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首页> 外文期刊>Nitric oxide: Biology and chemistry >Activation of the BRCA1/Chk1/p53/p21 ~(Cip1/Waf1) pathway by nitric oxide and cell cycle arrest in human neuroblastoma NB69 cells
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Activation of the BRCA1/Chk1/p53/p21 ~(Cip1/Waf1) pathway by nitric oxide and cell cycle arrest in human neuroblastoma NB69 cells

机译：一氧化氮对BRCA1 / Chk1 / p53 / p21〜（Cip1 / Waf1）通路的激活和人神经母细胞瘤NB69细胞的细胞周期阻滞

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摘要

Nitric oxide (NO) works as a bi-modal effector of cell proliferation, inducing either the increase or decrease of cell growth when cells are exposed, respectively, to low or high NO concentrations. To get further insight into the action of NO, we tested the effect of short- and long-lived NO donors on the control of the cell cycle in human neuroblastoma NB69 cells. We demonstrated that long-time exposure of cells to NO not only decreased the expression and/or the phosphorylation of elements involved in the control of the G _1/S transition, such as the transcriptional repressor pRb and cyclin D1, but also down-regulated systems controlling the S and G _2/M phases, such as the phosphorylation of Cdk1(cdc2) and the expression of cyclins A and B1. Increasing concentrations of NO also induced a biphasic effect on the expression of cyclins D1, A and B1, while this effect was less pronounced for cyclin E expression, but the levels of mRNAs of those cyclins changed in a distinct and complex manner. NO also changed the phosphorylation pattern of cyclin E and decreased the levels of phospho-cyclins D1 and B1. Moreover, NO decreased the expression of the Cdk inhibitors p16 ~(Ink4a) and p19 ~(Ink4d), without affecting p27 ~(Kip1). In contrast, NO induced a biphasic effect on p21 ~(Cip1/Waf1) expression. The BRCA1/Chk1/p53 pathway mediated the upregulation of p21 ~(Cip1/Waf1). We also demonstrated that the NO-mediated up-regulation of p21 ~(Cip1/Waf1) was inversely correlated with the activation status of the p38MAPK pathway.
机译：一氧化氮（NO）充当细胞增殖的双峰效应子，当细胞分别暴露于低或高NO浓度时，诱导细胞生长的增加或减少。为了进一步了解NO的作用，我们测试了短期和长期NO供体对人类神经母细胞瘤NB69细胞中细胞周期控制的影响。我们证明，长时间暴露于NO的细胞不仅会降低G _1 / S过渡调控因子（如转录阻遏物pRb和cyclin D1）的表达和/或磷酸化，而且还下调系统控制S和G _2 / M相，例如Cdk1（cdc2）的磷酸化以及细胞周期蛋白A和B1的表达。 NO浓度的增加也对细胞周期蛋白D1，A和B1的表达产生了双相影响，虽然这种作用在细胞周期蛋白E的表达中并不明显，但是这些细胞周期蛋白的mRNA水平却以独特而复杂的方式变化。 NO也改变了细胞周期蛋白E的磷酸化模式，并降低了磷酸化细胞周期蛋白D1和B1的水平。此外，NO降低了Cdk抑制剂p16〜（Ink4a）和p19〜（Ink4d）的表达，而不影响p27〜（Kip1）。相反，NO诱导p21〜（Cip1 / Waf1）表达的双相效应。 BRCA1 / Chk1 / p53途径介导p21〜（Cip1 / Waf1）的上调。我们还证明，NO介导的p21〜（Cip1 / Waf1）的上调与p38MAPK途径的激活状态呈负相关。

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