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

J Biol Chem. 2003 Oct 3;278(40):38214-9. doi: 10.1074/jbc.C300252200. Epub 2003 Jul 25.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Cell Separation
  • Cells, Cultured
  • Clusterin
  • Down-Regulation
  • Fibroblasts / metabolism
  • Flow Cytometry
  • Gene Expression Regulation, Enzymologic*
  • Glycoproteins / genetics
  • Glycoproteins / metabolism*
  • Glycoproteins / physiology*
  • Humans
  • I-kappa B Kinase
  • Inhibitor of Apoptosis Proteins
  • Luciferases / metabolism
  • Mice
  • Mice, Knockout
  • Molecular Chaperones / genetics
  • Molecular Chaperones / metabolism*
  • Molecular Chaperones / physiology*
  • NF-kappa B / metabolism*
  • Neoplasm Invasiveness
  • Plasmids / metabolism
  • Protein Biosynthesis
  • Protein-Serine-Threonine Kinases / metabolism*
  • Proteins*
  • Retroviridae
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction*
  • Time Factors
  • Transcription, Genetic
  • Transcriptional Activation
  • Transfection
  • Tumor Cells, Cultured
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • CLU protein, human
  • Clu protein, mouse
  • Clusterin
  • Glycoproteins
  • Inhibitor of Apoptosis Proteins
  • Molecular Chaperones
  • NF-kappa B
  • Proteins
  • Tumor Suppressor Protein p53
  • Luciferases
  • Protein-Serine-Threonine Kinases
  • CHUK protein, human
  • Chuk protein, mouse
  • I-kappa B Kinase
  • IKBKB protein, human
  • IKBKE protein, human
  • Ikbkb protein, mouse
  • Ikbke protein, mouse