Essential requirement of apolipoprotein J (clusterin) signaling for IκB expression and regulation of NF-κB activity
Essential requirement of apolipoprotein J (clusterin) signaling for IκB expression and regulation of NF-κB activity
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DOI：
10.1074/jbc.c300252200
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发表时间：
2003-10-03
影响因子：
4.8
通讯作者：
Sala, A
中科院分区：
文献类型：
--
作者：
Santilli, G;Aronow, BJ;Sala, A
载脂蛋白J/丛生蛋白是一种在炎症、细胞凋亡和癌症中高度调节的神秘蛋白。尽管进行了广泛的研究，但其生物学功能仍然不清楚。在这里，我们表明，载脂蛋白J抑制神经母细胞瘤细胞的侵袭。由于这一功能可以通过NF-κ B调节，我们探讨了载脂蛋白J可能干扰NF-κ B信号传导的可能性。异位载脂蛋白J表达通过稳定NF-κ B抑制剂（IkappaBs）强烈抑制人神经母细胞瘤细胞和鼠胚胎成纤维细胞中NF-κ B的活性。载脂蛋白J基因破坏后小鼠胚胎成纤维细胞中IkappaB蛋白的稳态水平急剧降低。缺乏载脂蛋白J导致IkappaB稳定性降低、NF-κ B活性的肿瘤坏死因子依赖性增加、NF-κ B靶基因c-IAP转录增加和p53蛋白下调。这些结果表明，载脂蛋白J的一个意想不到的生理作用是通过稳定IkappaB抑制NF-κ B信号传导，这种活性可能导致抑制肿瘤细胞运动。
Apolipoprotein J/clusterin is an enigmatic protein highly regulated in inflammation, apoptosis, and cancer. Despite extensive studies, its biological function has remained obscure. Here we show that apolipoprotein J inhibits neuroblastoma cell invasion. Since this function can be regulated by NF-kappaB, we explored the possibility that apolipoprotein J might interfere with NF-kappaB signaling. Ectopic apolipoprotein J expression strongly inhibited NF-kappaB activity in human neuroblastoma cells and murine embryonic fibroblasts by stabilizing inhibitors of NF-kappaB (IkappaBs). Steady state levels of IkappaB proteins are drastically reduced in mouse embryo fibroblasts after disruption of the apolipoprotein J gene. Absence of apolipoprotein J causes reduction of IkappaB stability, a tumor necrosis factor-dependent increase in NF-kappaB activity, increased transcription of the NF-kappaB target gene c-IAP and down-modulation of p53 protein. These results suggest that an unexpected physiological role of apolipoprotein J is to inhibit NF-kappaB signaling through stabilization of IkappaBs and that this activity may result in suppression of tumor cell motility.