In adult cardiocytes, eIF4E (eukaryotic initiation factor 4E) activity and protein synthesis are increased concomitantly in response to stimuli that induce hypertrophic growth. We tested the hypothesis that increases in eIF4E activity selectively improve the translational efficiency of mRNAs that have an excessive amount of secondary structure in the 5´-UTR (5´-untranslated region). The activity of eIF4E was modified in primary cultures of adult cardiocytes using adenoviral gene transfer to increase either the amount of eIF4E or the extent of endogenous eIF4E phosphorylation. Subsequently, the effects of eIF4E on translational efficiency were assayed following adenoviral-mediated expression of luciferase reporter mRNAs that were either ‘stronger’ (less structure in the 5´-UTR) or ‘weaker’ (more structure in the 5´-UTR) with respect to translational efficiency. The insertion of G+C-rich repeats into the 5´-UTR doubled the predicted amount of secondary structure and was sufficient to reduce translational efficiency of the reporter mRNA by 48±13%. Translational efficiency of the weaker reporter mRNA was not significantly improved by overexpression of wild-type eIF4E when compared with the stronger reporter mRNA. In contrast, overexpression of the eIF4E kinase Mnk1 [MAP (mitogen-activated protein) kinase signal-integrating kinase 1] was sufficient to increase the translational efficiency of either reporter mRNA, independent of the amount of secondary structure in their respective 5´-UTRs. The increases in translational efficiency produced by Mnk1 occurred in association with corresponding decreases in mRNA levels. These findings indicate that the positive effect of eIF4E phosphorylation on translational efficiency in adult cardiocytes is coupled with the stability of mRNA.
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Research Article|
February 15 2004
Regulation of protein synthesis by eIF4E phosphorylation in adult cardiocytes: the consequence of secondary structure in the 5′-untranslated region of mRNA
William J. TUXWORTH, Jr;
William J. TUXWORTH, Jr
Department of Medicine, the Gazes Cardiac Research Institute, Medical University of South Carolina, and the Ralph H. Johnson Department of Veterans Affairs Medical Center, Charleston, SC 29403, U.S.A.
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Atif N. SAGHIR;
Atif N. SAGHIR
Department of Medicine, the Gazes Cardiac Research Institute, Medical University of South Carolina, and the Ralph H. Johnson Department of Veterans Affairs Medical Center, Charleston, SC 29403, U.S.A.
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Laura S. SPRUILL;
Laura S. SPRUILL
Department of Medicine, the Gazes Cardiac Research Institute, Medical University of South Carolina, and the Ralph H. Johnson Department of Veterans Affairs Medical Center, Charleston, SC 29403, U.S.A.
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Donald R. MENICK;
Donald R. MENICK
Department of Medicine, the Gazes Cardiac Research Institute, Medical University of South Carolina, and the Ralph H. Johnson Department of Veterans Affairs Medical Center, Charleston, SC 29403, U.S.A.
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Paul J. McDERMOTT
Paul J. McDERMOTT
1
Department of Medicine, the Gazes Cardiac Research Institute, Medical University of South Carolina, and the Ralph H. Johnson Department of Veterans Affairs Medical Center, Charleston, SC 29403, U.S.A.
1To whom correspondence should be addressed, at Gazes Cardiac Research Institute, Strom Thurmond Biomedical Research Building, Room 303, 114 Doughty Street, Charleston, SC 29403, U.S.A. (e-mail mcdermp@musc.edu).
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Publisher: Portland Press Ltd
Received:
July 09 2003
Revision Received:
October 31 2003
Accepted:
November 20 2003
Accepted Manuscript online:
November 20 2003
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London ©2004
2004
Biochem J (2004) 378 (1): 73–82.
Article history
Received:
July 09 2003
Revision Received:
October 31 2003
Accepted:
November 20 2003
Accepted Manuscript online:
November 20 2003
Citation
William J. TUXWORTH, Atif N. SAGHIR, Laura S. SPRUILL, Donald R. MENICK, Paul J. McDERMOTT; Regulation of protein synthesis by eIF4E phosphorylation in adult cardiocytes: the consequence of secondary structure in the 5′-untranslated region of mRNA. Biochem J 15 February 2004; 378 (1): 73–82. doi: https://doi.org/10.1042/bj20031027
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