Abstract
Recent studies in human fibroblasts have provided a new general paradigm of tumor suppression according to which oncogenic signaling produces DNA damage and this, in turn, results in ATM/p53-dependent cellular senescence. Here, we have tested this model in a variety of murine experimental systems. Overexpression of oncogenic Ras in murine fibroblasts efficiently induced senescence but this occurred in the absence of detectable DNA damage signaling, thus suggesting a fundamental difference between human and murine cells. Moreover, lung adenomas initiated by endogenous levels of oncogenic K-Ras presented abundant senescent cells, but undetectable DNA damage signaling. Accordingly, K-Ras-driven adenomas were also senescent in Atm-null mice, and the tumorigenic progression of these lesions was only modestly accelerated by Atm-deficiency. Finally, we have examined chemically-induced fibrosarcomas, which possess a persistently activated DNA damage response and are highly sensitive to the activity of p53. We found that the absence of Atm favored genomic instability in the resulting tumors, but did not affect the persistent DNA damage response and did not impair p53-dependent tumor suppression. All together, we conclude that oncogene-induced senescence in mice may occur in the absence of a detectable DNA damage response. Regarding murine Atm, our data suggest that it plays a minor role in oncogene-induced senescence or in p53-dependent tumor suppression, being its tumor suppressive activity probably limited to the maintenance of genomic stability.
Highlights
ATM plays an important role in tumor suppression as indicated by the in vivo consequences of ATM deficiency both in human and mice
Senescent cells overexpressing oncogenic H-Ras did not present evidence of an ongoing DNA damage response, not even in a minority of cells (Fig. 1B). These results suggest that murine fibroblasts undergo Ras-triggered oncogene-induced senescence in the absence of detectable DNA damage signaling
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 [17,18]
Summary
ATM plays an important role in tumor suppression as indicated by the in vivo consequences of ATM deficiency both in human and mice. The activation of p53 by ATM has gained great relevance lately as a general tumor suppressive mechanism after the proposal of a paradigm meant to apply to the majority of cancers [17,18]. According to this model, oncogenic signaling in emerging tumor cells induces per se sufficient DNA damage to trigger p53-dependent oncogene-induced senescence. Oncogenic signaling in emerging tumor cells induces per se sufficient DNA damage to trigger p53-dependent oncogene-induced senescence This model is based on two main sets of evidences. Inactivation of individual components of the DNA damage response, such as ATM, in cultured human fibroblasts eliminates oncogene-induced senescence and renders these cells permissive to oncogene-driven proliferation [21,22,23]
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