The oncoprotein gankyrin interacts with RelA and suppresses NF-kappaB activity.
Gankyrin is an oncoprotein commonly overexpressed in hepatocellular carcinomas. It interacts with multiple proteins and accelerates degradation of tumor suppressors Rb and p53. Since gankyrin consists of 7 ankyrin repeats and is structurally similar to IkappaBs, we investigated its interaction with NF-kappaB. We found that gankyrin directly binds to RelA. In HeLa and 293 cells, overexpression of gankyrin suppressed the basal as well as TNFalpha-induced transcriptional activity of NF-kappaB, whereas down-regulation of gankyrin increased it. Gankyrin did not affect the NF-kappaB DNA-binding activity or nuclear translocation of RelA induced by TNFalpha in these cells. Leptomycin B that inhibits nuclear export of RelA suppressed the NF-kappaB activity, which was further suppressed by gankyrin. The inhibitory effect of gankyrin was abrogated by nicotinamide as well as down-regulation of SIRT1, a class III histone deacetylase. Thus, gankyrin binds to NF-kappaB and suppresses its activity at the transcription level by modulating acetylation via SIRT1.
Pubmed ID: 17904523 RIS Download
Binding Sites | Blotting, Western | Cell Line | Cell Line, Tumor | Electrophoretic Mobility Shift Assay | Fatty Acids, Unsaturated | Green Fluorescent Proteins | HeLa Cells | Humans | Immunoprecipitation | Interferon-alpha | Luciferases | Microscopy, Fluorescence | NF-kappa B | Niacinamide | Proteasome Endopeptidase Complex | Protein Binding | Proto-Oncogene Proteins | RNA, Small Interfering | Recombinant Fusion Proteins | Sirtuin 1 | Sirtuins | Transcription Factor RelA | Transcription, Genetic | Transfection