p53 Efficiently Suppresses Tumor Development in the Complete Absence of Its Cell-Cycle Inhibitory and Proapoptotic Effectors p21, Puma, and Noxa
- Author(s)
- Valente, LJ; Gray, DHD; Michalak, EM; Pinon-Hofbauer, J; Egle, A; Scott, CL; Janic, A; Strasser, A;
- Details
- Publication Year 2013-05,Volume 3,Issue #5,Page 1339-1345
- Journal Title
- CELL REPORTS
- Publication Type
- Journal Article
- Abstract
- Activation of apoptosis through transcriptional induction of Puma and Noxa has long been considered to constitute the critical (if not sole) process by which p53 suppresses tumor development, although G1/S boundary cell-cycle arrest via induction of the CDK inhibitor p21 has also been thought to contribute. Recent analyses of mice bearing mutations that impair p53-mediated induction of select target genes have indicated that activation of apoptosis and G1/S cell-cycle arrest may, in fact, be dispensable for p53-mediated tumor suppression. However, the expression of Puma, Noxa, and p21 was not abrogated in these mutants, only reduced; therefore, the possibility that the reduced levels of these critical effectors of p53-mediated apoptosis and G1/S-cell-cycle arrest sufficed to prevent tumorigenesis could not be excluded. To resolve this important issue, we have generated mice deficient for p21, Puma, and Noxa (p21(-/-)puma(-/-)noxa(-/-) mice). Cells from these mice were deficient in their ability to undergo p53-mediated apoptosis, G1/S cell-cycle arrest, and senescence. Nonetheless, these animals remained tumor free until at least 500 days, in contrast to p53-deficient mice, which had all succumbed to lymphoma or sarcoma by 250 days. Interestingly, DNA lesions induced by gamma-irradiation persisted longer in p53-deficient cells compared to wild-type or p21(-/-)puma(-/-)noxa(-/-) cells, and the former failed to transcriptionally activate several p53 target genes implicated in DNA repair. These results demonstrate beyond a doubt that the induction of apoptosis, cell-cycle arrest, and possibly senescence is dispensable for p53-mediated suppression of spontaneous tumor development and indicate that coordination of genomic stability and possibly other processes, such as metabolic adaptation, may instead be critical.
- Publisher
- CELL PRESS
- Keywords
- Apoptosis ; Puma ; Noxa ; p53-mediated tumor suppression
- Research Division(s)
- Molecular Genetics Of Cancer; Stem Cells And Cancer
- Publisher's Version
- https://doi.org/10.1016/j.celrep.2013.04.012
- Open Access at Publisher's Site
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Creation Date: 2013-05-01 12:00:00