| Identification of an acetylation-dependant Ku70/FLIP complex that regulates FLIP expression and HDAC inhibitor-induced apoptosis. | |
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MedLine Citation:
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PMID: 22322857 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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FLIP is a potential anti-cancer therapeutic target that inhibits apoptosis by blocking caspase 8 activation by death receptors. We report a novel interaction between FLIP and the DNA repair protein Ku70 that regulates FLIP protein stability by inhibiting its polyubiquitination. Furthermore, we found that the histone deacetylase (HDAC) inhibitor Vorinostat (SAHA) enhances the acetylation of Ku70, thereby disrupting the FLIP/Ku70 complex and triggering FLIP polyubiquitination and degradation by the proteasome. Using in vitro and in vivo colorectal cancer models, we further demonstrated that SAHA-induced apoptosis is dependant on FLIP downregulation and caspase 8 activation. In addition, an HDAC6-specific inhibitor Tubacin recapitulated the effects of SAHA, suggesting that HDAC6 is a key regulator of Ku70 acetylation and FLIP protein stability. Thus, HDAC inhibitors with anti-HDAC6 activity act as efficient post-transcriptional suppressors of FLIP expression and may, therefore, effectively act as 'FLIP inhibitors'. |
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Authors:
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E Kerr; C Holohan; K M McLaughlin; J Majkut; S Dolan; K Redmond; J Riley; K McLaughlin; I Stasik; M Crudden; S Van Schaeybroeck; C Fenning; R O'Connor; P Kiely; M Sgobba; D Haigh; P G Johnston; D B Longley |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2012-02-10 |
Journal Detail:
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Title: Cell death and differentiation Volume: 19 ISSN: 1476-5403 ISO Abbreviation: Cell Death Differ. Publication Date: 2012 Aug |
Date Detail:
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Created Date: 2012-07-09 Completed Date: 2013-01-18 Revised Date: 2013-04-16 |
Medline Journal Info:
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Nlm Unique ID: 9437445 Medline TA: Cell Death Differ Country: England |
Other Details:
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Languages: eng Pagination: 1317-27 Citation Subset: IM |
Affiliation:
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Centre for Cancer Research and Cell Biology, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Northern Ireland, UK. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Acetylation Amino Acid Sequence Animals Antigens, Nuclear / genetics, metabolism* Apoptosis / drug effects* CASP8 and FADD-Like Apoptosis Regulating Protein / biosynthesis, genetics, metabolism* Caspase 8 / metabolism DNA-Binding Proteins / genetics, metabolism* Down-Regulation Female HCT116 Cells HT29 Cells Histone Deacetylase Inhibitors / pharmacology* Histone Deacetylases / metabolism Humans Hydroxamic Acids / pharmacology Mice Mice, Inbred BALB C Protein Processing, Post-Translational RNA, Small Interfering / administration & dosage, genetics Transfection |
| Grant Support | |
ID/Acronym/Agency:
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//Cancer Research UK |
| Chemical | |
Reg. No./Substance:
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0/Antigens, Nuclear; 0/CASP8 and FADD-Like Apoptosis Regulating Protein; 0/DNA-Binding Proteins; 0/Histone Deacetylase Inhibitors; 0/Hydroxamic Acids; 0/Ku autoantigen; 0/RNA, Small Interfering; 149647-78-9/vorinostat; EC 3.4.22.-/CASP8 protein, human; EC 3.4.22.-/Caspase 8; EC 3.5.1.98/HDAC6 protein, human; EC 3.5.1.98/Histone Deacetylases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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