Cleavage of the transactivation-inhibitory domain of p63 by caspases enhances apoptosis

p63 is a p53-related transcription factor. Utilization of two different promoters and alternative splicing at the C terminus lead to generation of six isoforms. The a isoforms of TAp63 and [DELTA]Np63 contain a transactivation-inhibitory (TI) domain at the C termini, which can bind to the transactivation (TA) domain and inhibit its transcriptional activity. Consequently, TAp63[alpha] can directly inhibit its activity through an intramolecular interaction; similarly, [DELTA]Np63[alpha] can inhibit the activity of the active TAp63 isoforms through an intermolecular interaction. In this work, we demonstrate that after induction of apoptosis, the TI domain of the p63[alpha] isoforms is cleaved by activated caspases. Cleavage of [DELTA]Np63[alpha] relieves its inhibitory effect on the transcriptionally active p63 proteins, and the cleavage of TAp63[alpha] results in production of a TAp63 protein with enhanced transcriptional activity. In agreement with these data, generation of the N-terminal TAp63 fragment has a role in apoptosis because stable cell lines expressing wild-type TAp63 are more sensitive to apoptosis compared with cells expressing the noncleavable mutant. We also used a model system in which TAp63 expression was induced by trichostatin-A treatment in HCT116 cells. Trichostatin-A sensitized these cells to apoptosis, and this sensitization was associated with cleavage of up-regulated p63. cancer | p53 | transcription | histone deacetylase inhibitor | trichostatin A