Tuberous sclerosis complex tumor suppressor-mediated S6 kinase inhibition by phosphatidylinositide-3-OH kinase is mTOR independent

doi:10.1083/jcb.jcb.200206108

Published 28 October 2002. doi:10.1083/jcb.jcb.200206108

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© The Rockefeller University Press, 0021-9525/2002/10/217 $5.00
The Journal of Cell Biology, Volume 159, Number 2, 217-224

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Tuberous sclerosis complex tumor suppressor–mediated S6 kinase inhibition by phosphatidylinositide-3-OH kinase is mTOR independent

Anja Jaeschke², Joerg Hartkamp¹, Masao Saitoh², Wendy Roworth¹, Takahiro Nobukuni², Angela Hodges³, Julian Sampson³, George Thomas² and Richard Lamb¹

¹ Cancer Research UK Centre for Cell and Molecular Biology, Institute for Cancer Research, London SW3 6JB, United Kingdom
² Friedrich Miescher Institute, Maulbeerstrasse 66, CH-4058, Basel, Switzerland
³ Institute of Medical Genetics, University of Wales College of Medicine, Heath Park, Cardiff CF14 4XN, United Kingdom

Address correspondence to Richard Lamb, Cancer Research UK Centre for Cell and Molecular Biology, Institute for Cancer Research, 237 Fulham Rd., London SW36JB, UK. Tel.: 44-207-970-6096. Fax.: 44-207-352-5630. E-mail: rlamb{at}icr.ac.uk; or George Thomas, Friedrich Miescher Institute, Maulbeerstrasse 66, CH-4058, Basel, Switzerland. Tel.: 41-61-6973012. Fax: 41-61-6973976. E-mail: gthomas{at}fmi.ch

The evolution of mitogenic pathways has led to the parallelrequirement for negative control mechanisms, which prevent aberrantgrowth and the development of cancer. Principally, such negativecontrol mechanisms are represented by tumor suppressor genes,which normally act to constrain cell proliferation (Macleod,K. 2000. Curr. Opin. Genet. Dev. 10:81–93). Tuberous sclerosiscomplex (TSC) is an autosomal-dominant genetic disorder, characterizedby mutations in either TSC1 or TSC2, whose gene products hamartin(TSC1) and tuberin (TSC2) constitute a putative tumor suppressorcomplex (TSC1-2; van Slegtenhorst, M., M. Nellist, B. Nagelkerken,J. Cheadle, R. Snell, A. van den Ouweland, A. Reuser, J. Sampson,D. Halley, and P. van der Sluijs. 1998. Hum. Mol. Genet. 7:1053–1057).Little is known with regard to the oncogenic target of TSC1-2,however recent genetic studies in Drosophila have shown thatS6 kinase (S6K) is epistatically dominant to TSC1-2 (Tapon,N., N. Ito, B.J. Dickson, J.E. Treisman, and I.K. Hariharan.2001. Cell. 105:345–355; Potter, C.J., H. Huang, and T.Xu. 2001. Cell. 105:357–368). Here we show that loss ofTSC2 function in mammalian cells leads to constitutive S6K1activation, whereas ectopic expression of TSC1-2 blocks thisresponse. Although activation of wild-type S6K1 and cell proliferationin TSC2-deficient cells is dependent on the mammalian targetof rapamycin (mTOR), by using an S6K1 variant (GST- ${Delta}$ C-S6K1),which is uncoupled from mTOR signaling, we demonstrate thatTSC1-2 does not inhibit S6K1 via mTOR. Instead, we show by usingwortmannin and dominant interfering alleles of phosphatidylinositide-3-OHkinase (PI3K) that increased S6K1 activation is contingent uponthe suppression of TSC2 function by PI3K in normal cells andis PI3K independent in TSC2-deficient cells.

Key Words: TSC; S6K1; 4E-BP1; PI3K; rapamycin

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