Hemann, M. T., Zilfou, J. T., Zhao, Z., Burgess, D. J., Hannon, G. J., Lowe, S. W. (June 2004) Suppression of tumorigenesis by the p53 target PUMA. Proc Natl Acad Sci U S A, 101 (25). pp. 9333-8. ISSN 0027-8424 (Print)
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Abstract
The p53 tumor suppressor regulates diverse antiproliferative processes such that cells acquiring p53 mutations have impaired cell-cycle checkpoints, senescence, apoptosis, and genomic stability. Here, we use stable RNA interference to examine the role of PUMA, a p53 target gene and proapoptotic member of the Bcl2 family, in p53-mediated tumor suppression. PUMA short hairpin RNAs (shRNAs) efficiently suppressed PUMA expression and p53-dependent apoptosis but did not impair nonapoptotic functions of p53. Like p53 shRNAs, PUMA shRNAs promoted oncogenic transformation of primary murine fibroblasts by the E1A/ras oncogene combination and dramatically accelerated myc-induced lymphomagenesis without disrupting p53-dependent cell-cycle arrest. However, the ability of PUMA to execute p53 tumor suppressor functions was variable because, in contrast to p53 shRNAs, PUMA shRNAs were unable to cooperate with oncogenic ras in transformation. These results demonstrate that the p53 effector functions involved in tumor suppression are context dependent and, in some settings, depend heavily on the expression of a single proapoptotic effector. Additionally, they demonstrate the utility of RNA interference for evaluating putative tumor suppressor genes in vivo.
| Item Type: | Paper |
|---|---|
| Uncontrolled Keywords: | Animals Cell Cycle genetics Cell Transformation, Neoplastic genetics Cells Cultured DNA Damage Embryo Fibroblasts cytology physiology Gene Transfer Techniques Genes ras genetics Lymphoma B-Cell genetics Mice Proto-Oncogene Proteins genetics metabolism RNA genetics Suppression Genetic genetics Tumor Suppressor Protein p53 deficiency genetics metabolism Tumor Suppressor Proteins genetics |
| Subjects: | bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > RNAi bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > p53 bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > shRNA |
| CSHL Authors: | |
| Communities: | CSHL labs > Hannon lab CSHL labs > Lowe lab School of Biological Sciences > Publications |
| Depositing User: | CSHL Librarian |
| Date: | 22 June 2004 |
| Date Deposited: | 01 Feb 2012 18:28 |
| Last Modified: | 09 Nov 2017 17:07 |
| PMCID: | PMC438977 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/22385 |
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