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J Biol Chem, Vol. 274, Issue 51, 36168-36175, December 17, 1999
From the Department of Cellular and Molecular Physiology, The
Pennsylvania State University, College of Medicine,
Hershey, Pennsylvania 17033
Leucine, glutamine, and tyrosine, three amino
acids playing key modulatory roles in hepatic proteolysis, were
evaluated for activation of signaling pathways involved in regulation
of liver protein synthesis. Furthermore, because leucine signals to
effectors that lie distal to the mammalian target of rapamycin, these
downstream factors were selected for study as candidate mediators of
amino acid signaling. Using the perfused rat liver as a model system, we observed a 25% stimulation of protein synthesis in response to
balanced hyperaminoacidemia, whereas amino acid imbalance due to
elevated concentrations of leucine, glutamine, and tyrosine resulted in
a protein synthetic depression of roughly 50% compared with
normoaminoacidemic controls. The reduction in protein synthesis accompanying amino acid imbalance became manifest at high physiologic concentrations and was dictated by the guanine nucleotide exchange activity of translation initiation factor eIF2B. Paradoxically, this
phenomenon occurred concomitantly with assembly of the mRNA cap
recognition complex, eIF4F as well as activation of the 70-kDa ribosomal S6 kinase, p70S6k. Dual and reciprocal
modulation of eIF4F and eIF2B was leucine-specific because isoleucine,
a structural analog, was ineffective in these regards. Thus, we
conclude that amino acid imbalance, heralded by leucine, initiates a
liver-specific translational failsafe mechanism that deters protein
synthesis under unfavorable circumstances despite promotion of the
eIF4F complex.
Leucine, Glutamine, and Tyrosine Reciprocally Modulate the
Translation Initiation Factors eIF4F and eIF2B in Perfused Rat
Liver*
*
This work was supported by National Institutes of Health
Grants DK 13499 (to L. S. J.) and GM 08619 (to O. J. S.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Dept. of Cellular and
Molecular Physiology, The Pennsylvania State University College of
Medicine, P.O. Box 850, Hershey, PA 17033. Tel.: 717-531-8567; Fax:
717-531-7667; E-mail: jjefferson@psu.edu.
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