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

doi:10.1128/MCB.21.24.8671-8683.2001

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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 translationalmachinery. Previously it has been shown that they are subjectto selective translational repression upon growth arrest and thattheir translational behavior correlates with the activity of S6K1.We now show that the translation of TOP mRNAs is rapidly repressedby amino acid withdrawal and that this nutritional control dependsstrictly on the integrity of the 5'TOP motif. However, neitherphosphorylation of ribosomal protein (rp) S6 nor activation ofS6K1 per se is sufficient to relieve the translational repressionof TOP mRNAs in amino acid-starved cells. Likewise, inhibitionof S6K1 activity and rpS6 phosphorylation by overexpression ofdominant-negative S6K1 mutants failed to suppress the translationalactivation of TOP mRNAs in amino acid-refed cells. Furthermore,TOP mRNAs were translationally regulated by amino acid sufficiencyin embryonic stem cells lacking both alleles of the S6K1 gene.Inhibition of mTOR by rapamycin led to fast and complete repressionof S6K1, as judged by rpS6 phosphorylation, but to only partialand delayed repression of translational activation of TOP mRNAs.In contrast, interference in the phosphatidylinositol 3-kinase(PI3-kinase)-mediated pathway by chemical or genetic manipulationsblocked rapidly and completely the translational activation ofTOP mRNAs. It appears, therefore, that translational regulationof TOP mRNAs, at least by amino acids, (i) is fully dependenton PI3-kinase, (ii) is partially sensitive to rapamycin, and (iii)requires neither S6K1 activity nor rpS6phosphorylation.

^* 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.

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