. Contributing to this uncertainty, the TP63 locus can express multiple gene products from two different promoters. Utilization of the upstream promoter results in expression of the TAp63 variant with an activation domain similar to p53. In contrast, the NH2-terminally deleted (DeltaN) p63 variant, transcribed from a cryptic promoter in intron 3, lacks such an activation domain. Thus, the TAp63 and DeltaNp63 variants possess a wide ranging ability to up-regulate p53 target genes. Consequentially, the disparity in transactivation potential between p63 variants has given rise to the hypothesis that the DeltaNp63 variant can serve as oncoprotein by opposing the activity of the TAp63 variant and p53. However, recent studies have revealed a transcriptional activity for DeltaNp63. This study was undertaken to address the transcriptional activity of the DeltaNp63 variant. Here, we showed that all NH2-terminally deleted p63 isoforms retain a potential in transactivation and growth suppression. Interestingly, DeltaNp63beta possesses a remarkable ability to suppress cell proliferation and transactivate target genes, which is consistently higher than that seen with DeltaNp63alpha. In contrast, DeltaNp63gamma has a weak or undetectable activity dependent upon the cell lines used. We also demonstrate that an intact DNA-binding domain is required for DeltaNp63 function. In addition, we found that the novel activation domain for the DeltaNp63 variant is composed of the 14 unique DeltaN residues along with the adjacent region, including a PXXP motif. Finally, we demonstrated that a PPXY motif shared by DeltaNp63alpha and DeltaNp63beta is required for optimal transactivation of target gene promoters, suggesting that the PPXY motif is requisite for DeltaNp63 function.