Document Detail


Myb proteins repress human Ig epsilon germline transcription by inhibiting STAT6-dependent promoter activation.
MedLine Citation:
PMID:  12044779     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Cytokine-dependent induction of correctly spliced germline (GL) transcripts is required to target the appropriate switch region for class switch recombination. GL transcription is linked to the cell cycle and the number of cell divisions through mechanisms that have not been defined. The human proximal epsilon GL promoter contains an IL-4 responsive element (IL-4RE) that binds STAT6 and is sufficient to confer IL-4 inducibility to a heterologous promoter in transient transfection studies. We show herein that the IL-4RE contains a novel Myb binding motif that overlaps the 3' end of the STAT6 palindrome. EMSA analysis showed binding to the IL-4RE of endogenous Myb proteins expressed in BL-2 B cells and Jurkat T cells. However, double occupancy of a probe spanning both STAT6 and Myb binding motifs could not be detected. Thus, binding of either factor may prevent protein/DNA interactions at the other site, raising the possibility that Myb binding may interfere with STAT6-dependent activation of the IL-4RE. Indeed, cotransfection of A-Myb or c-Myb expression vectors in HEK293 and BL-2 cells suppressed STAT6-dependent transcription from a reporter construct containing four copies of the IL-4RE cloned upstream of a minimal thymidine kinase promoter. Most importantly, overexpression of A-Myb was sufficient to suppress IL-4-induced endogenous epsilon GL transcription in BL-2 cells. Our results indicate that Myb proteins, which are known to act as cell cycle sensors, may play an important mechanistic role in the in vivo regulation of epsilon GL transcription in human B cells.
Authors:
Silvia Monticelli; Raffaella Ghittoni; Michael Kabesch; Donata Vercelli
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Molecular immunology     Volume:  38     ISSN:  0161-5890     ISO Abbreviation:  Mol. Immunol.     Publication Date:  2002 Jun 
Date Detail:
Created Date:  2002-06-04     Completed Date:  2003-07-22     Revised Date:  2008-11-21    
Medline Journal Info:
Nlm Unique ID:  7905289     Medline TA:  Mol Immunol     Country:  England    
Other Details:
Languages:  eng     Pagination:  1129-38     Citation Subset:  IM    
Affiliation:
Arizona Respiratory Center, College of Medicine, University of Arizona, 1501 N. Campbell Avenue, Tucson, AZ 85724, USA.
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MeSH Terms
Descriptor/Qualifier:
B-Lymphocytes / metabolism
Humans
Immunoglobulin Class Switching / genetics
Immunoglobulin epsilon-Chains / genetics*,  metabolism
Oncogene Proteins v-myb / genetics*,  metabolism
Promoter Regions, Genetic*
STAT6 Transcription Factor
Trans-Activators / genetics,  metabolism*
Grant Support
ID/Acronym/Agency:
P01 HL67672-03/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Immunoglobulin epsilon-Chains; 0/Oncogene Proteins v-myb; 0/STAT6 Transcription Factor; 0/STAT6 protein, human; 0/Trans-Activators

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