Policing of oncogene activity by p53

Alejo Efeyan; Isabel Garcia-Cao; Daniel Herranz; Susana Velasco-Miguel; Manuel Serrano

Policing of oncogene activity by p53

Susana Velasco

2006, Nature

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The tumour-suppressor protein p53 plays a crucial role in cancer defense by responding to both DNA damage and oncogenic signaling. However, nuances in its activation pathways remain unclear. This study demonstrates that oncogenic signaling is vital for p53-dependent tumor protection, overshadowing the impact of DNA damage. Using genetically modified mice, it was revealed that the absence of ARF disrupts the crucial response to oncogenic signals, leading to an increased risk of neoplastic transformation, whereas the response to DNA damage remains intact. These findings may explain the frequent loss of ARF in human cancers and provide insight into p53's mechanisms of action.

Vol 443|14 September 2006 BRIEF COMMUNICATIONS Policing of oncogene activity by p53 Oncogenes, rather than DNA damage, may provide the key signal to p53 to trigger tumour suppression. E1a/Hras1-induced neoplastic foci Survival (%) Survival (%) Apoptotic cells (%) The tumour-suppressor protein DNA adducts and results in fiba b 40 rosarcomas carrying oncogenic p53 provides the most important 60 mutations in ras genes (see supgenetic defence against cancer1 and 30 plementary information). This is activated in response to DNA 40 carcinogenic protocol is highly damage and to oncogenic signal20 sensitive to the functionality of ling, both of which occur almost 20 10 p53, as indicated by the greater universally in malignant tumours. resistance to the agent of p53 super But the relative contribution of WT Null Null WT ARF WT ARF WT WT Null Null WT WT WT these two pathways in inducing mice compared with p53wt mice3. Super WT Super Null p53 WT p53 WT Super WT Super Null WT Super p53-dependent protection against As with the spontaneous tumours, c d 100 cancer is unclear. Here we show the extra gene dose of p53 became 100 that p53-dependent protection irrelevant in the absence of ARF 75 75 against cancer is lost in mice that (Fig. 1d). 50 50 have been genetically manipuTogether, our results indicate lated so that their p53 is activated that the cancer-protective activity 25 25 in response to DNA damage but of p53 is abolished in the absence 0 0 not to oncogenic signalling. We of ARF. We conclude that onco0 5 10 15 20 0 10 20 30 40 60 conclude that oncogenic signalgenic signalling is critical for trigMonths Weeks after 3-MC injection ling is the critical event that elicits gering protection by p53, whereas p53-dependent protection and Figure 1 | ARF is necessary for tumour suppression by p53. a, The p53activation of p53 as a result of dependent DNA-damage response in vivo does not depend on ARF. DNA damage has a lesser impact that the DNA-damage stimulus is Mice (nǃ3 per genotype) were irradiated (10 Gy) and the percentage of on the ultimate development of less important. apoptotic thymocytes was determined 3 h later. Blue bars, non-irradiated tumours. Although there are difDNA damage and oncogenic controls; red bars, cells from irradiated mice. b, ARF is essential for the signalling are communicated to defensive response to oncogenic signals. Primary embryonic fibroblasts ferences in these pathways in mice p53 through separate routes, which (from nǃ2 embryos per genotype) were retrovirally transduced with E1a and humans, our findings may also are, respectively, a p53-phosphory- and oncogenic Hras1 and plated as indicated, and the number of resulting explain the high incidence of ARF 2,000 cells; blue bars, 50,000 cells. lation cascade that involves the neoplastic foci was scored. Red bars, loss in human cancers9, as well as null wt null super c , Lifespans of ARF /p53 and ARF /p53 mice (nǃ21 WT, wild type. ATM/Chk2/ATR/Chk1 series of the low incidence of mutations in significantly kinases, and a p53-stabilization (blue) and nǃ23 (green) per genotype, respectively) were not the kinase enzymes of the p53wt wt different (log rank test, Pǃ0.26). d, Mice of genotype ARF /p53 (nǃ12; pathway that requires the tumour- black), ARFwt/p53 super (nǃ9; red), ARF null/p53wt (nǃ10; blue) or ARF null/ phosphorylation cascade10 that is suppressor protein ARF and the p53 super (nǃ11; green) were treated with the DNA-damaging agent 3-methyl induced by DNA damage. ubiquitin-ligase MDM2 (ref. 1). cholanthrene (3-MC) and monitored for the development of fibrosarcomas. Alejo Efeyan, Isabel Garcia-Cao, Daniel Herranz, Susana VelascoTo investigate the role of onco- The protection against tumour development provided by the p53super Miguel, Manuel Serrano genic signalling in p53-mediated allele in the presence of ARF disappears in the absence of ARF; (see also protection against cancer, we used supplementary information). Spanish National Cancer Centre (CNIO), Madrid 28029, Spain mice with two genetically engineered traits: one had no ARF allele (ARF null whether ARF was present or absent (Fig.1a). e-mail: [email protected] mice)2 and the other had a ‘super’ p53 allele3 However, ARF null cells were unable to respond 1. Harris, S. L. & Levine, A. J. Oncogene 24, 2899–2908 (p53 super mice; these mice carry a single addi- effectively to oncogenic signalling6–8 and (2005). tional transgenic copy of the intact p53 gene, underwent neoplastic transformation by onco- 2. Kamijo, T. et al. Cell 91, 649–659 (1997). which behaves in the same way as endogenous genes in vitro, irrespective of the presence or 3. Garcia-Cao, I. et al. EMBO J. 21, 6225–6235 (2002). 4. Stott, F. J. et al. EMBO J. 17, 5001–5014 (1998). p53). Compared with wild-type mice (p53wt absence of the p53 super allele (Fig. 1b). 5. Kamijo, T. et al. Cancer Res. 59, 2464–2469 (1999). mice), which have just two copies of p53, the As p53 responds normally to DNA damage 6. Palmero, I., Pantoja, C. & Serrano, M. Nature 395, 125–126 (1998). p53 super mice have additional protection against in the absence of ARF, we reasoned that p53super F. et al. Genes Dev. 12, 2424–2433 (1998). cancer development3. This experimental sys- might provide some protection against tumour 7.8. Zindy, de Stanchina, E. et al. Genes Dev. 12, 2434–2442 (1998). tem is therefore well suited for quantifying development in vivo, even without the ability 9. Sharpless, N. E. Mutat. Res. 576, 22–38 (2005). p53-dependent protection against cancer. (See to detect oncogenic signalling. However, we 10. Bartek, J. & Lukas, J. Cancer Cell 3, 421–429 (2003). found that p53 super/ARF null mice succumbed supplementary information for methods.) Supplementary information accompanies this Before analysing their susceptibility to can- to spontaneous tumours at the same rate as communication on Nature’s website. null wt null cer, we confirmed that ARF mice respond p53 /ARF mice (Fig. 1c), producing the Received 1 August; accepted 22 August 2006. normally to DNA damage4,5 by showing that same profile of sarcomas, lymphomas and Competing financial interests: declared none. doi:10.1038/443159a apoptosis of their thymocytes after irradia- histiocytic sarcomas (results not shown). tion was unaffected (Fig. 1a). We found that We also treated p53super/ARF null and p53wt/ mice with the p53 super allele showed the same ARF null mice with the DNA-damaging agent BRIEF COMMUNICATIONS ARISING online enhancement of apoptosis irrespective of 3-methyl cholanthrene. This agent produces ➧ www.nature.com/bca see Nature contents. 159 ©2006 Nature Publishing Group

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