A role for p63 in the regulation of cell cycle progression and cell death

by Helton, Eric Scott.

p63 is a member of the p53 family of transcription factors that is a critical regulator of epithelial development. Studies have shown that p63 does not appear to function as a classical tumor suppressor like p53. Instead, the expression pattern of p63 in cancers suggests that p63 retains the potential to function as either a tumor suppressor or an onco-protein. Here, we provide evidence describing the transcriptional activity of the p63 isoforms and provide mechanisms whereby p63 function is regulated in a context dependent manner. Our data shows that both the ?Np63 and TAp63 variants retain the potential to regulate transcription and inhibit proliferation. We suggest that the intrinsic transactivation potential of p63 isoforms is established at the level of transcription. Promoter selection determines which N-terminal activation domain is encoded in the p63 protein. For example, we propose that transactivation by ?Np63 is more dependent upon co-activator binding to the C-terminal proline-rich region than the TAp63 variant that possesses the strong, acidic activation domain. In addition, alternative splicing regulates expression of either the ?, ?, or ? C-termini. The ? C-terminus has been previously described as inhibitory. Here we demonstrate that expression of the PPXY motif in the ? and ?, but not ?, termini affords additional transactivation potential to these isoforms. Finally, we show that p63 transactivation potential is dependent upon PXXP and PPXY motifs suggesting that signaling pathways can modulate p63 function through posttranslational modifications or protein-protein interactions occurring at these proline-rich motifs. ii