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Regulation of NF-κB/P65 by MDM2 in acute lymphoblastic leukemia in childhood
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- Author:
- No author available
- Journal Title:
- CHINESE JOURNAL OF PEDIATRICS
- Issue:
- 12
- DOI:
- 10.3760/cma.j.issn.0578-1310.2003.12.114
- Key Word:
- 白血病,淋巴细胞,急性;原癌基因蛋白质类;NF-κB
Abstract： 目的 MDM2是一种原癌基因,可与P53结合使P53失去抑癌功能.有证据表明,MDM2可能有P53不依赖的癌基因活性,作为一个转录因子直接调节细胞周期调控和转化过程中的其他基因的表达.研究显示,NF-κB的P65亚型是一个肿瘤药物诱导的细胞凋亡的重要抑制因子,在细胞转化及凋亡的调控中起着重要的作用.探讨儿童急性淋巴细胞白血病MDM2,NF-κB及P53相互作用的机制.方法应用儿童急性淋巴细胞白血病细胞EU-4细胞株作为模型,转染MDM2进入EU-4细胞,用免疫印迹及Northern杂交法检测转染前后P65的表达.因为E-Selectin的表达是P65依赖性的,共转染MDM2,P65及E-Selectin启动子CAT报告基因进入EU-4细胞,用ELISA测CAT活性.同时分别将不同浓度的阿霉素(15 μg/ml, 7.5 μg/ml, 5 μg/ml, 及1 μg/ml)加入转染前后的EU-4细胞,用MTT法检测细胞的药物敏感性.结果 MDM2的转染能上调P65的表达并增加了NF-κB的活性,该作用为P53不依赖性.而在缺乏P65的情况下,MDM2对CAT活性没有影响.MDM2反义寡核苷酸处理对CAT活性没有影响.MTT检测表明,稳定转染MDM2的细胞对阿霉素(ADM)耐药.结论 (1)MDM2上调了儿童白血病细胞P65的表达.(2)MDM2增加了白血病细胞对阿霉素的抗药性.(3)在P53缺乏时,MDM2作为一个转录因子直接激活白血病细胞P65基因的表达及增加NF-κB活性,从而发挥其抗凋亡的效应并揭示了肿瘤细胞化疗耐药的新机制.
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