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.
Higashitsuji
Hisako
H
Department of Clinical Molecular Biology, Faculty of Medicine, Kyoto University, 54 shogoin Kawaharacho, Sakyo-ku, 606-8507, Kyoto, Japan.
Higashitsuji
Hiroaki
H
Nagao
Toshikazu
T
Nonoguchi
Kohsuke
K
Fujii
Shingo
S
Itoh
Katsuhiko
K
Fujita
Jun
J
D000595:Amino Acid Sequence; D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology*; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002467:Cell Nucleus / Q000378:metabolism*; D003001:Cloning, Molecular; D003593:Cytoplasm / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D024202:Electrophoretic Mobility Shift Assay; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D021381:Protein Transport; D017386:Sequence Homology, Amino Acid; D013869:Thiolester Hydrolases / Q000378:metabolism; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D015854:Up-Regulation; D000099301:Hydroxyacylglutathione Hydrolase
D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D020672:I-kappa B Proteins; D008156:Luciferases; D016328:NF-kappa B; D013869:Thiolester Hydrolases; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53; D000099301:Hydroxyacylglutathione Hydrolase