Journal
ONCOGENE
Volume 35, Issue 29, Pages 3866-3871Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2015.457
Keywords
-
Funding
- Cancer Council of Victoria
- Leukaemia Foundation Australia
- Lady Tata Memorial Trust Research Award
- Leukemia & Lymphoma Society of America
- Beatriu de Pinos Foundation
- Cancer Australia
- Cure Cancer Australia Foundation [1067571]
- National Health and Medical Research Council (NHMRC) [1016701, 1020363]
- Leukemia & Lymphoma Society of America (Specialized Center of Research (SCOR)) [7001-13]
- Australian Government Independent Medical Research Institutes Infrastructure Support Scheme (IRIISS)
- Victorian State Government Operational Infrastructure Support (OIS)
Ask authors/readers for more resources
The tumor suppressor p53 is mutated in similar to 50% of human cancers. P53 is activated by a range of stimuli and regulates several cellular processes, including apoptotic cell death, cell cycle arrest, senescence and DNA repair. P53 induces apoptosis via transcriptional induction of the BH3-only proteins PUMA (p53-upregulated modulator of apoptosis) and NOXA, and cell cycle arrest via p21. Induction of these processes was proposed to be critical for p53-mediated tumor suppression. It is therefore surprising that mice lacking PUMA, NOXA and p21, as well as mice bearing mutations in p53 that impair the transcriptional activation of these genes, are not tumor prone, unlike mice lacking p53 function, which spontaneously develop tumors with 100% incidence. These p53 target genes and the processes they regulate may, however, impact differently on tumor development depending on the oncogenic drivers. For example, loss of PUMA enhances c-MYC-driven lymphoma development in mice, but, interestingly, the acceleration was less impressive compared with that caused by the loss of even a single p53 allele. Different studies have reported that loss of p21 can accelerate, delay or have no impact on tumorigenesis. In an attempt to resolve this controversy, we examined whether loss of p21-mediated cell cycle arrest cooperates with PUMA deficiency in accelerating lymphoma development in E mu-Myc mice (overexpressing c-MYC in B-lymphoid cells). We found that E mu-Myc mice lacking both p21 and PUMA (E mu-Myc; Puma(-/-); p21(-/-)) developed lymphoma at a rate comparable to E mu-Myc; Puma(-/-) animals, notably with considerably longer latency than E mu-Myc; p53(+/-) mice. Loss of p21 had no impact on the numbers, cycling or survival of pre-leukemic E mu-Myc B-lymphoid cells, even when PUMA was lost concomitantly. These results demonstrate that even in the context of deregulated c-MYC expression, p53 must suppress tumor development by activating processes apart from, or in addition to, PUMA-mediated apoptosis and p21-induced cell cycle arrest.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available