主页 > 医药科学 >
【Nature编译】癌初期病害的DNA损伤检查点活化
Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions
来源
Nature 434, 907 - 913 (14 April 2005); doi:10.1038/nature03485
http://www.nature.com/cgi-taf/DynaPage.taf?file=/nature/journal/v434/n7035/abs/nature03485_fs.html
摘要原文
DNA damage checkpoint genes, such as p53, are frequently mutated in human cancer, but the selective pressure for their inactivation remains elusive. We analysed a panel of human lung hyperplasias, all of which retained wild-type p53 genes and had no signs of gross chromosomal instability, and found signs of a DNA damage response, including histone H2AX and Chk2 phosphorylation, p53 accumulation, focal staining of p53 binding protein 1 (53BP1) and apoptosis. Progression to carcinoma was associated with p53 or 53BP1 inactivation and decreased apoptosis. A DNA damage response was also observed in dysplastic nevi and in human skin xenografts, in which hyperplasia was induced by overexpression of growth factors. Both lung and experimentally-induced skin hyperplasias showed allelic imbalance at loci that are prone to DNA double-strand break formation when DNA replication is compromised (common fragile sites). We propose that, from its earliest stages, cancer development is associated with DNA replication stress, which leads to DNA double-strand breaks, genomic instability and selective pressure for p53 mutations.
编译
DNA损伤检查点基因，如p53，在人癌中经常变异，但对它们钝化的选择性压力至今还不清楚。我们分析了人肺部增生过剩的小部分基因组，这些基因组都保留野生p53，并且没有明显染色体不稳定的信号，也发现了DNA损伤反应信号——包括组蛋白H2AX和Chk2磷酸化，p53累积，p53结合蛋白1(53BP1)灶点形成和凋亡。瘤的演进与p53或53BP1钝化和减少凋亡有关。DNA损伤反应和人皮肤异种移植中也有发现—增生过剩由生长因子高表达所诱导。在肺和实验性地诱导皮肤增生过剩中都证明：当DNA复制遭损时（一般的薄弱位点），易于形成DNA双链断裂位点的等位基因不平衡。我们建议，从癌症最早的形成来说，癌的演化与DNA复制压力—导致DNA双链断裂，基因组不稳定和p53变异的选择性压力有关。 [标签:content1][标签:content2]
阅读本文的人还阅读：
作者:admin@医学,生命科学 2011-03-28 17:14
医学,生命科学网