Nuclear factor -: κB-dependent regulation of p53 gene expression induced by daunomycin genotoxic drug
Nuclear factor -: κB-dependent regulation of p53 gene expression induced by daunomycin genotoxic drug
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DOI：
10.1038/sj.onc.1201638
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发表时间：
1998-03-05
期刊：
影响因子：
8
通讯作者：
Merville, MP
中科院分区：
文献类型：
--
作者：
Hellin, AC;Calmant, P;Merville, MP
蒽环类药物广泛用于实体瘤和白血病的治疗，但其生物学效应的分子基础尚不清楚。在保留野生型可诱导p53基因的HCT 116结肠癌细胞系中，我们发现蒽环类道霉素是p53和NF-kappa B转录因子的有效诱导剂，由于蛋白质稳定性增加和基因表达增强，p53蛋白发生核积累。道霉素通过p50/p65 NF-kappa B异源二聚体结合p53启动子中的kappa B位点诱导p53启动子。在我们的实验条件下，自由基清除剂NAC和PDTC不能阻断NF-kappa B的激活或p53的诱导，表明活性氧中间体不参与细胞对道霉素刺激的反应。在HCT116细胞中，过表达一个稳定的无应答的I kappa B α突变体导致NF-kappa B激活完全抑制，但仅部分损害道霉素诱导的p53蛋白积累。我们得出结论，道霉素产生的p53激活信号部分受NF-kappa B调节。
Anthracycline drugs are widely used for the treatment of solid tumors and leukemia, but the molecular basis of their biological effect is still poorly understood, In the HCT 116 colon carcinoma cell line, which retains a wild-type inducible p53 gene, we show that the anthracycline daunomycin is a potent inducer of p53 and NF-kappa B transcription factors, Nuclear accumulation of p53 protein occurred because of increased protein stability and enhanced gene expression, In addition, daunomycin induced the p53 promoter through the binding of p50/p65 NF-kappa B heterodimers to the kappa B site in the p53 promoter, Under our conditions, the free radical scavengers NAC and PDTC were not able to block NF-kappa B activation or p53 induction, indicating that reactive oxygen intermediates were not involved in the cellular response to daunomycin stimulation. Overexpression of a stable unresponsive I kappa B alpha mutant in HCT116 cells resulted in a complete inhibition of the NF-kappa B activation but only a partial impairment of the p53 protein accumulation induced by daunomycin, We conclude that the p53-activating signal generated by daunomycin is partially regulated by NF-kappa B.