Document Detail


The Brd4 extraterminal domain confers transcription activation independent of pTEFb by recruiting multiple proteins, including NSD3.
MedLine Citation:
PMID:  21555454     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Shaila Rahman; Mathew E Sowa; Matthias Ottinger; Jennifer A Smith; Yang Shi; J Wade Harper; Peter M Howley
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2011-05-09
Journal Detail:
Title:  Molecular and cellular biology     Volume:  31     ISSN:  1098-5549     ISO Abbreviation:  Mol. Cell. Biol.     Publication Date:  2011 Jul 
Date Detail:
Created Date:  2011-06-10     Completed Date:  2011-08-23     Revised Date:  2014-10-06    
Medline Journal Info:
Nlm Unique ID:  8109087     Medline TA:  Mol Cell Biol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2641-52     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
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:
AG011085/AG/NIA NIH HHS; GM054137/GM/NIGMS NIH HHS; R01 CA116720/CA/NCI 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:
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
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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