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 alpha isoforms of TAp63 and DeltaNp63 contain a transactivation-inhibitory (TI) domain at the C termini, which can bind to the transactivation (TA) domain and inhibit its transcriptional activity. Consequently, TAp63alpha can directly inhibit its activity through an intramolecular interaction; similarly, DeltaNp63alpha 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 p63alpha isoforms is cleaved by activated caspases. Cleavage of DeltaNp63alpha relieves its inhibitory effect on the transcriptionally active p63 proteins, and the cleavage of TAp63alpha 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.
Sayan
Berna S
BS
*Medical Research Council, Toxicology Unit, Leicester University, Leicester LE1 9HN, United Kingdom.
Sayan
A Emre
AE
Yang
Ai Li
AL
Aqeilan
Rami I
RI
Candi
Eleonora
E
Cohen
Gerald M
GM
Knight
Richard A
RA
Croce
Carlo M
CM
Melino
Gerry
G
D017209:Apoptosis; D020169:Caspases / Q000378:metabolism*; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D006868:Hydrolysis; D020033:Protein Isoforms; D017434:Protein Structure, Tertiary; D015534:Trans-Activators / Q000737:chemistry / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000378:metabolism*
D004268:DNA-Binding Proteins; D020033:Protein Isoforms; C115051:TP63 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D020169:Caspases