PML is a potent tumor suppressor and proapoptotic factor and is functionally regulated by post-translational modifications such as phosphorylation, sumoylation, and ubiquitination. Histone deacetylase (HDAC) inhibitors are a promising class of targeted anticancer agents and induce apoptosis in cancer cells by largely unknown mechanisms. We report here a novel post-transcriptional modification, acetylation, of PML. PML exists as an acetylated protein in HeLa cells, and its acetylation is enhanced by coexpression of p300 or treatment with a HDAC inhibitor, trichostatin A. Increased PML acetylation is associated with increased sumoylation of PML in vitro and in vivo. PML is involved in trichostatin A-induced apoptosis and PML with an acetylation-defective mutation shows an inability to mediate apoptosis, suggesting the importance of PML acetylation. Our work provides new insights into PML regulation by post-translational modification and new information about the therapeutic mechanism of HDAC inhibitors.

Acetylation of PML is involved in histone deacetylase inhibitor-mediated apoptosis.

PANDOLFI DE RINALDIS, Pier Paolo;
2008

Abstract

PML is a potent tumor suppressor and proapoptotic factor and is functionally regulated by post-translational modifications such as phosphorylation, sumoylation, and ubiquitination. Histone deacetylase (HDAC) inhibitors are a promising class of targeted anticancer agents and induce apoptosis in cancer cells by largely unknown mechanisms. We report here a novel post-transcriptional modification, acetylation, of PML. PML exists as an acetylated protein in HeLa cells, and its acetylation is enhanced by coexpression of p300 or treatment with a HDAC inhibitor, trichostatin A. Increased PML acetylation is associated with increased sumoylation of PML in vitro and in vivo. PML is involved in trichostatin A-induced apoptosis and PML with an acetylation-defective mutation shows an inability to mediate apoptosis, suggesting the importance of PML acetylation. Our work provides new insights into PML regulation by post-translational modification and new information about the therapeutic mechanism of HDAC inhibitors.
283
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24425
http://www.jbc.org/content/283/36/24420.full.pdf+html
Acetylation; Animals; Apoptosis; Apoptosis Regulatory Proteins; Enzyme Inhibitors; Hela Cells; Histone Deacetylases; Humans; Hydroxamic Acids; Mice; Mutation; Nuclear Proteins; Phosphorylation; Protein Processing; Post-Translational; Transcription Factors; Tumor Suppressor Proteins; Ubiquitination
F. Hayakawa;A. Abe;I. Kitabayashi;P. P. Pandolfi;T. Naoe
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2318/61191
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