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Molecular and Cellular Biology, December 2001, p. 8671-8683, Vol. 21, No. 24
0270-7306/01/$04.00+0 DOI: 10.1128/MCB.21.24.8671-8683.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Amino Acid-Induced Translation of TOP mRNAs Is Fully Dependent on
Phosphatidylinositol 3-Kinase-Mediated Signaling, Is Partially
Inhibited by Rapamycin, and Is Independent of S6K1 and rpS6
Phosphorylation
Hua
Tang,1
Eran
Hornstein,1
Miri
Stolovich,1
Galit
Levy,1
Mark
Livingstone,2
Dennis
Templeton,3
Joseph
Avruch,4 and
Oded
Meyuhas1,*
Department of Biochemistry, The Hebrew University-Hadassah
Medical School, Jerusalem 91120, Israel1;
Cell Signaling Technology, Beverly, Massachusetts
019152; Department of Pathology,
University of Virginia Medical School, Charlottesville, Virginia
229083; and Diabetes Unit, Medical
Services, and Department of Molecular Biology, Massachusetts
General Hospital and Harvard Medical School, Boston, Massachusetts
021144
Received 20 July 2001/Returned for modification 10 September
2001/Accepted 24 September 2001
Vertebrate TOP mRNAs contain an oligopyrimidine tract at their
5' termini (5'TOP) and encode components of the translational machinery. Previously it has been shown that they are subject to
selective translational repression upon growth arrest and that their
translational behavior correlates with the activity of S6K1. We now
show that the translation of TOP mRNAs is rapidly repressed by
amino acid withdrawal and that this nutritional control depends strictly on the integrity of the 5'TOP motif. However, neither phosphorylation of ribosomal protein (rp) S6 nor activation of S6K1 per
se is sufficient to relieve the translational repression of TOP
mRNAs in amino acid-starved cells. Likewise, inhibition of S6K1
activity and rpS6 phosphorylation by overexpression of dominant-negative S6K1 mutants failed to suppress the translational activation of TOP mRNAs in amino acid-refed cells. Furthermore, TOP
mRNAs were translationally regulated by amino acid sufficiency in
embryonic stem cells lacking both alleles of the S6K1 gene. Inhibition of mTOR by rapamycin led to fast and complete repression of
S6K1, as judged by rpS6 phosphorylation, but to only partial and
delayed repression of translational activation of TOP mRNAs. In
contrast, interference in the phosphatidylinositol 3-kinase (PI3-kinase)-mediated pathway by chemical or genetic manipulations blocked rapidly and completely the translational activation of TOP
mRNAs. It appears, therefore, that translational regulation of TOP
mRNAs, at least by amino acids, (i) is fully dependent on
PI3-kinase, (ii) is partially sensitive to rapamycin, and (iii) requires neither S6K1 activity nor rpS6 phosphorylation.
*
Corresponding author. Mailing address: Department of
Biochemistry, Hebrew University-Hadassah Medical School, P.O. Box
12272, Jerusalem 91120, Israel. Phone: 972-2-6758290. Fax:
972-2-6758911. E-mail: meyuhas{at}cc.huji.ac.il.
Molecular and Cellular Biology, December 2001, p. 8671-8683, Vol. 21, No. 24
0270-7306/01/$04.00+0 DOI: 10.1128/MCB.21.24.8671-8683.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
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