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首页> 外文期刊>Molecular and Cellular Biology >The Absence of Ser389 Phosphorylation in p53 Affects the Basal Gene Expression Level of Many p53-Dependent Genes and Alters the Biphasic Response to UV Exposure in Mouse Embryonic Fibroblasts
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The Absence of Ser389 Phosphorylation in p53 Affects the Basal Gene Expression Level of Many p53-Dependent Genes and Alters the Biphasic Response to UV Exposure in Mouse Embryonic Fibroblasts

机译：p53缺乏Ser389磷酸化影响许多p53依赖基因的基础基因表达水平，并改变小鼠胚胎成纤维细胞对紫外线照射的双相反应。

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Phosphorylation is important in p53-mediated DNA damage responses. After UV irradiation, p53 is phosphorylated specifically at murine residue Ser389. Phosphorylation mutant p53.S389A cells and mice show reduced apoptosis and compromised tumor suppression after UV irradiation. We investigated the underlying cellular processes by time-series analysis of UV-induced gene expression responses in wild-type, p53.S389A, and p53?/? mouse embryonic fibroblasts. The absence of p53.S389 phosphorylation already causes small endogenous gene expression changes for 2,253, mostly p53-dependent, genes. These genes showed basal gene expression levels intermediate to the wild type and p53?/?, possibly to readjust the p53 network. Overall, the p53.S389A mutation lifts p53-dependent gene repression to a level similar to that of p53?/? but has lesser effect on p53-dependently induced genes. In the wild type, the response of 6,058 genes to UV irradiation was strictly biphasic. The early stress response, from 0 to 3 h, results in the activation of processes to prevent the accumulation of DNA damage in cells, whereas the late response, from 12 to 24 h, relates more to reentering the cell cycle. Although the p53.S389A UV gene response was only subtly changed, many cellular processes were significantly affected. The early response was affected the most, and many cellular processes were phase-specifically lost, gained, or altered, e.g., induction of apoptosis, cell division, and DNA repair, respectively. Altogether, p53.S389 phosphorylation seems essential for many p53 target genes and p53-dependent processes.
机译：磷酸化在p53介导的DNA损伤反应中很重要。紫外线照射后，p53在鼠残基Ser389上特异性磷酸化。磷酸化突变体p53.S389A细胞和小鼠在紫外线照射后显示出降低的凋亡和受损的肿瘤抑制作用。通过时间序列分析野生型p53.S389A和p53 ？/？小鼠胚胎成纤维细胞中紫外线诱导的基因表达反应，我们研究了潜在的细胞过程。 p53.S389磷酸化的缺乏已经引起2,253个主要是p53依赖性基因的小内源基因表达变化。这些基因的基础基因表达水平介于野生型和p53 ？/？之间，可能是为了重新调节p53网络。总体而言，p53.S389A突变将p53依赖的基因阻抑提高到与p53 ？/？相似的水平，但对p53依赖的诱导基因的影响较小。在野生型中，6,058个基因对紫外线辐射的反应是严格双相的。早期的应激反应（从0到3小时）导致激活过程，以防止DNA损伤在细胞中积累，而后期的应激反应（从12到24小时）更多地与重新进入细胞周期有关。尽管p53.S389A UV基因应答仅发生了细微变化，但许多细胞过程均受到显着影响。早期反应受到的影响最大，并且许多细胞过程是阶段特异性丢失，获得或改变的，例如分别诱导凋亡，细胞分裂和DNA修复。总而言之，p53.S389磷酸化似乎对于许多p53靶基因和p53依赖性过程至关重要。

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