A single nucleotide polymorphism in the MDM2 gene disrupts the oscillation of p53 and MDM2 levels in cells
A single nucleotide polymorphism in the MDM2 gene disrupts the oscillation of p53 and MDM2 levels in cells
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DOI：
10.1158/0008-5472.can-06-2656
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发表时间：
2007-03-15
期刊：
影响因子：
11.2
通讯作者：
Levine, Arnold J.
中科院分区：
文献类型：
--
作者：
Hu, Wenwei;Feng, Zhaohui;Levine, Arnold J.
在暴露于应激后的细胞中已经观察到p53和MDM 2蛋白的振荡。描述这些振荡的数学模型预测，振荡只发生在选定的p53和MDM 2蛋白水平。该模型预测表明，振荡将在含有高水平MDM 2的细胞中消失，如在MDM 2基因（SNP 309）中的单核苷酸多态性所观察到的。在各种人细胞系中检测了SNP 309对p53-MDM 2振荡的影响，并且在具有至少一个SNP 309野生型等位基因（T/T或T/G）的细胞中观察到振荡，但在SNP 309纯合（G/G）的细胞中未观察到振荡。此外，雌激素优先刺激SNP 309 G等位基因MDM 2的转录，并增加SNP 309（G/G）纯合雌激素反应细胞中MDM 2蛋白的水平。这些结果表明，SNP 309 G等位基因可能通过进一步升高MDM 2水平和破坏p53-MDM 2振荡而促进性别特异性肿瘤发生。此外，使用在四环素调节的启动子下表达野生型p53的H1299-HW 24细胞，仅当p53水平在特定范围内时观察到p53-MDM 2振荡，并且发现DNA损伤是触发p53-MDM 2振荡所必需的。这项研究表明，在SNP 309（G/G）纯合细胞中较高水平的MDM 2不允许应激后协调的p53-MDM 2振荡，这可能导致p53途径效率降低并与临床表型相关（即，女性癌症发病年龄较早）。
Oscillations of both p53 and MDM2 proteins have been observed in cells after exposure to stress. A mathematical model describing these oscillations predicted that oscillations occur only at selected levels of p53 and MDM2 proteins. This model prediction suggests that oscillations will disappear in cells containing high levels of MDM2 as observed with a single nucleotide polymorphism in the MDM2 gene (SNP309). The effect of SNP309 upon the p53-MDM2 oscillation was examined in various human cell lines and the oscillations were observed in the cells with at least one wild-type allele for SNP309 (T/T or T/G) but not in cells homozygous for SNP309 (G/G). Furthermore, estrogen preferentially stimulated the transcription of MDM2 from SNP309 G allele and increased the levels of MDM2 protein in estrogen-responsive cells homozygous for SNP309 (G/G). These results suggest the possibility that SNP309 G allele may contribute to gender-specific tumorigenesis through further elevating the MDM2 levels and disrupting the p53-MDM2 oscillation. Furthermore, using the H1299-HW24 cells expressing wild-type p53 under a tetracycline-regulated promoter, the p53-MDM2 oscillation was observed only when p53 levels were in a specific range, and DNA damage was found to be necessary for triggering the p53-MDM2 oscillation. This study shows that higher levels of MDM2 in cells homozygous for SNP309 (G/G) do not permit coordinated p53-MDM2 oscillation after stress, which might contribute to decreased efficiency of the p53 pathway and correlates with a clinical phenotype (i.e., the development of cancers at earlier age of onset in female).