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首页> 外文期刊>Molecular and Cellular Biology >p53 Downregulates Its Activating Vaccinia-Related Kinase 1, Forming a New Autoregulatory Loop
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p53 Downregulates Its Activating Vaccinia-Related Kinase 1, Forming a New Autoregulatory Loop

机译：p53下调其激活的痘苗相关激酶1，形成一个新的自调节回路

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The stable accumulation of p53 is detrimental to the cell because it blocks cell growth and division. Therefore, increases in p53 levels are tightly regulated, mainly by its transcriptional target, mdm2, that downregulates p53. Elucidation of new signaling pathways requires the characterization of the members and the nature of their connection. Vaccinia-related kinase 1 (VRK1) contributes to p53 stabilization by partly interfering with its mdm2-mediated degradation, among other mechanisms; therefore, it is likely that some form of autoregulation between VRK1 and p53 must occur. We report here the identification of an autoregulatory loop between p53 and its stabilizing VRK1. There is an inverse correlation between VRK1 and p53 levels in cell lines, and induction of p53 by UV light downregulates VRK1 in fibroblasts. As the amount of p53 protein increases, there is a downregulation of the VRK1 protein level independent of its promoter. This effect is indirect but requires a transcriptionally active p53. The three most common transcriptionally inactive mutations detected in hereditary (Li-Fraumeni syndrome) and sporadic human cancer, p53(R175H), p53(R248W), and p53(R273H), as well as p53(R280K), are unable to induce downregulation of VRK1 protein. The p53 isoforms Δ40p53 and p53β, lacking the transactivation and oligomerization domains, respectively, do not downregulate VRK1. VRK1 downregulation induced by p53 is independent of mdm2 activity and proteasome-mediated degradation since it occurs in the presence of proteasome inhibitors and in mdm2-deficient cells. The degradation of VRK1 is sensitive to chloroquine, an inhibitor of the late endosome-lysosome transport, and to serine protease inhibitors of the lysosomal pathway.
机译：p53的稳定积累对细胞有害，因为它会阻止细胞生长和分裂。因此，p53水平的升高受到下调p53的转录目标 mdm2 的严格调控。要阐明新的信号传导途径，需要表征成员及其连接的性质。牛痘相关激酶1（VRK1）通过部分干扰其 mdm2 介导的降解，从而促进p53的稳定。因此，很可能必须在VRK1和p53之间发生某种形式的自动调节。我们在这里报告了p53及其稳定VRK1之间的自动调节回路的鉴定。细胞系中的VRK1和p53水平之间呈负相关，而紫外线诱导的p53下调了成纤维细胞中的VRK1。随着p53蛋白量的增加，VRK1蛋白水平下调，而与其启动子无关。这种作用是间接的，但需要转录活性的p53。在遗传性（Li-Fraumeni综合征）和散发性人类癌症中检测到的三个最常见的转录失活突变p53（R175H），p53（R248W）和p53（R273H）以及p53（R280K）无法诱导下调VRK1蛋白。分别缺乏反式激活和低聚结构域的p53亚型Δ40p53和p53β不会下调VRK1。 p53诱导的VRK1下调与 mdm2 活性和蛋白酶体介导的降解无关，因为它在蛋白酶体抑制剂存在和 mdm2 缺陷细胞中发生。 VRK1的降解对晚期内体-溶酶体运输的抑制剂氯喹和溶酶体途径的丝氨酸蛋白酶抑制剂敏感。

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