Essential Requirement of Apolipoprotein J (Clusterin) Signaling for IκB Expression and Regulation of NF-κB Activity

• Published in: The Journal of biological chemistry 2003-10, Vol.278 (40), p.38214-38219
• Main Authors: Santilli, Giorgia, Aronow, Bruce J., Sala, Arturo
• Format: Article
• Language: English
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.C300252200

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-κB, we explored the possibility that apolipoprotein J might interfere with NF-κB signaling. Ectopic apolipoprotein J expression strongly inhibited NF-κB activity in human neuroblastoma cells and murine embryonic fibroblasts by stabilizing inhibitors of NF-κB (IκBs). Steady state levels of IκB proteins are drastically reduced in mouse embryo fibroblasts after disruption of the apolipoprotein J gene. Absence of apolipoprotein J causes reduction of IκB stability, a tumor necrosis factor-dependent increase in NF-κB activity, increased transcription of the NF-κB 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-κB signaling through stabilization of IκBs and that this activity may result in suppression of tumor cell motility.