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

Anja Jaeschke, Joerg Hartkamp, Masao Saitoh, Wendy Roworth, Takahiro Nobukuni, Angela Hodges, Julian Sampson, George Thomas, Richard Lamb

Research output: Contribution to journalArticlepeer-review

179 Citations (Scopus)

Abstract

The evolution of mitogenic pathways has led to the parallel requirement for negative control mechanisms, which prevent aberrant growth and the development of cancer. Principally, such negative control 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 sclerosis complex (TSC) is an autosomal-dominant genetic disorder, characterized by mutations in either TSC1 or TSC2, whose gene products hamartin (TSC1) and tuberin (TSC2) constitute a putative tumor suppressor complex (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 that S6 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 of TSC2 function in mammalian cells leads to constitutive S6K1 activation, whereas ectopic expression of TSC1-2 blocks this response. Although activation of wild-type S6K1 and cell proliferation in TSC2-deficient cells is dependent on the mammalian target of rapamycin (mTOR), by using an S6K1 variant (GST-AC-S6K1), which is uncoupled from mTOR signaling, we demonstrate that TSCl-2 does not inhibit S6K1 via mTOR. Instead, we show by using wortmannin and dominant interfering alleles of phosphatidylinositide-3-OH kinase (PI3K) that increased S6K1 activation is contingent upon the suppression of TSC2 function by P13K in normal cells and is P13K independent in TSC2-deficient cells.

Original languageEnglish
Pages (from-to)217-224
Number of pages8
JournalJournal of Cell Biology
Volume159
Issue number2
DOIs
Publication statusPublished - 2002 Oct 28
Externally publishedYes

Keywords

  • 4E-BP1
  • P13K1
  • Rapamycin
  • S6K1
  • TSC

ASJC Scopus subject areas

  • Cell Biology

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