Published online before print March 4, 2004, doi: 10.1161/01.RES.0000124977.59827.80
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Submitted on October 9, 2003
Revised on February 20, 2004
Accepted on February 23, 2004
Phosphorylation of Eukaryotic Translation Initiation Factor 2B
by Glycogen Synthase Kinase-3
Regulates -Adrenergic Cardiac Myocyte Hypertrophy
Stefan E. Hardt ;
From the Department of Cell Biology and Molecular Medicine (S.E.H., H.T., J.S.), Cardiovascular Research Institute, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, NJ; and the Department of Cardiology (S.E.H., H.A.K.), University of Heidelberg, Germany.
* To whom correspondence should be addressed. E-mail: sadoshju{at}umdnj.edu.
Glycogen synthase kinase 3
(GSK-3) negatively regulates cardiac hypertrophy. A potential target mediating the antihypertrophic effect of GSK-3 is eukaryotic translation initiation factor 2B
(eIF2B). Overexpression of GSK-3 increased the cellular kinase activity toward GST-eIF2B in neonatal rat cardiac myocytes, whereas LiCl (10 mmol/L) or isoproterenol (ISO) (10 µmol/L), a treatment known to inhibit GSK-3, decreased it. Immunoblot analyses using anti-S535 phosphospecific eIF2B antibody showed that S535 phosphorylation of endogenous eIF2B was decreased by LiCl or ISO, suggesting that GSK-3 is the predominant kinase regulating phosphorylation of eIF2B-S535 in cardiac myocytes. Decreases in eIF2B-S535 phosphorylation were also observed in a rat model of cardiac hypertrophy in vivo. Overexpression of wild-type eIF2B alone moderately increased cell size (+31±11%; P<0.05 versus control), whereas treatment of eIF2B-transduced myocytes with LiCl (+73±22% versus eIF2B only; P<0.05) or ISO (+84±33% versus eIF2B only; P<0.05) enhanced the effect of eIF2B. Overexpression of eIF2B-S535A, which is not phosphorylated by GSK-3, increased cell size (+107±35%) as strongly as ISO (+95±25%), and abolished antihypertrophic effects of GSK-3, indicating that S535 phosphorylation of eIF2B critically mediates antihypertrophic effects of GSK-3. Furthermore, expression of eIF2B- F259L, a dominant-negative mutant, inhibited ISO-induced hypertrophy, indicating that eIF2B is required for -adrenergic hypertrophy. Interestingly, expression of eIF2B-S535A partially increased cytoskeletal reorganization, whereas it did not increase expression of atrial natriuretic factor gene. These results suggest that GSK-3 is the predominant kinase mediating phosphorylation of eIF2B-S535 in cardiac myocytes, which in turn plays an important role in regulating cardiac hypertrophy primarily through protein synthesis.
Key words: hypertrophy • glycogen synthase kinase 3
•
eukaryotic translation initiation factor 2B •
protein synthesis
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