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首页> 外文期刊>Cell cycle >The p27-Skp2 axis mediates glucocorticoidinduced cell cycle arrest in T-lymphoma cells
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The p27-Skp2 axis mediates glucocorticoidinduced cell cycle arrest in T-lymphoma cells

机译：p27-Skp2轴介导糖皮质激素诱导的T淋巴瘤细胞的细胞周期停滞

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Glucocorticoid therapy is an important treatment modality of hematological malignancies, especially T-cell acute lymphoblastic leukemia (T-ALL). Glucocorticoids are known to induce a cell cycle arrest and apoptosis in T-lymphoma cells. We could demonstrate that the cell cycle arrest induced by the synthetic glucocorticoid dexamethasone (Dex) clearly precedes apoptosis in human CEM T-ALL and murine S49.1 T-lymphoma cells. Cyclin D3 is strongly downregulated, whereas the CDK inhibitor p27Kip1 (p27) is strongly upregulated in response to dexamethasone in these cells. RNAi-mediated knockdown of p27 as well as overexpression of its negative regulator Skp2 revealed the critical function of p27 in the Dex-induced G1 arrest of CEM cells. Our studies indicate that several mechanisms contribute to the increase of p27 protein in our T-lymphoma cell lines. We found a significant upregulation of p27 mRNA in S49.1 and CEM cells. In addition, Dex treatment activated the mouse p27 promotor in reporter gene experiments, indicating a transcriptional regulation. However, the relatively moderate induction of p27 mRNA levels by Dex did not explain the strong increase of p27 protein in CEM and S49.1 cells. We found clear evidence for a posttranslational mechanism responsible for the robust increase in p27 protein. Dex treatment of S49.1 and CEM cells increases the half-life of p27 protein, which indicates that decreased protein degradation is the primary mechanism of p27 induction by glucocorticoids. Interestingly, we found that Dex treatment decreased the protein and mRNA levels of the negative regulator of p27 protein and E3 ubiquitin ligase subunit Skp2. We conclude that the cell cycle inhibitor p27 and its negative regulator Skp2 are key players in the glucocorticoid-induced growth suppression of T-lymphoma cells and should be considered as potential drug targets to improve therapies of T-cell malignancies.
机译：糖皮质激素治疗是血液系统恶性肿瘤尤其是T细胞急性淋巴细胞白血病（T-ALL）的重要治疗方式。已知糖皮质激素在T淋巴瘤细胞中诱导细胞周期停滞和凋亡。我们可以证明合成的糖皮质激素地塞米松（Dex）诱导的细胞周期停滞显然先于人CEM T-ALL和鼠S49.1 T淋巴瘤细胞的凋亡。细胞周期蛋白D3被强烈下调，而CDK抑制剂p27Kip1（p27）在这些细胞中对地塞米松的响应被强烈上调。 RNAi介导的p27的敲低以及其负调控因子Skp2的过度表达揭示了p27在Dex诱导的CEM细胞G1阻滞中的关键功能。我们的研究表明，几种机制有助于我们的T淋巴瘤细胞系中p27蛋白的增加。我们发现S49.1和CEM细胞中p27 mRNA的显着上调。此外，在记者基因实验中，Dex处理激活了小鼠p27启动子，表明其转录调控。然而，Dex对p27 mRNA水平的相对中等诱导不能解释CEM和S49.1细胞中p27蛋白的强烈增加。我们找到了明显的证据证明翻译后机制负责p27蛋白的强劲增加。 S49.1和CEM细胞的敏捷处理延长了p27蛋白的半衰期，这表明减少的蛋白降解是糖皮质激素诱导p27的主要机制。有趣的是，我们发现Dex处理降低了p27蛋白和E3泛素连接酶亚基Skp2负调节剂的蛋白和mRNA水平。我们得出的结论是，细胞周期抑制剂p27及其负调节剂Skp2是糖皮质激素诱导的T淋巴瘤细胞生长抑制的关键因素，应被视为改善T细胞恶性肿瘤治疗的潜在药物靶标。

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