Coagulation FVII (Factor VII) is a vitamin K-dependent glycoprotein synthesized in hepatocytes. It was reported previously that FVII gene (F7) expression was up-regulated by ribavirin treatment in hepatitis C virus-infected haemophilia patients; however, its precise mechanism is still unknown. In the present study, we investigated the molecular mechanism of ribavirin-induced up-regulation of F7 expression in HepG2 (human hepatoma cell line). We found that intracellular GTP depletion by ribavirin as well as other IMPDH (inosine-5′-monophosphate dehydrogenase) inhibitors, such as mycophenolic acid and 6-mercaptopurine, up-regulated F7 expression. FVII mRNA transcription was mainly enhanced by accelerated transcription elongation, which was mediated by the P-TEFb (positive-transcription elongation factor b) complex, rather than by promoter activation. Ribavirin unregulated ELL (eleven-nineteen lysine-rich leukaemia) 3 mRNA expression before F7 up-regulation. We observed that ribavirin enhanced ELL3 recruitment to F7, whereas knockdown of ELL3 diminished ribavirin-induced FVII mRNA up-regulation. Ribavirin also enhanced recruitment of CDK9 (cyclin-dependent kinase 9) 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 up-regulation by acceleration of transcription elongation, which may be crucial in understanding its pleiotropic functions in vivo.
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January 2013
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Research Article|
December 07 2012
Ribavirin-induced intracellular GTP depletion activates transcription elongation in coagulation Factor VII gene expression
Atsuo Suzuki
;
Atsuo Suzuki
*Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine, Nagoya 461-8673, Japan
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Yuhri Miyawaki
;
Yuhri Miyawaki
*Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine, Nagoya 461-8673, Japan
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Eriko Okuyama
;
Eriko Okuyama
*Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine, Nagoya 461-8673, Japan
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Moe Murata
;
Moe Murata
*Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine, Nagoya 461-8673, Japan
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Yumi Ando
;
Yumi Ando
*Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine, Nagoya 461-8673, Japan
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Io Kato
;
Io Kato
*Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine, Nagoya 461-8673, Japan
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Yuki Takagi
;
Yuki Takagi
*Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine, Nagoya 461-8673, Japan
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Akira Takagi
;
Akira Takagi
*Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine, Nagoya 461-8673, Japan
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Takashi Murate
;
Takashi Murate
*Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine, Nagoya 461-8673, Japan
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Hidehiko Saito
;
Hidehiko Saito
†National Hospital Organization-Nagoya Medical Center, Nagoya 460-0001, Japan
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Tetsuhito Kojima
Tetsuhito Kojima
1
*Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine, Nagoya 461-8673, Japan
1To whom correspondence should be addressed (email kojima@met.nagoya-u.ac.jp).
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Biochem J (2013) 449 (1): 231–239.
Article history
Received:
August 14 2012
Revision Received:
September 25 2012
Accepted:
October 11 2012
Accepted Manuscript online:
October 11 2012
Citation
Atsuo Suzuki, Yuhri Miyawaki, Eriko Okuyama, Moe Murata, Yumi Ando, Io Kato, Yuki Takagi, Akira Takagi, Takashi Murate, Hidehiko Saito, Tetsuhito Kojima; Ribavirin-induced intracellular GTP depletion activates transcription elongation in coagulation Factor VII gene expression. Biochem J 1 January 2013; 449 (1): 231–239. doi: https://doi.org/10.1042/BJ20121286
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