Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 104, Issue 26, Pages 10871-10876Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0700761104
Keywords
cancer; p53; transcription; histone cleacetylase inhibitor; trichostatin A
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Funding
- Medical Research Council [MC_U132670600, MC_U132615750] Funding Source: Medline
- Telethon [GGP04110] Funding Source: Medline
- MRC [MC_U132670600, MC_U132615750] Funding Source: UKRI
- Medical Research Council [MC_U132670600, MC_U132615750] Funding Source: researchfish
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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 alpha 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.
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