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首页> 外文期刊>Oncogene >Dose|[ndash]|response transition from cell cycle arrest to apoptosis with selective degradation of Mdm2 and p21WAF1|[sol]|CIP1 in response to the novel anticancer agent, aminoflavone (NSC 686288)
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Dose|[ndash]|response transition from cell cycle arrest to apoptosis with selective degradation of Mdm2 and p21WAF1|[sol]|CIP1 in response to the novel anticancer agent, aminoflavone (NSC 686288)

机译:响应新型抗癌药氨基黄酮(NSC 686288),Mdm2和p21WAF1 | [sol] | CIP1选择性降解,剂量从细胞周期停滞到凋亡的反应转变。

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Aminoflavone (AF, NSC 686288) is beginning clinical trials. It induces replication-mediated histone H2AX phosphorylation, DNA–protein crosslinks and activates p53. Here, we studied p21CIP1/WAF1 and Mdm2 responses to AF. Although p53 stabilization and phosphorylation at serine 15 increased with dose and time of exposure, Mdm2 and p21CIP1/WAF1 protein levels displayed a biphasic response, as they accumulated at submicromolar doses and then decreased with increasing AF. As both Mdm2 and p21CIP1/WAF1 mRNA levels increased with AF concentration without reduction at higher concentrations, we measured the half-lives of Mdm2 and p21CIP1/WAF1 proteins. Mdm2 and p21CIP1/WAF1 half-lives were shortened with increasing AF concentrations. Proteasomal degradation appears responsible for the decrease of both Mdm2 and p21CIP1/WAF1, as MG-132 prevented their degradation and revealed AF-induced Mdm2 polyubiquitylation. AF also induced protein kinase B (Akt) activation, which was reduced with increasing AF concentrations. Suppression of Akt by small interfering RNA was associated with downregulation of Mdm2 and p21CIP1/WAF1 and with enhanced apoptosis. These results suggest that the cellular responses to AF are determined at least in part by Mdm2 and p21CIP1/WAF1 protein levels, as well as by Akt activity, leading either to cell cycle arrest when Mdm2 and p21CIP1/WAF1 are elevated, or to apoptosis when Mdm2 and p21CIP1/WAF1 are degraded by the proteasome and Akt insufficiently activated to protect against apoptosis.
机译:氨黄酮(AF,NSC 686288)正在开始临床试验。它诱导复制介导的组蛋白H2AX磷酸化,DNA-蛋白质交联并激活p53。在这里,我们研究了p21CIP1 / WAF1和Mdm2对AF的反应。尽管丝氨酸15的p53稳定和磷酸化随剂量和暴露时间的增加而增加,但Mdm2和p21CIP1 / WAF1蛋白水平显示出双相反应,因为它们以亚微摩尔剂量累积,然后随着AF增加而降低。由于Mdm2和p21CIP1 / WAF1 mRNA水平均随AF浓度的增加而增加,而在较高浓度下却没有降低,因此我们测量了Mdm2和p21CIP1 / WAF1蛋白的半衰期。随着AF浓度的增加,Mdm2和p21CIP1 / WAF1的半衰期缩短。蛋白酶体降解似乎是Mdm2和p21CIP1 / WAF1降低的原因,因为MG-132阻止了它们的降解并揭示了AF诱导的Mdm2多泛素化。 AF还诱导蛋白激酶B(Akt)活化,其随AF浓度增加而降低。小干扰RNA抑制Akt与Mdm2和p21CIP1 / WAF1的下调以及细胞凋亡的增强有关。这些结果表明,对AF的细胞反应至少部分由Mdm2和p21CIP1 / WAF1蛋白水平以及Akt活性决定,导致当Mdm2和p21CIP1 / WAF1升高时导致细胞周期停滞,或在细胞凋亡时导致凋亡Mdm2和p21CIP1 / WAF1被蛋白酶体降解,而Akt活化不足以防止细胞凋亡。

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