DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis
DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis
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DOI：
10.1038/nature03482
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发表时间：
2005-04-14
期刊：
影响因子：
64.8
通讯作者：
Bartek, J
中科院分区：
文献类型：
--
作者：
Bartkova, J;Horejsi, Z;Bartek, J
在癌症的演变过程中，初期肿瘤经历了“致癌应激”，这引起了消除这种危险细胞的反反应。然而，这种压力的性质仍然难以捉摸，诱导生长停滞或细胞死亡的诱导型抗癌屏障也是如此。在这里，我们表明，在不同阶段的膀胱，乳腺，肺和结肠的人类肿瘤的临床标本中，早期前驱病变（但不是正常组织）通常表达活化的DNA损伤反应的标志物。这些包括磷酸化激酶ATM和Chk 2，以及磷酸化组蛋白H2 AX和p53。类似的检查点反应诱导培养细胞后，表达不同的癌基因，解除DNA复制。连同遗传分析，包括等位基因不平衡的全基因组评估，我们的数据表明，在肿瘤发生的早期（在基因组不稳定性和恶性转化之前），人类细胞激活ATR/ATM调节的DNA损伤反应网络，其延迟或预防癌症。损害该检查点的突变，包括ATM-Chk 2 p53通路中的缺陷，可能会导致细胞增殖、存活、基因组不稳定性增加和肿瘤进展。
During the evolution of cancer, the incipient tumour experiences 'oncogenic stress', which evokes a counter- response to eliminate such hazardous cells. However, the nature of this stress remains elusive, as does the inducible anti-cancer barrier that elicits growth arrest or cell death. Here we show that in clinical specimens from different stages of human tumours of the urinary bladder, breast, lung and colon, the early precursor lesions ( but not normal tissues) commonly express markers of an activated DNA damage response. These include phosphorylated kinases ATM and Chk2, and phosphorylated histone H2AX and p53. Similar checkpoint responses were induced in cultured cells upon expression of different oncogenes that deregulate DNA replication. Together with genetic analyses, including a genome-wide assessment of allelic imbalances, our data indicate that early in tumorigenesis ( before genomic instability and malignant conversion), human cells activate an ATR/ATM- regulated DNA damage response network that delays or prevents cancer. Mutations compromising this checkpoint, including defects in the ATM - Chk2 p53 pathway, might allow cell proliferation, survival, increased genomic instability and tumour progression.