| Deacetylation of the DNA-binding domain regulates p53-mediated apoptosis. | |
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MedLine Citation:
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PMID: 21148320 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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In unstressed cells, the p53 tumor suppressor is highly unstable. DNA damage and other forms of cellular stress rapidly stabilize and activate p53. This process is regulated by a complex array of post-translational modifications that are dynamically deposited onto p53. Recent studies show that these modifications orchestrate p53-mediated processes such as cell cycle arrest and apoptosis. Cancer cells carry inherent genetic damage, but avoid arrest and apoptosis by inactivating p53. Defining the enzymatic machinery that regulates the stress-induced modification of p53 at single-residue resolution is critical to our understanding of the biochemical mechanisms that control this critical tumor suppressor. Specifically, acetylation of p53 at lysine 120, a DNA-binding domain residue mutated in human cancer, is essential for triggering apoptosis. Given the oncogenic properties of deacetylases and the success of deacetylase inhibitors as anticancer agents, we investigated the regulation of Lys(120) deacetylation using pharmacologic and genetic approaches. This analysis revealed that histone deacetylase 1 is predominantly responsible for the deacetylation of Lys(120). Furthermore, treatment with the clinical-grade histone deacetylase inhibitor entinostat enhances Lys(120) acetylation, an event that is mechanistically linked to its apoptotic effect. These data expand our understanding of the mechanisms controlling p53 function and suggest that regulation of p53 modification status at single-residue resolution by targeted therapeutics can selectively alter p53 pathway function. This knowledge may impact the rational application of deacetylase inhibitors in the treatment of human cancer. |
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Authors:
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Hestia S Mellert; Timothy J Stanek; Stephen M Sykes; Frank J Rauscher; David C Schultz; Steven B McMahon |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2010-12-09 |
Journal Detail:
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Title: The Journal of biological chemistry Volume: 286 ISSN: 1083-351X ISO Abbreviation: J. Biol. Chem. Publication Date: 2011 Feb |
Date Detail:
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Created Date: 2011-02-07 Completed Date: 2011-03-24 Revised Date: 2012-02-13 |
Medline Journal Info:
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Nlm Unique ID: 2985121R Medline TA: J Biol Chem Country: United States |
Other Details:
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Languages: eng Pagination: 4264-70 Citation Subset: IM |
Affiliation:
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Biomedical Graduate Studies, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Acetylation
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drug effects Apoptosis* Benzamides / pharmacology Cell Line, Tumor DNA Damage / drug effects, genetics Histone Deacetylase Inhibitors / pharmacology Humans Mutation, Missense Neoplasms / drug therapy, genetics, metabolism Protein Structure, Tertiary Pyridines / pharmacology Tumor Suppressor Protein p53 / genetics, metabolism* |
| Grant Support | |
ID/Acronym/Agency:
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CA090465/CA/NCI NIH HHS; CA098172/CA/NCI NIH HHS; CA152786/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Benzamides; 0/Histone Deacetylase Inhibitors; 0/N-(2-aminophenyl)-4-(N-(pyridin-3-ylmethoxycarbonyl)aminomethyl)benzamide; 0/Pyridines; 0/TP53 protein, human; 0/Tumor Suppressor Protein p53 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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