Essential requirement of apolipoprotein J (clusterin) signaling for IkappaB expression and regulation of NF-kappaB activity.
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.
Santilli
Giorgia
G
Molecular Haematology and Cancer Biology Unit, Institute of Child Health, University College London, London WC1N, United Kingdom.
Aronow
Bruce J
BJ
Sala
Arturo
A
D000818:Animals; D015153:Blotting, Western; D002469:Cell Separation; D002478:Cells, Cultured; D051152:Clusterin; D015536:Down-Regulation; D005347:Fibroblasts / Q000378:metabolism; D005434:Flow Cytometry; D015971:Gene Expression Regulation, Enzymologic; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D006801:Humans; D051550:I-kappa B Kinase; D051034:Inhibitor of Apoptosis Proteins; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D016328:NF-kappa B / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D010957:Plasmids / Q000378:metabolism; D014176:Protein Biosynthesis; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011506:Proteins; D012190:Retroviridae; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013997:Time Factors; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
C495242:CLU protein, human; C495243:Clu protein, mouse; D051152:Clusterin; D006023:Glycoproteins; D051034:Inhibitor of Apoptosis Proteins; D018832:Molecular Chaperones; D016328:NF-kappa B; D011506:Proteins; D016159:Tumor Suppressor Protein p53; D008156:Luciferases; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse