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Ribavirin-induced intracellular GTP depletion activates transcription elongation in coagulation factor VII gene expression.
MedLine Citation:
PMID:  23050902     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Coagulation factor VII (FVII) is a vitamin K-dependent glycoprotein synthesized in hepatocytes. Previously, it was reported that FVII gene (F7) expression was upregulated by ribavirin treatment in hepatitis C virus-infected hemophilia patients; however, its precise mechanism is still unknown. Here, we investigated the molecular mechanism of ribavirin-induced upregulation of F7 expression in HepG2 cells. We found that intracellular GTP depletion by ribavirin as well as other IMP dehydrogenase inhibitors, such as mycophenolic acid and 6-mercaptopurine, upregulated F7 expression. FVII mRNA transcription was mainly enhanced by accelerated transcription elongation, which was mediated by the positive-transcription elongation factor b (P-TEFb) complex, rather than by promoter activation. Ribavirin unregulated eleven-nineteen lysine-rich leukemia 3 (ELL3) mRNA expression prior to F7 upregulation. We observed that ribavirin enhanced ELL3 recruitment to F7, whereas knockdown of ELL3 diminished ribavirin-induced FVII mRNA upregulation. Ribavirin also enhanced recruitment of CDK9 and AFF4 to F7. These data suggest that ribavirin-induced intracellular GTP depletion recruits a super elongation complex containing P-TEFb, AFF4 and ELL3, to F7, and modulates FVII mRNA transcription elongation. Collectively, we have elucidated a basal mechanism for ribavirin-induced FVII mRNA upregulation by acceleration of transcription elongation, which may be crucial in understanding its pleiotropic functions in vivo.
Authors:
Atsuo Suzuki; Yuhri Miyawaki; Eriko Okuyama; Moe Murata; Yumi Ando; Io Kato; Yuki Takagi; Akira Takagi; Takashi Murate; Hidehiko Saito; Tetsuhito Kojima
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-10-11
Journal Detail:
Title:  The Biochemical journal     Volume:  -     ISSN:  1470-8728     ISO Abbreviation:  Biochem. J.     Publication Date:  2012 Oct 
Date Detail:
Created Date:  2012-10-11     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  2984726R     Medline TA:  Biochem J     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
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