UV-induced stabilization of c-fos and other short-lived mRNAs
UV-induced stabilization of c-fos and other short-lived mRNAs
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DOI：
10.1128/mcb.20.10.3616-3625.2000
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发表时间：
2000-05-01
影响因子：
5.3
通讯作者：
Herrlich, P
中科院分区：
文献类型：
--
作者：
Blattner, C;Kannouche, P;Herrlich, P
短波长紫外线（UVC）照射细胞改变了基因表达的程序，部分在不到15分钟。作为一个立即早期的基因在响应于UV，表达的癌基因c-fos的上调。这种直接诱导受转录水平的调节，并且由于自催化的转录关闭和c-fos mRNA的快速周转而具有瞬时性。在一个实验中分析的动力学的c-fos mRNA表达在小鼠成纤维细胞照射UVC，我们发现，除了最初的瞬时诱导，c-fos mRNA积累在第二波开始在4至5小时照射后，在8小时达到最大值，并持续几个小时以上。这是伴随着Fos蛋白合成的增加。c-fos RNA的第二个峰是由mRNA半衰期从约10分钟增加到60分钟的UV剂量依赖性增加引起的。Kin 17基因、c-jun、I κ B和c-myc）被稳定化（例如，Kin 17 RNA从80分钟到超过8小时）。延迟响应不是由于自分泌细胞因子分泌与随后的分泌细胞的自刺激或UV诱导的生长因子受体激活。不能修复紫外线诱导的DNA损伤的细胞对较低剂量的紫外线的反应是c-for和Kin 17 mRNA的积累比修复熟练的野生型细胞更大，这表明修复蛋白参与的过程调节mRNA的稳定性。虽然类似于p53的诱导，但p53的DNA损伤依赖性增加不是稳定反应中的必要中间体，因为来自p53敲除小鼠的细胞显示与野生型细胞相同的c-fos和Kin 17 mRNA积累模式。这些数据表明，由UV辐射诱导的信号流不仅涉及蛋白质稳定性（p53）和转录，而且涉及RNA稳定性，这是迄今为止UV诱导的调节的未被认识的水平。
Irradiation of cells with short-wavelength ultraviolet light (UVC) changes the program of gene expression, in part within less than 15 min. As one of the immediate early genes in response to UV, expression of the oncogene c-fos is upregulated. This immediate induction is regulated nt the transcriptional level and is transient in character, due to the autocatalyzed shutoff of transcription and the rapid turnover of c-fos mRNA. In an experiment analyzing the kinetics of c-fos mRNA expression in murine fibroblasts irradiated with UVC, we found that, in addition to the initial transient induction, c-fos mRNA accumulated in a second wave starting at 4 to 5 h after irradiation, reaching a maximum at 8 h, and persisting for several more hours. It was accompanied by an increase in Fos protein synthesis. The second peak of c-fos RNA was caused by an UV dose-dependent increase in mRNA half-life from about 10 to 60 min. With similar kinetics, the mRNAs of other UV target genes (i.e., the Kin17 gene, c-jun, I kappa B, and c-myc) were stabilized (e.g., Kin17 RNA from 80 min to more than 8 h). The delayed response was not due to autocrine cytokine secretion with subsequent autostimulation of the secreting cells or to UV-induced growth factor receptor activation. Cells unable to repair UVC-induced DNA damage responded to lower doses of UVC with an even greater accumulation of c-for and Kin17 mRNAs than repair-proficient wild-type cells, suggesting that a process in which a repair protein is involved regulates mRNA stability. Although resembling the induction of p53, a DNA damage-dependent increase in p53 was not a necessary intermediate in the stabilization reaction, since cells derived from p53 knockout mice showed the same pattern of c-fos and Kin17 mRNA accumulation as wild-type cells. The data indicate that the signal flow induced by UV radiation addresses not only protein stability (p53) and transcription but also RNA stability, a hitherto-unrecogoized level of UV-induced regulation.