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Molecular and Cellular Biology, February 2009, p. 640-649, Vol. 29, No. 3
0270-7306/09/$08.00+0     doi:10.1128/MCB.00980-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

The TSC-mTOR Pathway Mediates Translational Activation of TOP mRNAs by Insulin Largely in a Raptor- or Rictor-Independent Manner{triangledown} ,{ddagger}

Ilona Patursky-Polischuk,1 Miri Stolovich-Rain,1,{dagger} Mirit Hausner-Hanochi,1,§ Judith Kasir,1 Nadine Cybulski,2 Joseph Avruch,3 Markus A. Rüegg,2 Michael N. Hall,2 and Oded Meyuhas1*

Department of Biochemistry, the Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel,1 Biozentrum, University of Basel, Klingelbergstrasse 70, CH-4056 Basel, Switzerland,2 Diabetes Unit, Medical Services, and Department of Molecular Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 021143

Received 22 June 2008/ Returned for modification 11 July 2008/ Accepted 18 November 2008

The stimulatory effect of insulin on protein synthesis is due to its ability to activate various translation factors. We now show that insulin can increase protein synthesis capacity also by translational activation of TOP mRNAs encoding various components of the translation machinery. This translational activation involves the tuberous sclerosis complex (TSC), as the knockout of TSC1 or TSC2 rescues TOP mRNAs from translational repression in mitotically arrested cells. Similar results were obtained upon overexpression of Rheb, an immediate TSC1-TSC2 target. The role of mTOR, a downstream effector of Rheb, in translational control of TOP mRNAs has been extensively studied, albeit with conflicting results. Even though rapamycin fully blocks mTOR complex 1 (mTORC1) kinase activity, the response of TOP mRNAs to this drug varies from complete resistance to high sensitivity. Here we show that mTOR knockdown blunts the translation efficiency of TOP mRNAs in insulin-treated cells, thus unequivocally establishing a role for mTOR in this mode of regulation. However, knockout of the raptor or rictor gene has only a slight effect on the translation efficiency of these mRNAs, implying that mTOR exerts its effect on TOP mRNAs through a novel pathway with a minor, if any, contribution of the canonical mTOR complexes mTORC1 and mTORC2. This conclusion is further supported by the observation that raptor knockout renders the translation of TOP mRNAs rapamycin hypersensitive.

* Corresponding author. Mailing address: Department of Biochemistry, Hebrew University-Hadassah Medical School, P.O. Box 12272, Jerusalem 91120, Israel. Phone: 972-2-6758290. Fax: 972-2-6757379. E-mail: meyuhas{at}cc.huji.ac.il

{triangledown} Published ahead of print on 1 December 2008.

{ddagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{dagger} Present address: Department of Cellular Biochemistry and Human Genetics, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.

§ Present address: Pediatric Endocrinology Unit, Division of Pediatrics, Chaim Sheba Medical Center, Tel-Hashomer 52621, Israel.

Molecular and Cellular Biology, February 2009, p. 640-649, Vol. 29, No. 3
0270-7306/09/$08.00+0     doi:10.1128/MCB.00980-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



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