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Involvement of the histone deacetylase SIRT1 in chicken ovalbumin upstream promoter transcription factor (COUP-TF)-interacting protein 2-mediated transcriptional repression
被引:107
作者:
Senawong, T
Peterson, VJ
Avram, D
Shepherd, DM
Frye, RA
Minucci, S
Leid, M
[1
]
机构:
[1] Oregon State Univ, Coll Pharm, Dept Pharmaceut Sci, Mol Pharmacol Lab, Corvallis, OR 97331 USA
[2] Oregon State Univ, Coll Pharm, Mol & Cellular Biol Program, Corvallis, OR 97331 USA
[3] Oregon State Univ, Environm Hlth Sci Ctr, Corvallis, OR 97331 USA
[4] Albany Med Coll, Ctr Cell Biol & Canc Res, Albany, NY 12208 USA
[5] Univ Montana, Coll Pharm, Dept Pharmaceut Sci, Ctr Environm Hlth Sci, Missoula, MT 59812 USA
[6] Univ Pittsburgh, Dept Pathol, Pittsburgh Vet Affairs Med Ctr 132L, Pittsburgh, PA 15240 USA
[7] Univ Milan, Dept Physiol & Biochem, European Inst Oncol, Dept Expt Oncol, I-20126 Milan, Italy
关键词:
D O I:
10.1074/jbc.M307477200
中图分类号:
Q5 [生物化学];
Q7 [分子生物学];
学科分类号:
071010 ;
081704 ;
摘要:
Chicken ovalbumin upstream promoter transcription factor (COUP-TF)-interacting proteins 1 and 2 (CTIP1 and CTIP2) enhance transcriptional repression mediated by COUP-TF II and have been implicated in hematopoietic cell development and malignancies. CTIP1 and CTIP2 are also sequence-specific DNA-binding proteins that repress transcription through direct, COUP-TF-independent binding to a GC-rich response element. CTIP1- and CTIP2-mediated transcriptional repression is insensitive to trichostatin A, an inhibitor of known class I and II histone deacetylases. However, chromatin immunoprecipitation assays revealed that expression of CTIP2 in mammalian cells resulted in deacetylation of histones H3 and/or H4 that were associated with the promoter region of a reporter gene. CTIP2-mediated transcriptional repression, as well as deacetylation of promoter-associated histones H3/H4 in CTIP2-transfected cells, was reversed by nicotinamide, an inhibitor of class III histone deacetylases such as the mammalian homologs of yeast Silent Information Regulator 2 (Sir2). The human homolog of yeast Sir2, SIRT1, was found to interact directly with CTIP2 and was recruited to the promoter template in a CTIP2-dependent manner. Moreover, SIRT1 enhanced the deacetylation of template-associated histones H3/H4 in CTIP2-transfected cells, and stimulated CTIP2-dependent transcriptional repression. Finally, endogenous SIRT1 and CTIP2 co-purified from Jurkat cell nuclear extracts in the context of a large (1-2 mDa) complex. These findings implicate SIRT1 as a histone H3/H4 deacetylase in mammalian cells and in transcriptional repression mediated by CTIP2.
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页码:43041 / 43050
页数:10
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