The pro- or anti-apoptotic function of NF-κB is determined by the nature of the apoptotic stimulus
The pro- or anti-apoptotic function of NF-κB is determined by the nature of the apoptotic stimulus
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DOI：
10.1046/j.1432-1327.2000.01421.x
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发表时间：
2000-06-01
期刊：
影响因子：
--
通讯作者：
Schmitz, ML
中科院分区：
文献类型：
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作者：
Kaltschmidt, B;Kaltschmidt, C;Schmitz, ML
为了测试转录因子NF-κ B作为细胞凋亡的促进剂或拮抗剂的行为是否取决于细胞凋亡刺激，我们确定了NF-κ B对给定细胞类型内的多种诱导剂引起的细胞杀伤的影响。通过遗传和药理学方法抑制NF-κ B使HeLa细胞更容易受到TNF-α诱导的细胞杀伤，但几乎完全保护它们免受H2 O2和过钒酸盐诱导的细胞凋亡。TNF-α不能保护HeLa细胞免受H2 O2和过钒酸盐诱导的细胞凋亡，并进一步增强这两种不良试剂诱导的细胞毒性。来自稳定过表达I κ B-α的反式显性阴性形式的HeLa细胞的上清液选择性地增加了TNF-α对HeLa细胞的细胞毒性，这表明这些细胞的增强的易感性可以归因于一种或多种分泌因子。Supershift实验表明，各种凋亡刺激诱导相同的DNA结合亚基的子集。因此，由相应的死亡诱导物引起的信号的性质决定了NF-κ B诱导是否导致细胞凋亡或存活，这表明NF-κ B活性的操纵可能为癌症治疗中的辅助治疗提供新的方法。
To test whether the behaviour of transcription factor NF-kappa B as a promoter or antagonist of apoptosis depends on the apoptotic stimulus, we determined the influence of NF-kappa B on cell killing elicited by a variety of inducers within a given cell type. Inhibition of NF-kappa B by genetic and pharmacological approaches rendered HeLa cells more susceptible to TNF-alpha-induced cell killing, but protected them almost completely from H2O2- and pervanadate-induced apoptosis. TNF-alpha was unable to protect HeLa from H2O2- and pervanadate-induced apoptosis and further enhanced the cytotoxicity induced by these two adverse agents. Supernatants from HeLa cells stably overexpressing a transdominant negative form of I kappa B-alpha selectively increased the cytotoxicity of TNF-alpha for HeLa cells, suggesting that the enhanced susceptibility of these cells can be attributed to one or more secretable factors. Supershift experiments showed that the various apoptotic stimuli induced the same subset of DNA-binding subunits. Therefore, the nature of the signals elicited by the respective death inducers determines whether NF-kappa B induction leads to apoptosis or survival, suggesting that the manipulation of NF-kappa B activity may provide a new approach to adjuvant therapy in cancer treatment.