Enhanced deacetylation of p53 by the anti-apoptotic protein HSCO in association with histone deacetylase 1.
HSCO (hepatoma subtracted-cDNA library clone one, also called ETHE1) was originally identified by its frequent overexpression in hepatocellular carcinomas. HSCO inhibits function of NF-kappaB by binding to RelA and accelerating its export from the nucleus. We show here that HSCO exhibits anti-apoptotic activity in cells exposed to DNA-damaging agents by ... suppressing transcriptional activity of p53. Induction of pro-apoptotic genes, Noxa, Perp, PIG3, and Bax were suppressed in cells over-expressing HSCO. By increasing ubiquitylation and degradation of p53, HSCO reduces p53 protein levels. HSCO specifically associates with histone deacetylase 1 (HDAC1) independently of Mdm2 and facilitates deacetylation of p53 at Lys-373/382 by HDAC1. The metallo-beta-lactamase family consensus sequence in HSCO is important for its effect on p53 deacetylation. Co-immunoprecipitation and immunofluorescence studies suggested that HSCO, HDAC1, and p53 form a complex in the nucleus. Thus, HSCO is a cofactor that increases the deacetylase activity of HDAC1 toward p53, leading to suppression of apoptosis. Treatment of hepatocellular carcinomas that retain wild-type p53 and overexpress HSCO with anti-HSCO agents might re-establish the p53 response and revert chemoresistance.
Mesh Terms:
Acetylation, Animals, Apoptosis, Cell Line, Transformed, Cell Line, Tumor, Cell Nucleus, Drug Resistance, Neoplasm, Genes, Tumor Suppressor, Histone Deacetylase 1, Histone Deacetylases, Humans, Inhibitor of Apoptosis Proteins, Intracellular Signaling Peptides and Proteins, Membrane Proteins, Mice, Mice, Knockout, Mitochondrial Proteins, Multiprotein Complexes, Nucleocytoplasmic Transport Proteins, Protein Processing, Post-Translational, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-bcl-2, Transcription Factor RelA, Tumor Suppressor Protein p53, Ubiquitins, bcl-2-Associated X Protein
Acetylation, Animals, Apoptosis, Cell Line, Transformed, Cell Line, Tumor, Cell Nucleus, Drug Resistance, Neoplasm, Genes, Tumor Suppressor, Histone Deacetylase 1, Histone Deacetylases, Humans, Inhibitor of Apoptosis Proteins, Intracellular Signaling Peptides and Proteins, Membrane Proteins, Mice, Mice, Knockout, Mitochondrial Proteins, Multiprotein Complexes, Nucleocytoplasmic Transport Proteins, Protein Processing, Post-Translational, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-bcl-2, Transcription Factor RelA, Tumor Suppressor Protein p53, Ubiquitins, bcl-2-Associated X Protein
J. Biol. Chem.
Date: May. 04, 2007
PubMed ID: 17353187
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