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首页> 外文期刊>Oncogenesis. >Tumor suppressor protein Pdcd4 interacts with Daxx and modulates the stability of Daxx and the Hipk2-dependent phosphorylation of p53 at serine 46
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Tumor suppressor protein Pdcd4 interacts with Daxx and modulates the stability of Daxx and the Hipk2-dependent phosphorylation of p53 at serine 46

机译：肿瘤抑制蛋白Pdcd4与Daxx相互作用并调节Daxx的稳定性和丝氨酸46处p53的Hipk2依赖性磷酸化

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The tumor suppressor protein Pdcd4 is a nuclear/cytoplasmic shuttling protein that has been implicated in the development of several types of human cancer. In the nucleus, Pdcd4 affects the transcription of specific genes by modulating the activity of several transcription factors. We have identified the Daxx protein as a novel interaction partner of Pdcd4. Daxx is a scaffold protein with roles in diverse processes, including transcriptional regulation, DNA-damage signaling, apoptosis and chromatin remodeling. We show that the interaction of both proteins is mediated by the N-terminal domain of Pdcd4 and the central part of Daxx, and that binding to Pdcd4 stimulates the degradation of Daxx, presumably by disrupting the interaction of Daxx with the de-ubiquitinylating enzyme Hausp. Daxx has previously been shown to serve as a scaffold for protein kinase Hipk2 and tumor suppressor protein p53 and to stimulate the phosphorylation of p53 at serine 46 (Ser-46) in response to genotoxic stress. We show that Pdcd4 also disrupts the Daxx–Hipk2 interaction and inhibits the phosphorylation of p53. We also show that ultraviolet irradiation decreases the expression of Pdcd4. Taken together, our results support a model in which Pdcd4 serves to suppress the phosphorylation of p53 in the absence of DNA damage, while the suppressive effect of Pdcd4 is abrogated after DNA damage owing to the decrease of Pdcd4. Overall, our data demonstrate that Pdcd4 is a novel modulator of Daxx function and provide evidence for a role of Pdcd4 in restraining p53 activity in unstressed cells.
机译：肿瘤抑制蛋白Pdcd4是一种核/胞质穿梭蛋白，与多种类型的人类癌症的发展有关。在细胞核中，Pdcd4通过调节几种转录因子的活性来影响特定基因的转录。我们已将Daxx蛋白鉴定为Pdcd4的新型相互作用伴侣。 Daxx是一种支架蛋白，在多种过程中起作用，包括转录调控，DNA损伤信号转导，凋亡和染色质重塑。我们显示这两种蛋白质的相互作用是由Pdcd4的N末端结构域和Daxx的中央部分介导的，并且与Pdcd4的结合刺激了Daxx的降解，大概是通过破坏Daxx与去泛素化酶Hausp的相互作用。 Daxx先前已被证明可充当蛋白激酶Hipk2和肿瘤抑制蛋白p53的支架，并响应基因毒性应激而刺激丝氨酸46（Ser-46）上p53的磷酸化。我们显示，Pdcd4还破坏了Daxx–Hipk2相互作用并抑制p53的磷酸化。我们还表明，紫外线照射会降低Pdcd4的表达。两者合计，我们的结果支持一个模型，其中在没有DNA损伤的情况下Pdcd4可以抑制p53的磷酸化，而在DNA损伤后由于Pdcd4的减少而废除了Pdcd4的抑制作用。总体而言，我们的数据表明Pdcd4是Daxx功能的新型调节剂，并为Pdcd4在抑制未应激细胞中p53活性中的作用提供了证据。

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