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1 Division of Pediatric Cardiology, Department of Pediatrics and 2 Center for Cell Signaling, University of Virginia, Charlottesville, Virginia 22908-1356; and 3 Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, New York 10021-6399
Increased protein synthesis is
the cardinal feature of cardiac hypertrophy. We have studied
angiotensin II (ANG II)-dependent regulation of eukaryotic elongation
factor-2 (eEF-2), an essential component of protein translation
required for polypeptide elongation, in rat neonatal cardiac myocytes.
eEF2 is fully active in its dephosphorylated state and is
inhibited following phosphorylation by eEF2 kinase. ANG II
treatment (10
10-107 M) for 30 min
produced an AT1 receptor-specific and concentration- and
time-dependent reduction in the phosphorylation of eEF-2. Protein
phosphatase 2A (PP2A) inhibitors okadaic acid and fostriecin, but not
the PP2B inhibitor FK506, attenuated ANG II-dependent dephosphorylation
of eEF-2. ANG II activated mitogen-activated protein kinase, (MAPK)
within 10 min of treatment, and blockade of MAPK activation with
PD-98059 (1-20 nM) inhibited eEF-2 dephosphorylation. The
effect of ANG II on eEF-2 dephosphorylation was also blocked by
LY-29004 (1-20 nM), suggesting a role for phosphoinositide 3-kinase, but the mammalian target rapamycin inhibitor rapamycin (10-100 nM) had no effect. Together these results suggest
that the ANG II-dependent increase in protein synthesis includes
activation of eEF-2 via dephosphorylation by PP2A by a process that
involves both PI3K and MAPK.
protein translation; mitogen-activated protein kinase; protein phosphatase 2A; phosphoinositide 3-kinase
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