The nuclear function of p53 is required for PUMA-mediated apoptosis induced by DNA damage
Open Access
- 6 March 2007
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences
- Vol. 104 (10) , 4054-4059
- https://doi.org/10.1073/pnas.0700020104
Abstract
The tumor suppressor p53 can induce apoptosis by activating gene expression in the nucleus, or by directly permeabilizing mitochondria in the cytoplasm. It has been shown that PUMA, a downstream target of p53 and a BH3-only Bcl-2 family member, plays an essential role in apoptosis induced by both nuclear and cytoplasmic p53. To understand how PUMA does so, we used homologous recombination to delete the binding sites of p53 in the promoter of PUMA in human colorectal cancer cells. As a result, the induction of PUMA and apoptosis in response to p53 and DNA-damaging agents were abrogated. Transcription coactivator recruitment and histone modifications in the PUMA promoter were suppressed. However, induction of PUMA and apoptosis in response to non-DNA-damaging stimuli were unaffected. These results indicate that the binding of nuclear p53 to the specific sites within the PUMA promoter is essential for its ability to induce apoptosis and is likely to be required for its tumor suppressive capacity.Keywords
This publication has 31 references indexed in Scilit:
- Facile methods for generating human somatic cell gene knockouts using recombinant adeno-associated virusesNucleic Acids Research, 2004
- p53- and Drug-Induced Apoptotic Responses Mediated by BH3-Only Proteins Puma and NoxaScience, 2003
- Pharmacologic activation of p53 elicits Bax-dependent apoptosis in the absence of transcriptionCancer Cell, 2003
- Puma is an essential mediator of p53-dependent and -independent apoptotic pathwaysCancer Cell, 2003
- PUMA mediates the apoptotic response to p53 in colorectal cancer cellsProceedings of the National Academy of Sciences, 2003
- Chromatin immunoprecipitation analysis fails to support the latency model for regulation of p53 DNA binding activity in vivoProceedings of the National Academy of Sciences, 2001
- Acetylation of p53 Activates Transcription through Recruitment of Coactivators/Histone AcetyltransferasesMolecular Cell, 2001
- Expression of bbc3 , a pro-apoptotic BH3-only gene, is regulated by diverse cell death and survival signalsProceedings of the National Academy of Sciences, 2001
- PUMA Induces the Rapid Apoptosis of Colorectal Cancer CellsMolecular Cell, 2001
- Surfing the p53 networkNature, 2000