The DNA damage checkpoint precedes activation of ARF in response to escalating oncogenic stress during tumorigenesis
The DNA damage checkpoint precedes activation of ARF in response to escalating oncogenic stress during tumorigenesis
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DOI：
10.1038/cdd.2013.76
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发表时间：
2013-11-01
影响因子：
12.4
通讯作者：
Gorgoulis, V. G.
中科院分区：
文献类型：
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作者：
Evangelou, K.;Bartkova, J.;Gorgoulis, V. G.
致癌刺激触发DNA损伤反应（DDR）和诱导替代阅读框（ARF）肿瘤抑制因子，这两者都可以激活p53通路并为肿瘤进展提供内在障碍。然而，在肿瘤发生过程中，ARF诱导和DDR激活的各自时间框架和信号阈值仍然难以捉摸。本文通过分析小鼠膀胱、结肠、胰腺和皮肤的癌前病变和恶性病变模型来解决这些问题。一致地，与DDR或p16（INK4A）的激活相比，ARF的表达发生在肿瘤进展的后期，p16是一种与ARF重叠的肿瘤抑制基因。在一些人类临床环境中获得了类似的结果，包括膀胱、头颈部、皮肤和胰腺的早期和进行性病变。对暴露于各种致癌基因的上皮细胞和成纤维细胞模型的机制分析表明，与DDR较低的激活阈值相比，ARF的延迟上调反映了对至少两种致癌“撞击”所引发的更高的、基于转录的致癌应激阈值的需求。我们认为，相对于DDR激活，ARF为肿瘤发展提供了一个互补和延迟的屏障，对不断升级的致癌过载的更强大的刺激做出反应。
Oncogenic stimuli trigger the DNA damage response (DDR) and induction of the alternative reading frame (ARF) tumor suppressor, both of which can activate the p53 pathway and provide intrinsic barriers to tumor progression. However, the respective timeframes and signal thresholds for ARF induction and DDR activation during tumorigenesis remain elusive. Here, these issues were addressed by analyses of mouse models of urinary bladder, colon, pancreatic and skin premalignant and malignant lesions. Consistently, ARF expression occurred at a later stage of tumor progression than activation of the DDR or p16(INK4A), a tumor-suppressor gene overlapping with ARF. Analogous results were obtained in several human clinical settings, including early and progressive lesions of the urinary bladder, head and neck, skin and pancreas. Mechanistic analyses of epithelial and fibroblast cell models exposed to various oncogenes showed that the delayed upregulation of ARF reflected a requirement for a higher, transcriptionally based threshold of oncogenic stress, elicited by at least two oncogenic 'hits', compared with lower activation threshold for DDR. We propose that relative to DDR activation, ARF provides a complementary and delayed barrier to tumor development, responding to more robust stimuli of escalating oncogenic overload.