| The Brd4 extraterminal domain confers transcription activation independent of pTEFb by recruiting multiple proteins, including NSD3. | |
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MedLine Citation:
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PMID: 21555454 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Bromodomain protein 4 (Brd4) plays critical roles in development, cancer progression, and virus-host pathogenesis. To gain mechanistic insight into the various biological functions of Brd4, we performed a proteomic analysis to identify and characterize Brd4-associated cellular proteins. We found that the extraterminal (ET) domain, whose function has to date not been determined, interacts with NSD3, JMJD6, CHD4, GLTSCR1, and ATAD5. These ET-domain interactions were also conserved for Brd2 and Brd3, the other human BET proteins tested. We demonstrated that GLTSCR1, NSD3, and JMJD6 impart a pTEFb-independent transcriptional activation function on Brd4. NSD3 as well as JMJD6 is recruited to regulated genes in a Brd4-dependent manner. Moreover, we found that depletion of Brd4 or NSD3 reduces H3K36 methylation, demonstrating that the Brd4/NSD3 complex regulates this specific histone modification. Our results indicate that the Brd4 ET domain through the recruitment of the specific effectors regulates transcriptional activity. In particular, we show that one of these effectors, NSD3, regulates transcription by modifying the chromatin microenvironment at Brd4 target genes. Our study thus identifies the ET domain as a second important transcriptional regulatory domain for Brd4 in addition to the carboxyl-terminal domain (CTD) that interacts with pTEFb. |
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Authors:
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Shaila Rahman; Mathew E Sowa; Matthias Ottinger; Jennifer A Smith; Yang Shi; J Wade Harper; Peter M Howley |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2011-05-09 |
Journal Detail:
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Title: Molecular and cellular biology Volume: 31 ISSN: 1098-5549 ISO Abbreviation: Mol. Cell. Biol. Publication Date: 2011 Jul |
Date Detail:
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Created Date: 2011-06-10 Completed Date: 2011-08-23 Revised Date: 2012-10-09 |
Medline Journal Info:
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Nlm Unique ID: 8109087 Medline TA: Mol Cell Biol Country: United States |
Other Details:
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Languages: eng Pagination: 2641-52 Citation Subset: IM |
Affiliation:
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Department of Pathology, Harvard Medical School, Boston, MA 02115, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Amino Acid Sequence Cell Line Histone-Lysine N-Methyltransferase / metabolism* Humans Jumonji Domain-Containing Histone Demethylases Molecular Sequence Data Nuclear Proteins / genetics, metabolism* Positive Transcriptional Elongation Factor B / metabolism* Protein Structure, Tertiary / genetics Transcription Factors / genetics, metabolism* Transcriptional Activation* Tumor Suppressor Proteins / metabolism |
| Grant Support | |
ID/Acronym/Agency:
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AG011085/AG/NIA NIH HHS; GM054137/GM/NIGMS NIH HHS; R01 GM054137/GM/NIGMS NIH HHS; R01 GM070565/GM/NIGMS NIH HHS; R01CA116720/CA/NCI NIH HHS; T32CA009361/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/BRD4 protein, human; 0/GLTSCR1 protein, human; 0/Nuclear Proteins; 0/Transcription Factors; 0/Tumor Suppressor Proteins; EC 1.14.11.-/JMJD6 protein, human; EC 1.14.11.-/Jumonji Domain-Containing Histone Demethylases; EC 2.1.1.43/Histone-Lysine N-Methyltransferase; EC 2.1.1.43/WHSC1L1 protein, human; EC 2.7.11.-/Positive Transcriptional Elongation Factor B |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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