Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Blotting, Western
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Cell Separation
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Cells, Cultured
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Clusterin
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Down-Regulation
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Fibroblasts / metabolism
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Flow Cytometry
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Gene Expression Regulation, Enzymologic*
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Glycoproteins / genetics
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Glycoproteins / metabolism*
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Glycoproteins / physiology*
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Humans
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I-kappa B Kinase
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Inhibitor of Apoptosis Proteins
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Luciferases / metabolism
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Mice
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Mice, Knockout
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Molecular Chaperones / genetics
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Molecular Chaperones / metabolism*
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Molecular Chaperones / physiology*
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NF-kappa B / metabolism*
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Neoplasm Invasiveness
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Plasmids / metabolism
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Protein Biosynthesis
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Protein Serine-Threonine Kinases / metabolism*
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Proteins*
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Retroviridae
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction*
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Time Factors
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Transcription, Genetic
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Transcriptional Activation
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Transfection
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Tumor Cells, Cultured
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Tumor Suppressor Protein p53 / metabolism
Substances
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CLU protein, human
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Clu protein, mouse
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Clusterin
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Glycoproteins
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Inhibitor of Apoptosis Proteins
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Molecular Chaperones
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NF-kappa B
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Proteins
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Tumor Suppressor Protein p53
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Luciferases
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Protein Serine-Threonine Kinases
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CHUK protein, human
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Chuk protein, mouse
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I-kappa B Kinase
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IKBKB protein, human
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IKBKE protein, human
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Ikbkb protein, mouse
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Ikbke protein, mouse