Maxwell Christopher A, Fleisch Markus C, Costes Sylvain V, Erickson Anna C, Boissière Arnaud, Gupta Rishi, Ravani Shraddha A, Parvin Bahram, Barcellos-Hoff Mary Helen
Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA.
Cancer Res. 2008 Oct 15;68(20):8304-11. doi: 10.1158/0008-5472.CAN-08-1212.
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 beta1 (TGFbeta), 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, TGFbeta inhibition significantly increased centrosome aberration frequency, tetraploidy, and aneuploidy in nonirradiated HMEC. Rather than preventing radiation-induced or spontaneous centrosome aberrations, TGFbeta 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 TGFbeta signaling.
辐射诱导的基因组不稳定性，即受辐射细胞的子代显示出高频的非克隆性基因组损伤，其发生频率与突变不一致。我们研究了低剂量辐射作用下人类乳腺上皮细胞（HMEC）中这种非靶向效应的机制。我们在受辐射的HMEC中鉴定出一种与中心体相关的表达特征，并在此表明，中心体失调在辐射后的第一个细胞周期就会发生，具有剂量依赖性，而且这些细胞的存活子代在基因组上是不稳定的，这可通过自发DNA损伤、四倍体和非整倍体得到证明。对基因组不稳定性的克隆分析显示阈值大于10 cGy。转化生长因子β1（TGFβ）参与基因组稳定性的调节且可被辐射激活，用其处理可降低受辐射HMEC中的中心体表达特征和中心体畸变。此外，TGFβ抑制可显著增加未受辐射HMEC中的中心体畸变频率、四倍体和非整倍体。TGFβ并非阻止辐射诱导的或自发的中心体畸变，而是通过p53依赖性凋亡选择性地清除不稳定细胞。总之，这些研究表明，辐射会破坏中心体稳定性，而这是正常人上皮细胞基因组不稳定的基础，并且这一过程可被辐射诱导的TGFβ信号通路所对抗。
