A novel protein overexpressed in hepatoma accelerates export of NF-kappa B from the nucleus and inhibits p53-dependent apoptosis.
NF-kappa B is a transcription factor that can protect from or contribute to apoptosis. Here we report identification of HSCO that binds to NF-kappa B and inhibits apoptosis. HSCO mRNA was overexpressed in 20 of 30 hepatocellular carcinomas analyzed. Overexpression of HSCO inhibited caspase 9 activation and apoptosis induced by DNA damaging agents, while it augmented apoptosis induced by TNFalpha. Like I kappa B alpha, HSCO inhibited NF-kappa B activity and abrogated p53-induced apoptosis. However, the underlying mechanism was different. HSCO is a nuclear-cytoplasmic shuttling protein, bound to RelA NF-kappa B, and HSCO sequestered it in the cytoplasm by accelerating its export from the nucleus. These results suggest that overexpression of HSCO suppresses p53-induced apoptosis by preventing nuclear localization of NF-kappa B during signaling and thus contributes to hepatocarcinogenesis.
Pubmed ID: 12398897 RIS Download
Amino Acid Sequence | Animals | Antigens, Neoplasm | Antineoplastic Agents | Apoptosis | Carcinoma, Hepatocellular | Cell Nucleus | Cloning, Molecular | Cytoplasm | Drug Resistance, Neoplasm | Electrophoretic Mobility Shift Assay | Fluorescent Antibody Technique | Gene Expression Regulation | Humans | I-kappa B Proteins | Liver | Liver Neoplasms | Luciferases | Mice | Molecular Sequence Data | NF-kappa B | Promoter Regions, Genetic | Protein Transport | Sequence Homology, Amino Acid | Thiolester Hydrolases | Transcription, Genetic | Tumor Cells, Cultured | Tumor Necrosis Factor-alpha | Tumor Suppressor Protein p53 | Up-Regulation