Differential responses of stress genes to low dose-rate gamma irradiation.
Differential responses of stress genes to low dose-rate gamma irradiation.
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发表时间：
2003-04
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通讯作者：
S. Amundson;Richard A. Lee;C. A. Koch-Paiz;M. Bittner;P. Meltzer;J. Trent;A. Fornace
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作者：
S. Amundson;Richard A. Lee;C. A. Koch-Paiz;M. Bittner;P. Meltzer;J. Trent;A. Fornace
在过去，大多数关于电离辐射反应的机理研究都采用了非常大的剂量，然后将结果外推到与人体照射相关的剂量。然而，越来越明显的是，这并不能准确或完整地说明大多数环境照射的影响，因为这些照射往往是低剂量的，而且是长期的。我们已经启动了低剂量暴露的直接研究，并使用相对敏感的ML-1细胞系，已经表明，基因表达的变化可以由剂量为10 cGy或更低的伽马射线在人体细胞中触发。我们现在已经将这些研究扩展到研究降低辐射率对基因诱导的影响。在ML-1人髓性白血病细胞系中，我们发现，将剂量率降低超过三个数量级会导致对诱导细胞凋亡的一些保护，但在2至50 cGy之间仍会导致p53调节基因CDKN 1A、GADD 45 A和MDM 2的线性诱导。降低暴露速率降低了CDKN 1A和GADD 45 A的诱导幅度，但不降低细胞周期延迟的幅度或持续时间。相比之下，MDM 2的诱导程度相同，与剂量递送速率无关。微阵列分析已经确定了额外的低剂量率诱导基因，并表明在ML-1中存在两种一般类型的低剂量率应答者。一组基因以剂量率依赖性方式诱导，类似于GADD 45 A和CDKN 1A。该基因簇的功能注释表明在细胞凋亡调控中具有已知作用的基因占优势。类似地，还鉴定了一组具有剂量率非依赖性诱导的基因，如MDM 2所见。该组中的大多数基因参与细胞周期调控。这种明显的差异调节应激信号通路和结果在长期辐射暴露的致癌作用和风险评估的影响，并不能预测从经典的高剂量研究。
In the past, most mechanistic studies of ionizing radiation response have employed very large doses, then extrapolated the results down to doses relevant to human exposure. It is becoming increasingly apparent, however, that this does not give an accurate or complete picture of the effects of most environmental exposures, which tend to be of low dose and protracted over time. We have initiated direct studies of low dose exposures, and using the relatively responsive ML-1 cell line, have shown that changes in gene expression can be triggered by doses of gamma-rays of 10 cGy and less in human cells. We have now extended these studies to investigate the effects on gene induction of reducing the rate of irradiation. In the ML-1 human myeloid leukemia cell line, we have found that reducing the dose rate over three orders of magnitude results in some protection against the induction of apoptosis, but still causes linear induction of the p53-regulated genes CDKN1A, GADD45A, and MDM2 between 2 and 50 cGy. Reducing the rate of exposure reduces the magnitude of induction of CDKN1A and GADD45A, but not the magnitude or duration of cell cycle delay. In contrast, MDM2 is induced to the same extent regardless of the rate of dose delivery. Microarray analysis has identified additional low dose-rate-inducible genes, and indicates the existence of two general classes of low dose-rate responders in ML-1. One group of genes is induced in a dose rate-dependent fashion, similar to GADD45A and CDKN1A. Functional annotation of this gene cluster indicates a preponderance of genes with known roles in apoptosis regulation. Similarly, a group of genes with dose rate-independent induction, such as seen for MDM2, was also identified. The majority of genes in this group are involved in cell cycle regulation. This apparent differential regulation of stress signaling pathways and outcomes in response to protracted radiation exposure has implications for carcinogenesis and risk assessment, and could not have been predicted from classical high dose studies.