{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T20:39:02Z","timestamp":1791146342135,"version":"4.1.0"},"reference-count":34,"publisher":"Rockefeller University Press","issue":"2","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2002,10,28]]},"abstract":"<jats:p>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\u201393). 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\u20131057). 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\u2013355; Potter, C.J., H. Huang, and T. Xu. 2001. Cell. 105:357\u2013368). 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-\u0394C-S6K1), which is uncoupled from mTOR signaling, we demonstrate that TSC1-2 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 PI3K in normal cells and is PI3K independent in TSC2-deficient cells.<\/jats:p>","DOI":"10.1083\/jcb.jcb.200206108","type":"journal-article","created":{"date-parts":[[2002,10,28]],"date-time":"2002-10-28T20:02:20Z","timestamp":1035835340000},"page":"217-224","update-policy":"https:\/\/doi.org\/10.1083\/jcb.crossmarkpolicy","source":"Crossref","is-referenced-by-count":173,"title":["Tuberous sclerosis complex tumor suppressor\u2013mediated S6 kinase inhibition by phosphatidylinositide-3-OH kinase is mTOR independent"],"prefix":"10.1083","volume":"159","author":[{"given":"Anja","family":"Jaeschke","sequence":"first","affiliation":[{"name":"2Friedrich Miescher Institute, Maulbeerstrasse 66, CH-4058, Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joerg","family":"Hartkamp","sequence":"additional","affiliation":[{"name":"1Cancer Research UK Centre for Cell and Molecular Biology, Institute for Cancer Research, London SW3 6JB, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masao","family":"Saitoh","sequence":"additional","affiliation":[{"name":"2Friedrich Miescher Institute, Maulbeerstrasse 66, CH-4058, Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wendy","family":"Roworth","sequence":"additional","affiliation":[{"name":"1Cancer Research UK Centre for Cell and Molecular Biology, Institute for Cancer Research, London SW3 6JB, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takahiro","family":"Nobukuni","sequence":"additional","affiliation":[{"name":"2Friedrich Miescher Institute, Maulbeerstrasse 66, CH-4058, Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Hodges","sequence":"additional","affiliation":[{"name":"3Institute of Medical Genetics, University of Wales College of Medicine, Heath Park, Cardiff CF14 4XN, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julian","family":"Sampson","sequence":"additional","affiliation":[{"name":"3Institute of Medical Genetics, University of Wales College of Medicine, Heath Park, Cardiff CF14 4XN, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George","family":"Thomas","sequence":"additional","affiliation":[{"name":"2Friedrich Miescher Institute, Maulbeerstrasse 66, CH-4058, Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Lamb","sequence":"additional","affiliation":[{"name":"1Cancer Research UK Centre for Cell and Molecular Biology, Institute for Cancer Research, London SW3 6JB, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2002,10,28]]},"reference":[{"key":"2023072213511829500_BIB1","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1038\/35077225","volume":"411","year":"2001","journal-title":"Nature."},{"key":"2023072213511829500_BIB2","doi-asserted-by":"crossref","first-page":"5256","DOI":"10.1002\/j.1460-2075.1996.tb00911.x","volume":"15","year":"1996","journal-title":"EMBO J."},{"key":"2023072213511829500_BIB3","first-page":"99","volume":"277","year":"1997","journal-title":"Science."},{"key":"2023072213511829500_BIB4","doi-asserted-by":"crossref","first-page":"1432","DOI":"10.1073\/pnas.95.4.1432","volume":"95","year":"1998","journal-title":"Proc. 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