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首页> 外文期刊>Molecular Cancer >Id4 dependent acetylation restores mutant-p53 transcriptional activity
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Id4 dependent acetylation restores mutant-p53 transcriptional activity

机译：Id4依赖的乙酰化恢复突变体p53转录活性

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Background The mechanisms that can restore biological activity of mutant p53 are an area of high interest given that mutant p53 expression is observed in one third of prostate cancer. Here we demonstrate that Id4, an HLH transcriptional regulator and a tumor suppressor, can restore the mutant p53 transcriptional activity in prostate cancer cells. Methods Id4 was over-expressed in prostate cancer cell line DU145 harboring mutant p53 (P223L and V274F) and silenced in LNCaP cells with wild type p53. The cells were used to quantitate apoptosis, p53 localization, p53 DNA binding and transcriptional activity. Immuno-precipitation/-blot studies were performed to demonstrate interactions between Id4, p53 and CBP/p300 and acetylation of specific lysine residues within p53. Results Ectopic expression of Id4 in DU145 cells resulted in increased apoptosis and expression of BAX, PUMA and p21, the transcriptional targets of p53. Mutant p53 gained DNA binding and transcriptional activity in the presence of Id4 in DU145 cells. Conversely, loss of Id4 in LNCaP cells abrogated wild type p53 DNA binding and transactivation potential. Gain of Id4 resulted in increased acetylation of mutant p53 whereas loss of Id4 lead to decreased acetylation in DU145 and LNCaP cells respectively. Id4 dependent acetylation of p53 was in part due to a physical interaction between Id4, p53 and acetyl-transferase CBP/p300. Conclusions Taken together, our results suggest that Id4 regulates the activity of wild type and mutant p53. Id4 promoted the assembly of a macromolecular complex involving CBP/P300 that resulted in acetylation of p53 at K373, a critical post-translational modification required for its biological activity.
机译：背景技术考虑到在前列腺癌的三分之一中观察到了突变体p53的表达，可以恢复突变体p53的生物学活性的机制是人们高度关注的领域。在这里，我们证明Id4，一种HLH转录调节因子和一种肿瘤抑制因子，可以在前列腺癌细胞中恢复突变的p53转录活性。方法Id4在带有突变p53（P223L和V274F）的前列腺癌细胞DU145中过表达，而在野生型p53的LNCaP细胞中沉默。这些细胞用于定量细胞凋亡，p53定位，p53 DNA结合和转录活性。进行了免疫沉淀/印迹研究，以证明Id4，p53和CBP / p300之间的相互作用以及p53中特定赖氨酸残基的乙酰化。结果Id145在DU145细胞中异位表达导致凋亡增加以及BAX，PUMA和p21（p53的转录靶标）的表达增加。突变的p53在DU145细胞中存在Id4时获得了DNA结合和转录活性。相反，LNCaP细胞中Id4的丧失消除了野生型p53 DNA结合和反式激活的潜力。 Id4的获得导致突变体p53的乙酰化增加，而Id4的丧失分别导致DU145和LNCaP细胞的乙酰化降低。 p53的Id4依赖性乙酰化部分是由于Id4，p53与乙酰基转移酶CBP / p300之间的物理相互作用。结论综上所述，我们的结果表明Id4调节野生型和突变型p53的活性。 Id4促进了涉及CBP / P300的大分子复合物的组装，该复合物导致p53在K373处乙酰化，这是其生物学活性所需的关键翻译后修饰。

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