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Effect of Distinct Anticancer Drugs on the Phosphorylation of p53 Protein at Serine 46 in Human MCF-7 Breast Cancer Cells

机译:不同的抗癌药物对人MCF-7乳腺癌细胞46位丝氨酸p53蛋白磷酸化的影响

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Roscovitine (ROSC), a potent cyclin-dependent kinase inhibitor (CDI), inactivates cyclin-dependent kinase (CDK)2 resulting in the arrest of human MCF-7 breast cancer cells in G2 phase of the cell cycle. We have recently observed a strong activation of wild-type (wt) p53 protein in human MCF-7 breast cancer cells upon treatment with ROSC implicating that upregulated p53 might additionally modulate the primary action of ROSC. ROSC stabilized wt p53 protein resulting in a marked extension of its half-life. Since ROSC exhibits low cytotoxicity, it seems to upregulate p53 protein in a way different from DNA damage. ROSC induced phosphorylation of p53 protein at serine 46. Therefore, we decided to examine whether other anticancer drugs are also able to in duce phosphorylation of wt p53 protein at serine 46. Exposure of MCF-7 cells to doxorubicin (DOX) at doses inducing a strong G2 arrest resulted in a weak upregulation of p53. No site-specific phosphorylation of p53 at serine 46 was detected. These results indicate that p53 activation is dispensable for DOX-induced G2 arrest. Moreover, the pattern of p53 phosphorylation strongly depends on the type of the stimulating factor.
机译:Roscovitine(ROSC)是一种有效的细胞周期蛋白依赖性激酶抑制剂(CDI),可以使细胞周期蛋白依赖性激酶(CDK)2失活,从而导致人MCF-7乳腺癌细胞停滞在细胞周期的G2期。我们最近发现,在用ROSC治疗后,人MCF-7乳腺癌细胞中的野生型(wt)p53蛋白有很强的活化作用,这暗示上调的p53可能还可以调节ROSC的主要作用。 ROSC稳定了wt p53蛋白,导致其半衰期显着延长。由于ROSC显示出低细胞毒性,因此似乎以不同于DNA损伤的方式上调p53蛋白。 ROSC诱导了丝氨酸46处p53蛋白的磷酸化。因此,我们决定检查其他抗癌药物是否也能够使丝氨酸46处wt p53蛋白的磷酸化降低。强烈的G2阻滞导致p53的弱上调。在丝氨酸46上未检测到p53的位点特异性磷酸化。这些结果表明,p53激活对于DOX诱导的G2阻滞是必不可少的。此外,p53磷酸化的模式在很大程度上取决于刺激因子的类型。

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