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 γ-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.
p53 efficiently suppresses tumor development in the complete absence of its cell-cycle inhibitory and proapoptotic effectors p21, Puma, and Noxa.
Liz J. Valente,D. Gray,Ewa M Michalak,Josefina Piñón-Hofbauer,A. Egle,C. Scott,Ana Janic,A. Strasser
Published 2013 in Cell Reports
ABSTRACT
PUBLICATION RECORD
- Publication year
2013
- Venue
Cell Reports
- Publication date
2013-05-30
- Fields of study
Biology, Medicine
- Identifiers
- External record
- Source metadata
Semantic Scholar, PubMed
CITATION MAP
EXTRACTION MAP
CLAIMS
CONCEPTS
- dna repair genes
Genes whose transcription is linked to DNA-damage repair responses in the p53 pathway.
- g1/s cell-cycle arrest
A checkpoint arrest that blocks progression from G1 into S phase.
- p21-/-puma-/-noxa-/- mice
Mice engineered to lack the p21, Puma, and Noxa genes simultaneously.
- p53-deficient cells
Cells lacking functional p53 used to assess DNA damage responses in the experiments.
- p53-deficient mice
Mice lacking functional p53 used here as the comparison genotype.
- p53-mediated apoptosis
Programmed cell death activated downstream of p53 signaling.
- p53-mediated tumor suppression
p53's role in preventing spontaneous tumor formation in vivo.
- senescence
A stable nondividing state associated with p53 signaling in the tested cells.
- γ-irradiation
Ionizing radiation used in the experiments to induce DNA lesions.
REFERENCES
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