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J Biol Chem, Vol. 274, Issue 2, 1092-1099, January 8, 1999
From the In human T-lymphoblastoid cells, downstream
signaling events of mammalian target of rapamycin (mTOR), including the
activity of p70s6k and phosphorylation of eukaryotic
initiation factor 4E-binding protein 1, were dependent on amino acid
concentration in the culture media, whereas other growth-related
protein kinases were not. Amino acid-induced p70s6k
activation was completely inhibited by rapamycin but only partially inhibited by wortmannin. Moreover, amino acid concentration similarly affected the p70s6k activity, which was dependent on a
rapamycin-resistant mutant (S2035I) of mTOR. These data indicate that
mTOR is required for amino acid-dependent activation of
p70s6k. The mechanism by which amino acids regulate
p70s6k activity was further explored: 1) amino acid
alcohols, which inhibit aminoacylation of tRNA by their competitive
binding to tRNA synthetases, suppressed p70s6k activity; 2)
suppression of p70s6k by amino acid depletion was blocked
by cycloheximide or puromycin, which inhibit utilization of
aminoacylated tRNA in cells; and 3) in cells having a
temperature-sensitive mutant of histidyl tRNA synthetase,
p70s6k was suppressed by a transition of cells to a
nonpermissible temperature, which was partially restored by addition of
high concentrations of histidine. These results indicate that
suppression of tRNA aminoacylation is able to inhibit
p70s6k activity. Deacylated tRNA may be a factor negatively
regulating p70s6k.
Amino Acid-dependent Control of
p70s6k
INVOLVEMENT OF tRNA AMINOACYLATION IN THE REGULATION
,,,
Department of Pediatrics, Division of Basic
Sciences, National Jewish Medical and Research Center,
Denver, Colorado 80206, the § Department of Molecular
Pharmacology, St. Jude Children's Research Hospital,
Memphis, Tennessee 38105, and the ¶ Mayo Clinic and Foundation,
Department of Immunology and Pharmacology,
Rochester, Minnesota 55905
Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.
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