Tumor suppression by p53 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 Atm- and 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. gamma-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 oncogene- or DNA damage-induced tumors, p53 retains tumor suppressor activity in the absence of Atm.
Bailey
S Lawrence
SL
Fred Hutchinson Cancer Research Center, Seattle, WA 90109-1024, USA.
Gurley
Kay E
KE
Hoon-Kim
Kyung
K
Kelly-Spratt
Karen S
KS
Kemp
Christopher J
CJ
D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000378:metabolism; D019656:Loss of Heterozygosity / Q000235:genetics; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency* / Q000378:metabolism; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000172:deficiency* / Q000378:metabolism
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D015127:9,10-Dimethyl-1,2-benzanthracene; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases