Targeted and Nontargeted Effects of Ionizing Radiation That Impact Genomic Instability
Targeted and Nontargeted Effects of Ionizing Radiation That Impact Genomic Instability
复制标题
DOI：
10.1158/0008-5472.can-08-1212
复制
发表时间：
2008-10-15
期刊：
影响因子：
11.2
通讯作者：
Barcellos-Hoff, Mary Helen
中科院分区：
文献类型：
--
作者：
Maxwell, Christopher A.;Fleisch, Markus C.;Barcellos-Hoff, Mary Helen
辐射诱导的基因组不稳定性，即受辐射细胞的后代表现出高频率的非克隆性基因组损伤，以与突变不一致的频率发生。我们研究了低剂量辐射对人乳腺上皮细胞(HMEC)产生这种非靶向效应的机制。我们在辐射后的HMEC中发现了一个中心体相关的表达特征，并在这里表明中心体去调控发生在照射后的第一个细胞周期中，是剂量依赖的，这些细胞的存活子代在基因组上是不稳定的，这一点从自发的DNA损伤、四倍体和非整倍体得到了证明。基因组不稳定性的克隆性分析表明，~gt；10cGy值为阈值。转化生长因子β1(TGFβ1)参与了基因组稳定性的调节，可被辐射激活，经治疗后，照射后HMEC的中心体表达特征和中心体异常均减少。此外，抑制转化生长因子β显著增加未照射的HMEC的中心体畸变率、四倍体和非整倍体。转化生长因子β并没有阻止辐射诱导或自发的中心体异常，而是通过依赖于p53的细胞凋亡选择性地删除了不稳定的细胞。总之，这些研究表明，辐射解除了中心体稳定性的调控，中心体稳定性是正常人类上皮细胞基因组不稳定的基础，这可以被辐射诱导的转化生长因子β信号所对抗。[癌症资源2008；68(20)：8304-11]
Radiation-induced genomic instability, in which the progeny of irradiated cells display a high frequency of nonclonal genomic damage, occurs at a frequency inconsistent with mutation. We investigated the mechanism of this nontargeted effect in human mammary epithelial cells (HMEC) exposed to low doses of radiation. We identified a centrosome-associated expression signature in irradiated HMEC and show here that centrosome deregulation occurs in the first cell cycle after irradiation, is dose dependent, and that viable daughters of these cells are genomically unstable as evidenced by spontaneous DNA damage, tetraploidy, and aneuploidy. Clonal analysis of genomic instability showed a threshold of >10 cGy. Treatment with transforming growth factor beta 1 (TGF beta), which is implicated in regulation of genomic stability and is activated by radiation, reduced both the centrosome expression signature and centrosome aberrations in irradiated HMEC. Furthermore, TGF beta inhibition significantly increased centrosome aberration frequency, tetraploidy, and aneuploidy in nonirradiated HMEC. Rather than preventing radiation-induced or spontaneous centrosome aberrations, TGF beta selectively deleted unstable cells via p53-dependent apoptosis. Together, these studies show that radiation deregulates centrosome stability, which underlies genomic instability in normal human epithelial cells, and that this can be opposed by radiation-induced TGF beta signaling. [Cancer Res 2008;68(20):8304-11]