The role of ATM in tumor suppression is solidly established and attributed, at least in part, to its well-known function in DNA damage repair. In addition to its function in guarding the genome, ATM has been recently proposed to act as a general tumor suppressor through its ability to activate p53 in response to oncogenic stress and the subsequent induction of oncogene-induced cellular senescence 
. This model is mainly based on human cultured fibroblasts where ATM plays an essential role in oncogene-induced senescence 
. In this work, we have attempted to find in vivo
supporting evidence for the role of ATM in p53-dependent tumor suppression and in oncogene-induced senescence using murine experimental systems, namely, Ras-induced senescence in mouse embryo fibroblasts (MEFs), Ras-induced senescence during lung tumorigenesis, and chemically-induced fibrosarcomas.
A first unexpected observation was the absence of a detectable DNA damage response upon ectopic overexpression of oncogenic H-Ras in MEFs, under conditions that resulted in upregulation of Arf, stabilization of p53, and acquisition of a fully senescent morphology. Given the absence of a detectable DNA damage response elicited by oncogenic H-Ras, it was not surprising that the stabilization of p53 in response to the oncogene was not affected by the absence of Atm. Conceptually similar observations were made in a more physiological model of oncogene-induced senescence in which an inducible endogenous K-Ras
V12 allele drives the development of adenomas (pre-malignant) and adenocarcinomas (malignant), being characterized the adenomas by a strong senescence response 
. Again, as in the case of MEFs, we could not detect evidence of persistent DNA damage signaling in the K-Ras
V12-driven adenomas, which were invariably senescent as shown in 
(). Consistently with this, Atm
deficiency did not ablate the senescent response characteristically present in lung adenomas. Interestingly, however, the absence of Atm
had a modest, albeit significant, effect in the degree of progression of adenomas. In contrast to these data, ablation of Arf
strongly accelerates lung tumorigenesis driven by oncogenic K-Ras
, and it eliminates oncogenic Ras-induced senescence during mammary tumorigenesis 
. Together, these results indicate that oncogene-induced senescence in murine fibroblasts and lung epithelial cells is not associated to an ongoing DNA damage response and, therefore, activation of p53 and establishment of senescence occur independently of Atm.
Based on the above data, we focused on a murine cancer model initiated by a DNA damage agent (3-methyl-cholanthrene or 3MC), known to be highly sensitive to the activity of p53 
, and accompanied by a persistent DNA damage response (see ). However, the absence of Atm
did not impact on the kinetics of tumor development, even under conditions able to detect a 1.5-fold difference in p53 activity. Histopathological analyses of these tumors indicated that the absence of Atm
did not decrease the persistent DNA damage response, which must be signaled by other kinases of the Atm family, such as Atr or Dnapk. Importantly, the absence of Atm did not relieve the strong selective pressure to inactivate p53, further confirming that the tumor suppressor activity of p53 in this cancer model is not regulated by Atm. These results are in agreement with previous reports that also failed to detect an impact of Atm on p53-mediated tumor suppression in murine brain and skin cancers 
. The absence of effect of Atm on p53-dependent tumor suppression is in sharp contrast with a number of reports where the absence of Arf essentially eliminates p53-mediated tumor suppression and completely alleviates the selective pressure to inactivate p53 in lymphomas, sarcomas and skin tumors 
. Moreover, the 3MC-fibrosarcomas originated in Arf
-null mice retained a functional response to DNA damage, as judged by the phosphorylation of Atm and H2AX, as well as, by the stabilization of p53 and the induction of p21 upon irradiation (). In summary, in this cancer model initiated by a DNA damage agent and associated to persistent DNA damage, the absence of Atm
does not have a detectable effect on DNA damage signaling or on p53-dependent tumor suppression. Finally, and interestingly, we found that Atm
-null fibrosarcomas were characterized by high levels of chromosomal instability (), thus testifying to the known role of Atm in genome stability.
It is critically important to emphasize that our data do not negate a tumor suppressor role for ATM, which is solidly established both in human and mice (see Introduction
), but question the generality of the model proposed for ATM as a critical mediator of p53-activation and senescence in response to oncogenic signaling 
. This model is mainly based on the behavior of human fibroblasts in vitro
and it does not seem to apply to the three murine experimental systems analyzed here, namely, oncogene-induced senescence in fibroblasts and during lung tumorigenesis, and p53-mediated tumor suppression during carcinogenesis initiated by a DNA damage agent. By large, the molecular biology of human and murine cancer seem to follow the same mechanistic paradigms, however, it is conceivable that ATM is an exceptional case playing a major tumor suppression role in human cancer, but not in murine cancer.