Document Detail

Epstein-Barr virus BZLF1 gene is activated by transforming growth factor-beta through cooperativity of Smads and c-Jun/c-Fos proteins.
MedLine Citation:
PMID:  11971895     Owner:  NLM     Status:  MEDLINE    
Induction of Epstein-Barr virus (EBV) production in an EBV-positive cell is achieved by expression of the gene BZLF1 that switches the latent state into a lytic state. The expression of the BZLF1 gene is initiated from the promoter Zp, which is normally suppressed in EBV-transformed B cells. The BZLF1 gene can be induced for expression by activating agents, such as transforming growth factor-beta (TGF-beta) and 12-O-tetradecanoylphorbol-13-acetate. The 12-O-tetradecanoylphorbol-13-acetate-responsive element located in the Zp is the AP-1 motif. The TGF-beta-responsive element, however, has not been determined. We demonstrated that the Smad4-binding element site, GTCTG, from -233 to -229, was located in the regulatory region of the Zp relative to the BZLF1 transcription initiation site and was physically associated with Smad4. This association was important for the TGF-beta induction of Zp. We also showed from the results of co-transfection experiments and electrophoretic mobility shift assays that both the AP-1 motif and Smad4-binding element site appeared to be required for the TGF-beta-induced activation of Zp. This effect was mediated through the cooperation of Smad3/Smad4 and c-Jun/c-Fos that formed a complex. TGF-beta treatment of Rael cells induced production of infectious EBV particles that was capable of infecting EBV-negative CA46 cells and transforming normal cord blood B cells, in vitro. Those data support a mechanism that TGF-beta induces the latent EBV in cells to enter the viral lytic cycle through regulation of key viral proteins by TGF-beta signal transducers. Those findings also suggest a role of TGF-beta in EBV-associated diseases.
Chih-Lung Liang; Jo-Lin Chen; Yun-Pung Paul Hsu; Jonathan T Ou; Yu-Sun Chang
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2002-04-23
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  277     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2002 Jun 
Date Detail:
Created Date:  2002-06-24     Completed Date:  2002-08-06     Revised Date:  2008-11-21    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  23345-57     Citation Subset:  IM    
Institute of Microbiology and Immunology, National Yang-Ming University, Shih-Pai 112, Taipei, Republic of China.
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MeSH Terms
Base Sequence
Binding Sites
Cell Line
DNA, Viral / analysis
DNA-Binding Proteins / genetics*,  physiology*
Gene Expression Regulation / drug effects*
MAP Kinase Signaling System
Molecular Sequence Data
Oligoribonucleotides, Antisense / pharmacology
Promoter Regions, Genetic
Proto-Oncogene Proteins c-fos / physiology*
Proto-Oncogene Proteins c-jun / physiology*
Smad4 Protein
Tetradecanoylphorbol Acetate / pharmacology
Trans-Activators / genetics*,  physiology*
Transforming Growth Factor beta / pharmacology*
Viral Proteins*
Reg. No./Substance:
0/BZLF1 protein, Herpesvirus 4, Human; 0/DNA, Viral; 0/DNA-Binding Proteins; 0/Oligoribonucleotides, Antisense; 0/Proto-Oncogene Proteins c-fos; 0/Proto-Oncogene Proteins c-jun; 0/SMAD4 protein, human; 0/Smad4 Protein; 0/Trans-Activators; 0/Transforming Growth Factor beta; 0/Viral Proteins; 16561-29-8/Tetradecanoylphorbol Acetate

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