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Proc Natl Acad Sci U S A. 2004 Jun 22;101(25):9333-8. Epub 2004 Jun 10.

Suppression of tumorigenesis by the p53 target PUMA.

Author information

1
Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY 11724, USA.

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.

PMID:
15192153
PMCID:
PMC438977
DOI:
10.1073/pnas.0403286101
[Indexed for MEDLINE]
Free PMC Article

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