Opposite effect of NF-κB and c-Jun N-terminal kinase on p53-independent GADD45 induction by arsenite
Opposite effect of NF-κB and c-Jun N-terminal kinase on p53-independent GADD45 induction by arsenite
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DOI：
10.1074/jbc.m011682200
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发表时间：
2001-04-06
影响因子：
4.8
通讯作者：
Shi, XL
中科院分区：
文献类型：
--
作者：
Chen, F;Lu, YJ;Shi, XL
细胞周期检查点是一种主要的基因组监测机制，是在应对环境胁迫时维持基因组稳定性和完整性的重要步骤。利用来自人支气管上皮细胞的细胞，我们证明了核因子-kappaB和c-jun氨基末端激酶(JNK)相互调节三氧化二砷(Asmonite)诱导的、不依赖于P53的GADD45蛋白的表达，GADD45蛋白是一种细胞周期检查点蛋白，可将细胞阻止在G(2)/M期转变。通过稳定表达一种激酶突变形式的I kappaB激酶来抑制NF-kappaB的激活，可以增加和延长亚砷酸盐对GADD45的诱导。相反，在核因子-kappaB激活途径正常的细胞中，亚砷酸盐诱导GADD45的作用是短暂的，而且效力较弱。流式细胞仪分析表明，抑制NF-kappaB可增强亚砷酸盐诱导的G(2)/M期细胞周期停滞。另一方面，阻断JNK激活可降低亚砷酸盐诱导的GADD45表达，提示JNK激活在GADD45诱导中起一定作用。这些结果表明，核因子-kappaB和JNK在亚砷酸盐诱导的细胞周期调控中可能有不同的分子机制。
Cell cycle checkpoint, a major genomic surveillance mechanism,is an important step in maintaining genomic stability and integrity in response to environmental stresses. Using cells derived from human bronchial epithelial cells, we demonstrate that NF-kappaB and c-Jun N-terminal kinase (JNK) reciprocally regulate arsenic trioxide (arsenite)-induced, p53-independent expression of GADD45 protein, a cell cycle checkpoint protein that arrests cells at the G(2)/M phase transition. Inhibition of NF-kappaB activation by stable expression of a kinase-mutated form of I kappaB kinase caused increased and prolonged induction of GADD45 by arsenite. In contrast, the induction of GADD45 by arsenite was transient and less potent in cells where the NF-kappaB activation pathway was normal. Analysis of the cell cycle profile by flow cytometry indicated that NF-kappaB inhibition potentiates arsenite-induced G(2)/M cell cycle arrest. Abrogation of JNK activation, on the other hand, decreased GADD45 expression induced by arsenite, suggesting a role for JNK activation in GADD45 induction. These results indicate a molecular mechanism by which NF-kappaB and JNK may differentially contribute to cell cycle regulation in response to arsenite.