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J Biol Chem. 2003 Oct 3;278(40):38214-9. Epub 2003 Jul 25.

Essential requirement of apolipoprotein J (clusterin) signaling for IkappaB expression and regulation of NF-kappaB activity.

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Molecular Haematology and Cancer Biology Unit, Institute of Child Health, University College London, London WC1N, United Kingdom.


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.

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