Tumor Suppression by p 53 in the Absence of Atm

Oncogenes can induce p53 through a signaling pathway involving p19/Arf. It was recently proposed that oncogenes can also induce DNA damage, and this can induce p53 through the Atm DNA damage pathway. To assess the relative roles of Atm, Arf, and p53 in the suppression of Ras-driven tumors, we examined susceptibility to skin carcinogenesis in 7,12-dimethylbenz (a)anthracene/12-O-tetradecanoylphorbol-13-acetate (TPA)–treated Atmand p53-deficient mice and compared these results to previous studies on Arf-deficient mice. Mice with epidermal-specific deletion of p53 showed increased papilloma number and progression to malignant invasive carcinomas compared with wild-type littermates. In contrast, Atm-deficient mice showed no increase in papilloma number, growth, or malignant progression. ;-H2AX and p53 levels were increased in both Atm and Atm / papillomas, whereas Arf / papillomas showed much lower p53 expression. Thus, although there is evidence of DNA damage, signaling through Arf seems to regulate p53 in these Ras-driven tumors. In spontaneous and radiation-induced lymphoma models, tumor latency was accelerated in Atm / p53 / compound mutant mice compared with the single mutant Atm / or p53 / mice, indicating cooperation between loss of Atm and loss of p53. Although p53-mediated apoptosis was impaired in irradiated Atm / lymphocytes, p53 loss was still selected for during lymphomagenesis in Atm / mice. In conclusion, in these models of oncogeneor DNA damage–induced tumors, p53 retains tumor suppressor activity in the absence of Atm. (Mol Cancer Res 2008;6(7):1185–92) Introduction Carcinogenesis is an evolutionary process driven by mutation and selection (1). To intervene in cancer development, it is important to understand the selective pressures that drive tumor evolution. The observation that p53 mutations are found at high frequency in most types of human cancers (2) indicates that selection for cells that have disabled p53 is a nearly universal feature of cancer. p53 can be activated by numerous stressors including DNA damage, oncogene activation, abnormal cell adhesion, altered ribonucleotide pools, hypoxia, telomere erosion, and nutrient deprivation (3, 4). Activated p53, in turn, can suppress tumor development through the induction of cell cycle arrest, senescence, or apoptosis (4). Of the many signals that have been reported to phosphorylate and activate p53, it is unclear which of these is physiologically relevant for tumor suppression in vivo . This is further complicated by variations between tissues and tumor etiology. DNA damage and activated oncogenes play direct causal roles in cancer induction and p53 activation, and so both are reasonable candidates for generating selective pressure against p53 during tumor progression. DNA damage is the best studied activator of p53. DNA double-strand breaks, which can be induced by ionizing radiation or other genotoxic agents, trigger a signaling cascade leading to p53-dependent cell cycle arrest or apoptosis. The protein kinase ATM, which is mutated in the inherited syndrome ataxia telangiectasia, is a primary signal transducer for the cellular response to double-strand breaks (5). DNA double-strand breaks activate ATM, which can directly phosphorylate p53 on Ser (6, 7). ATM also phosphorylates Chk2, which in turn phosphorylates p53 on Ser (8, 9). ATM impairs the activity of negative regulators of p53, including the ubiquitin ligases cop1 and mdm2 (10, 11). Collectively, these alterations lead to the rapid accumulation of p53 and activation of its transcriptional functions, which, in turn, can trigger cellular responses such as cell cycle arrest or apoptosis. Ataxia telangiectasia patients carry homozygous mutations in ATM and have an increased risk of developing lymphoreticular malignancies (12). Atm knockout mice are highly susceptible to lymphoid malignancies but have not shown a marked predisposition to tumors in other tissues (13, 14). The basis for this tissue specificity is not known. Westphal et al. (15) reported that loss of Atm and p53 cooperate to suppress spontaneous development of lymphomas. Liao et al. (16) showed that p53-dependent tumor suppression in a mouse brain tumor model driven by truncated SV40 T antigen is unaffected by Atm deficiency. In these mouse models, Atm does not seem to be an essential regulator of the tumor suppressor function of p53. Several recent studies showed that Atm deficiency accelerates Mycand mutant Apc–driven tumors, suggesting that Atm plays a role in these tumor models (17-19). Atm-dependent signaling in vivo is markedly tissue specific. Atm / mice have impaired p53-dependent apoptosis in irradiated lymphoid tissue and the developing central nervous Received 8/29/07; revised 2/13/08; accepted 3/26/08. Grant support: NIH research grant R01 CA70414 and National Institute of Environmental Health Sciences research grant U01 ES11045. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Note: Current address for K. Hoon-Kim: Trubion Pharmaceuticals, Seattle, WA 98121. Requests for reprints: Christopher J. Kemp, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, WA 90109-1024. Phone: 206-6674252; Fax: 206-667-5815. E-mail: cjkemp@fhcrc.org Copyright D 2008 American Association for Cancer Research. doi:10.1158/1541-7786.MCR-07-2009 Mol Cancer Res 2008;6(7). July 2008 1185 on May 29, 2017. © 2008 American Association for Cancer Research. mcr.aacrjournals. org Downloaded from Published OnlineFirst June 26, 2008; DOI: 10.1158/1541-7786.MCR-07-2009