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首页> 外文期刊>Cell cycle >Phospho-DeltaNp63alpha/NF-Y protein complex transcriptionally regulates DDIT3 expression in squamous cell carcinoma cells upon cisplatin exposure.
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Phospho-DeltaNp63alpha/NF-Y protein complex transcriptionally regulates DDIT3 expression in squamous cell carcinoma cells upon cisplatin exposure.

机译：顺铂暴露后，Phospho-DeltaNp63alpha / NF-Y蛋白复合物在鳞状细胞癌细胞中转录调节DDIT3表达。

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摘要

Cisplatin remains the most important chemotherapeutic agent for patients with human head and neck cancer. However, tumor cells often develop resistance to cisplatin-induced apoptosis. We previously found that head and neck squamous cell carcinoma (HNSCC) cells exposed to cisplatin display a marked ATM-induced phosphorylation of DeltaNp63alpha. However, the mutated Np63-S385G failed to undergo phosphorylation by ATM kinase. We used HNSCC cell lines expressing the wild type DeltaNp63alpha or mutated DeltaNp63alpha-S385G to determine the effect of S385G mutation on the DeltaNp63alpha transcriptional activity and protein-protein interactions. The S385G mutation in DeltaNp63alpha dramatically abolished the upregulation/downregulation of downstream gene targets and the binding of DeltaNp63alpha-S385G to certain promoters. In contrast to the non-phosphorylated DeltaNp63alpha-S385G, the phospho-DeltaNp63alpha forms protein-protein complexes with NF-YA transcription factor and regulates the transcription of DDIT3 gene implicated in the programmed cell death of HNSCC cells upon cisplatin exposure. We suggest that the transcriptional activation of DeltaNp63alpha through its phosphorylation by ATM kinase in HNSCC cells exposed to cisplatin is a critical step in the subsequent sensitivity of certain human head and neck cancers to platinum therapy.
机译：顺铂仍然是人类头颈部癌症患者最重要的化学治疗剂。然而，肿瘤细胞通常对顺铂诱导的细胞凋亡产生抗性。我们以前发现，暴露于顺铂的头颈部鳞状细胞癌（HNSCC）细胞显示出明显的ATM诱导的DeltaNp63alpha磷酸化。但是，突变的Np63-S385G无法通过ATM激酶进行磷酸化。我们使用表达野生型DeltaNp63alpha或突变的DeltaNp63alpha-S385G的HNSCC细胞系来确定S385G突变对DeltaNp63alpha转录活性和蛋白质相互作用的影响。 DeltaNp63alpha中的S385G突变极大地消除了下游基因靶标的上调/下调以及DeltaNp63alpha-S385G与某些启动子的结合。与非磷酸化的DeltaNp63alpha-S385G相反，磷酸化的DeltaNp63alpha与NF-YA转录因子形成蛋白质-蛋白质复合物，并调节与顺铂接触后HNSCC细胞程序性死亡有关的DDIT3基因的转录。我们建议，在暴露于顺铂的HNSCC细胞中，通过ATM激酶的磷酸化使DeltaNp63alpha转录激活是某些人类头颈癌对铂治疗的后续敏感性的关键步骤。

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