Nuclear factor-κB dimer exchange promotes a p21waf1/cip1 superinduction response in human T leukemic cells
Nuclear factor-κB dimer exchange promotes a p21waf1/cip1 superinduction response in human T leukemic cells
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DOI：
10.1158/1541-7786.mcr-05-0259
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发表时间：
2006-02-01
影响因子：
5.2
通讯作者：
Miyamoto, S
中科院分区：
文献类型：
--
作者：
Chang, PY;Miyamoto, S
核因子-κ B（NF-kappa B）/Rel转录因子被认为是重要的凋亡调节因子。我们以前报道过NF-κ B B部分通过诱导p21（waf 1/cip 1）的能力导致CEM人T白血病细胞的化疗耐药性。在这里，我们提供的证据表明，连续NF-κ B激活信号诱导增强NF-κ B DNA结合和p21（waf 1/cip 1）诱导CEM和其他T白血病细胞系。这种反应是由这些细胞系中NF κ B 1基因编码的p105/p50 NF-κ B亚基的极低基础表达引起的。初始NF-rB激活事件增强p65和ELF 1向NFKB 1启动子的募集，导致p105/p50的p65和ELF 1依赖性合成，其促进NF-rB复合物交换为含有p50的复合物，具有增加的DNA结合活性的某些NF-rB靶元件。随后用抗癌剂依托泊苷刺激这些细胞，导致增强的NF-κ B依赖性p21（waf 1/cip 1）诱导和白血病细胞的耐药性增加。因此，我们认为低基础NF-κ B 1表达加上连续NF-κ B激活事件可以促进某些T白血病细胞化疗耐药性的增加。
The nuclear factor-kappa B (NF-kappa B)/Rel transcription factors are recognized as critical apoptosis regulators. We reported previously that NF-kappa B contributes to chemoresistance of CEM human T leukemic cells in part through its ability to induce p21(waf1/cip1). Here, we provide evidence that sequential NF-kappa B-activating signals induce heightened NF-kappa B DNA binding and p21(waf1/cip1) induction in CEM and additional T leukemic cell lines. This response arises from exceedingly low basal expression of the p105/p50 NF-kappa B subunit encoded by the NFKB1 gene in these cell lines. An initial NF-rB activation event enhances the recruitment of p65 and ELF1 to the NFKB1 promoter, leading to p65- and ELF1-dependent synthesis of p105/p50, which promotes an exchange of NF-rB complexes to p50-containing complexes with an increased DNA-binding activity to certain NF-rB target elements. Subsequent stimulation of these cells with an anticancer agent, etoposide, results in augmented NF-kappa B-dependent p21(waf1/cip1) induction and increased chemoresistance of the leukemia cells. Thus, we propose that low basal NFKB1 expression coupled with sequential NF-kappa B activation events can promote increased chemoresistance in certain T leukemic cells.