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Molecular and Cellular Biology, December 2002, p. 8101-8113, Vol. 22, No. 23
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.23.8101-8113.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Transduction of Growth or Mitogenic Signals into Translational Activation of TOP mRNAs Is Fully Reliant on the Phosphatidylinositol 3-Kinase-Mediated Pathway but Requires neither S6K1 nor rpS6 Phosphorylation

Miri Stolovich,1 Hua Tang,1,{dagger} Eran Hornstein,1 Galit Levy,1 Ruth Cohen,1 Sun Sik Bae,2 Morris J. Birnbaum,2 and Oded Meyuhas1*

Department of Biochemistry, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel,1 Howard Hughes Medical Institute and Cox Institute at the University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 191042

Received 17 June 2002/ Returned for modification 25 July 2002/ Accepted 28 August 2002

Translation of terminal oligopyrimidine tract (TOP) mRNAs, which encode multiple components of the protein synthesis machinery, is known to be controlled by mitogenic stimuli. We now show that the ability of cells to progress through the cell cycle is not a prerequisite for this mode of regulation. TOP mRNAs can be translationally activated when PC12 or embryonic stem (ES) cells are induced to grow (increase their size) by nerve growth factor and retinoic acid, respectively, while remaining mitotically arrested. However, both growth and mitogenic signals converge via the phosphatidylinositol 3-kinase (PI3-kinase)-mediated pathway and are transduced to efficiently translate TOP mRNAs. Translational activation of TOP mRNAs can be abolished by LY294002, a PI3-kinase inhibitor, or by overexpression of PTEN as well as by dominant-negative mutants of PI3-kinase or its effectors, PDK1 and protein kinase B{alpha} (PKB{alpha}). Likewise, overexpression of constitutively active PI3-kinase or PKB{alpha} can relieve the translational repression of TOP mRNAs in quiescent cells. Both mitogenic and growth signals lead to phosphorylation of ribosomal protein S6 (rpS6), which precedes the translational activation of TOP mRNAs. Nevertheless, neither rpS6 phosphorylation nor its kinase, S6K1, is essential for the translational response of these mRNAs. Thus, TOP mRNAs can be translationally activated by growth or mitogenic stimuli of ES cells, whose rpS6 is constitutively unphosphorylated due to the disruption of both alleles of S6K1. Similarly, complete inhibition of mammalian target of rapamycin (mTOR) and its effector S6K by rapamycin in various cell lines has only a mild repressive effect on the translation of TOP mRNAs. It therefore appears that translation of TOP mRNAs is primarily regulated by growth and mitogenic cues through the PI3-kinase pathway, with a minor role, if any, for the mTOR pathway.

* 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.

{dagger} Present address: Department of Biological Regulation, The Weizmann Institute of Science, Rehovot 76100, Israel.

Molecular and Cellular Biology, December 2002, p. 8101-8113, Vol. 22, No. 23
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.23.8101-8113.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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