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Transgenic expression of E2F3a causes DNA damage leading to ATM-dependent apoptosis

机译：E2F3a的转基因表达引起DNA损伤，导致ATM依赖性细胞凋亡

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Many early stage human tumors display markers of a DNA-damage response (DDR), including ataxia telangiectasia mutated (ATM) kinase activation. This suggests that DNA damage accumulates during the process of carcinogenesis and that the ATM-dependent response to this damage may function to suppress cancer progression. The E2F3a transcription factor plays an important role in regulating cell proliferation and is amplified in a subset of human cancers. Similar to human premalignant lesions, we find activated ATM and other markers of the DDR in the hyperplastic epidermis of transgenic mice expressing E2F3a through a keratin 5 (K5) promoter. Primary keratinocytes from K5 E2F3a transgenic mice contain increased levels of DNA breaks compared to wild-type cells. E2F3a overexpression also induced DNA damage in primary human fibroblasts that was inhibited by blocking DNA replication. The absence of ATM impaired apoptosis induced by E2F3a and treating K5 E2F3a transgenic mice with caffeine, an inhibitor of ATM and Rad3-related (ATR), promoted skin tumor development. These findings demonstrate that the deregulated expression of E2F3a causes DNA damage under physiological conditions and indicate that the ATM-dependent response to this damage is important for the induction of apoptosis and tumor suppression.
机译：许多早期人类肿瘤显示出DNA损伤反应（DDR）的标记，包括共济失调毛细血管扩张突变（ATM）激酶激活。这表明DNA损伤在致癌过程中积累，并且对这种损伤的ATM依赖性反应可能起到抑制癌症进展的作用。 E2F3a转录因子在调节细胞增殖中起重要作用，并在一部分人类癌症中被扩增。与人类恶变前病变相似，我们在通过角蛋白5（K5）启动子表达E2F3a的转基因小鼠的增生表皮中发现了活化的ATM和DDR的其他标记。与野生型细胞相比，来自K5 E2F3a转基因小鼠的原代角质形成细胞含有更高水平的DNA断裂。 E2F3a的过表达还诱导人类原代成纤维细胞中的DNA损伤，这种损伤可通过阻止DNA复制来抑制。 ATM的缺乏会削弱E2F3a诱导的凋亡，并用咖啡因（一种ATM和Rad3相关（ATR）的抑制剂）治疗K5 E2F3a转基因小鼠，促进皮肤肿瘤的发展。这些发现表明，在生理条件下，E2F3a的表达失调会引起DNA损伤，并表明对这种损伤的ATM依赖性反应对于诱导凋亡和抑制肿瘤很重要。

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