Limited Role of Murine ATM in Oncogene-Induced Senescence and p53-Dependent Tumor Suppression
Limited Role of Murine ATM in Oncogene-Induced Senescence and p53-Dependent Tumor Suppression
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DOI：
10.1371/journal.pone.0005475
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发表时间：
2009-05-07
期刊：
影响因子：
3.7
通讯作者：
Serrano, Manuel
中科院分区：
文献类型：
--
作者：
Efeyan, Alejo;Murga, Matilde;Serrano, Manuel
最近对人成纤维细胞的研究提供了一种新的肿瘤抑制的通用范式，根据该范式，致癌信号产生DNA损伤，进而导致依赖ATM/P53的细胞衰老。在这里，我们已经在各种小鼠实验系统中测试了这个模型。在小鼠成纤维细胞中过表达致癌基因RAS可以有效地诱导衰老，但这是在缺乏可检测到的DNA损伤信号的情况下发生的，因此表明人和小鼠细胞之间存在根本的差异。此外，由内源性K-RAS引起的肺腺瘤具有丰富的衰老细胞，但未检测到DNA损伤信号。因此，在ATM缺失的小鼠中，K-RAS驱动的腺瘤也会衰老，而这些病变的肿瘤进展仅因ATM缺乏而略有加速。最后，我们研究了化学诱导的纤维肉瘤，它具有持续激活的DNA损伤反应，并且对P53的活性高度敏感。我们发现，在由此产生的肿瘤中，ATM的缺乏有利于基因组的不稳定性，但不会影响持续的DNA损伤反应，也不会损害P53依赖的肿瘤抑制。总之，我们得出结论，在缺乏可检测到的DNA损伤反应的情况下，癌基因诱导的小鼠衰老可能会发生。对于小鼠ATM，我们的数据表明，它在癌基因诱导的衰老或P53依赖的肿瘤抑制中起着次要的作用，因为它的肿瘤抑制活性可能仅限于维持基因组的稳定性。
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.