Published online before print March 4, 2004, doi: 10.1161/01.RES.0000124977.59827.80
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© 2004 American Heart Association, Inc.
Cellular Biology |
Phosphorylation of Eukaryotic Translation Initiation Factor 2B
by Glycogen Synthase Kinase-3ß Regulates ß-Adrenergic Cardiac Myocyte Hypertrophy
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.
Correspondence to Junichi Sadoshima, MD, PhD, Department of Cell Biology and Molecular Medicine, UMDNJ, 185 South Orange Ave, MSB G-609, Newark, NJ 07103-2714. E-mail sadoshju{at}umdnj.edu
Glycogen synthase kinase 3ß (GSK-3ß) negatively regulates cardiac hypertrophy. A potential target mediating the antihypertrophic effect of GSK-3ß is eukaryotic translation initiation factor 2B
(eIF2B). Overexpression of GSK-3ß 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-3ß, 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-3ß 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-3ß, increased cell size (+107±35%) as strongly as ISO (+95±25%), and abolished antihypertrophic effects of GSK-3ß, indicating that S535 phosphorylation of eIF2B critically mediates antihypertrophic effects of GSK-3ß. Furthermore, expression of eIF2B-F259L, a dominant-negative mutant, inhibited ISO-induced hypertrophy, indicating that eIF2B is required for ß-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-3ß 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 3ß • eukaryotic translation initiation factor 2B • protein synthesis
This article has been cited by other articles:
 |
|
 |
|
  H. Deng, G. A. Dokshin, J. Lei, A. M. Goldsmith, K. N. Bitar, D. C. Fingar, M. B. Hershenson, and J. K. Bentley Inhibition of Glycogen Synthase Kinase-3{beta} Is Sufficient for Airway Smooth Muscle Hypertrophy J. Biol. Chem., April 11, 2008; 283(15): 10198 - 10207. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Wang and C. G. Proud A Novel Mechanism for the Control of Translation Initiation by Amino Acids, Mediated by Phosphorylation of Eukaryotic Initiation Factor 2B Mol. Cell. Biol., March 1, 2008; 28(5): 1429 - 1442. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Hirotani, P. Zhai, H. Tomita, J. Galeotti, J. P. Marquez, S. Gao, C. Hong, A. Yatani, J. Avila, and J. Sadoshima Inhibition of Glycogen Synthase Kinase 3{beta} During Heart Failure Is Protective Circ. Res., November 26, 2007; 101(11): 1164 - 1174. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. W. Tullai, J. Chen, M. E. Schaffer, E. Kamenetsky, S. Kasif, and G. M. Cooper Glycogen Synthase Kinase-3 Represses Cyclic AMP Response Element-binding Protein (CREB)-targeted Immediate Early Genes in Quiescent Cells J. Biol. Chem., March 30, 2007; 282(13): 9482 - 9491. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. A.M. van de Schans, S. W.M. van den Borne, A. E. Strzelecka, B. J.A. Janssen, J. L.J. van der Velden, R. C.J. Langen, A. Wynshaw-Boris, J. F.M. Smits, and W. M. Blankesteijn Interruption of Wnt Signaling Attenuates the Onset of Pressure Overload-Induced Cardiac Hypertrophy Hypertension, March 1, 2007; 49(3): 473 - 480. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Shiojima and K. Walsh Regulation of cardiac growth and coronary angiogenesis by the Akt/PKB signaling pathway Genes & Dev., December 15, 2006; 20(24): 3347 - 3365. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Chen, S. P. Shevtsov, E. Hsich, L. Cui, S. Haq, M. Aronovitz, R. Kerkela, J. D. Molkentin, R. Liao, R. N. Salomon, et al. The {beta}-Catenin/T-Cell Factor/Lymphocyte Enhancer Factor Signaling Pathway Is Required for Normal and Stress-Induced Cardiac Hypertrophy Mol. Cell. Biol., June 15, 2006; 26(12): 4462 - 4473. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Hoshijima Mechanical stress-strain sensors embedded in cardiac cytoskeleton: Z disk, titin, and associated structures Am J Physiol Heart Circ Physiol, April 1, 2006; 290(4): H1313 - H1325. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. R Kimball and L. S Jefferson New functions for amino acids: effects on gene transcription and translation Am. J. Clinical Nutrition, February 1, 2006; 83(2): 500S - 507S. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Kubica, D. R. Bolster, P. A. Farrell, S. R. Kimball, and L. S. Jefferson Resistance Exercise Increases Muscle Protein Synthesis and Translation of Eukaryotic Initiation Factor 2B{epsilon} mRNA in a Mammalian Target of Rapamycin-dependent Manner J. Biol. Chem., March 4, 2005; 280(9): 7570 - 7580. [Abstract] [Full Text] [PDF]
|
|