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

Sayan, BS ORCID:, Sayan, AE, Ying, AL, Aqeilan, RI, Candi, E, Cohen, GM, Knight, RA, Croce, CM and Melino, G 2007, 'Cleavage of the transactivation-inhibitory domain of p63 by caspases enhances apoptosis' , Proceedings of the National Academy of Sciences, 104 (26) , pp. 10871-10876.

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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 α isoforms of TAp63 and ΔNp63 contain a transactivation-inhibitory (TI) domain at the C termini, which can bind to the transactivation (TA) domain and inhibit its transcriptional activity. Consequently, TAp63α can directly inhibit its activity through an intramolecular interaction; similarly, ΔNp63α 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 p63α isoforms is cleaved by activated caspases. Cleavage of ΔNp63α relieves its inhibitory effect on the transcriptionally active p63 proteins, and the cleavage of TAp63α 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.

Item Type: Article
Schools: Schools > School of Environment and Life Sciences
Journal or Publication Title: Proceedings of the National Academy of Sciences
Publisher: National Academy of Sciences
ISSN: 0027-8424
Depositing User: BS Sayan
Date Deposited: 06 Feb 2023 15:25
Last Modified: 06 Feb 2023 15:30

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