Dysregulation of the TSC-mTOR pathway in human disease (original) (raw)

• Heitman, J., Movva, N.R. & Hall, M.N. Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast. Science 253, 905–909 (1991).
  CAS PubMed Google Scholar
• Brown, E.J. et al. A mammalian protein targeted by G1-arresting rapamycin-receptor complex. Nature 369, 756–758 (1994).
  CAS PubMed Google Scholar
• Chiu, M.I., Katz, H. & Berlin, V. RAPT1, a mammalian homolog of yeast Tor, interacts with the FKBP12/rapamycin complex. Proc. Natl. Acad. Sci. USA 91, 12574–12578 (1994).
  CAS PubMed PubMed Central Google Scholar
• Sabatini, D.M., Erdjument-Bromage, H., Lui, M., Tempst, P. & Snyder, S.H. RAFT1: a mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs. Cell 78, 35–43 (1994).
  CAS PubMed Google Scholar
• Harris, T.E. & Lawrence, J.C. Jr. TOR signaling. Sci STKE 2003, re15 (2003).
  PubMed Google Scholar
• Jacinto, E. & Hall, M.N. Tor signalling in bugs, brain and brawn. Nat. Rev. Mol. Cell Biol. 4, 117–126 (2003).
  CAS PubMed Google Scholar
• Sarbassov dos, D. et al. Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr. Biol. 14, 1296–1302 (2004).
  Google Scholar
• Hara, K. et al. Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell 110, 177–189 (2002).
  CAS PubMed Google Scholar
• Kim, D.H. et al. mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 110, 163–175 (2002).
  CAS PubMed Google Scholar
• Loewith, R. et al. Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control. Mol. Cell 10, 457–468 (2002).
  CAS PubMed Google Scholar
• Avruch, J., Belham, C., Weng, Q., Hara, K. & Yonezawa, K. The p70 S6 kinase integrates nutrient and growth signals to control translational capacity. Prog. Mol. Subcell. Biol. 26, 115–154 (2001).
  CAS PubMed Google Scholar
• Meyuhas, O. Synthesis of the translational apparatus is regulated at the translational level. Eur. J. Biochem. 267, 6321–6330 (2000).
  CAS PubMed Google Scholar
• Gingras, A.C., Raught, B. & Sonenberg, N. eIF4 initiation factors: effectors of mRNA recruitment to ribosomes and regulators of translation. Annu. Rev. Biochem. 68, 913–963 (1999).
  CAS PubMed Google Scholar
• Mamane, Y. et al. eIF4E--from translation to transformation. Oncogene 23, 3172–3179 (2004).
  CAS PubMed Google Scholar
• Fingar, D.C. et al. mTOR controls cell cycle progression through its cell growth effectors S6K1 and 4E-BP1/eukaryotic translation initiation factor 4E. Mol. Cell. Biol. 24, 200–216 (2004).
  CAS PubMed PubMed Central Google Scholar
• Potter, C.J., Huang, H. & Xu, T. Drosophila Tsc1 functions with Tsc2 to antagonize insulin signaling in regulating cell growth, cell proliferation, and organ size. Cell 105, 357–368 (2001).
  CAS PubMed Google Scholar
• Tapon, N., Ito, N., Dickson, B.J., Treisman, J.E. & Hariharan, I.K. The Drosophila tuberous sclerosis complex gene homologs restrict cell growth and cell proliferation. Cell 105, 345–355 (2001).
  CAS PubMed Google Scholar
• Gao, X. & Pan, D. TSC1 and TSC2 tumor suppressors antagonize insulin signaling in cell growth. Genes Dev. 15, 1383–1392 (2001).
  CAS PubMed PubMed Central Google Scholar
• Stocker, H. et al. Rheb is an essential regulator of S6K in controlling cell growth in Drosophila. Nat. Cell Biol. 5, 559–565 (2003).
  CAS PubMed Google Scholar
• Saucedo, L.J. et al. Rheb promotes cell growth as a component of the insulin/TOR signalling network. Nat. Cell Biol. 5, 566–571 (2003).
  CAS PubMed Google Scholar
• Manning, B.D., Tee, A.R., Logsdon, M.N., Blenis, J. & Cantley, L.C. Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway. Mol. Cell 10, 151–162 (2002).
  CAS PubMed Google Scholar
• Inoki, K., Li, Y., Zhu, T., Wu, J. & Guan, K.L. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat. Cell Biol. 4, 648–657 (2002).
  CAS PubMed Google Scholar
• Potter, C.J., Pedraza, L.G. & Xu, T. Akt regulates growth by directly phosphorylating Tsc2. Nat. Cell Biol. 4, 658–665 (2002).
  CAS PubMed Google Scholar
• Zhang, Y. et al. Rheb is a direct target of the tuberous sclerosis tumour suppressor proteins. Nat. Cell Biol. 5, 578–581 (2003).
  CAS PubMed Google Scholar
• Garami, A. et al. Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2. Mol. Cell 11, 1457–1466 (2003).
  CAS PubMed Google Scholar
• Inoki, K., Li, Y., Xu, T. & Guan, K.L. Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Genes Dev. 17, 1829–1834 (2003).
  CAS PubMed PubMed Central Google Scholar
• Goncharova, E.A. et al. Tuberin regulates p70 S6 kinase activation and ribosomal protein S6 phosphorylation. J. Biol. Chem. 277, 30958–30967 (2002).
  CAS PubMed Google Scholar
• Kwiatkowski, D.J. et al. A mouse model of TSC1 reveals sex-dependent lethality from liver hemangiomas, and up-regulation of p70S6 kinase activity in Tsc1 null cells. Hum. Mol. Genet. 11, 525–534 (2002).
  CAS PubMed Google Scholar
• Podsypanina, K. et al. An inhibitor of mTOR reduces neoplasia and normalizes p70/S6 kinase activity in Pten+/− mice. Proc. Natl. Acad. Sci. USA 98, 10320–10325 (2001).
  CAS PubMed PubMed Central Google Scholar
• Gao, X. et al. Tsc tumour suppressor proteins antagonize amino-acid-TOR signalling. Nat. Cell Biol. 4, 699–704 (2002).
  CAS PubMed Google Scholar
• Dennis, P.B. et al. Mammalian TOR: a homeostatic ATP sensor. Science 294, 1102–1105 (2001).
  CAS PubMed Google Scholar
• Hardie, D.G., Carling, D. & Carlson, M. The AMP-activated/SNF1 protein kinase subfamily: metabolic sensors of the eukaryotic cell? Annu. Rev. Biochem. 67, 821–855 (1998).
  CAS PubMed Google Scholar
• Inoki, K., Zhu, T. & Guan, K.L. TSC2 mediates cellular energy response to control cell growth and survival. Cell 115, 577–590 (2003).
  CAS PubMed Google Scholar
• Hawley, S.A. et al. Complexes between the LKB1 tumor suppressor, STRADalpha/beta and MO25alpha/beta are upstream kinases in the AMP-activated protein kinase cascade. J. Biol. 2, 28 (2003).
  PubMed PubMed Central Google Scholar
• Hong, S.P., Leiper, F.C., Woods, A., Carling, D. & Carlson, M. Activation of yeast Snf1 and mammalian AMP-activated protein kinase by upstream kinases. Proc. Natl. Acad. Sci. USA 100, 8839–8843 (2003).
  CAS PubMed PubMed Central Google Scholar
• Woods, A. et al. LKB1 is the upstream kinase in the AMP-activated protein kinase cascade. Curr. Biol. 13, 2004–2008 (2003).
  CAS PubMed Google Scholar
• Corradetti, M.N., Inoki, K., Bardeesy, N., DePinho, R.A. & Guan, K.L. Regulation of the TSC pathway by LKB1: evidence of a molecular link between tuberous sclerosis complex and Peutz-Jeghers syndrome. Genes Dev. 18, 1533–1538 (2004).
  CAS PubMed PubMed Central Google Scholar
• Shaw, R.J. et al. The LKB1 tumor suppressor negatively regulates mTOR signaling. Cancer Cell 6, 91–99 (2004).
  CAS PubMed Google Scholar
• Shaw, R.J. et al. The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress. Proc. Natl. Acad. Sci. USA 101, 3329–3335 (2004).
  CAS PubMed PubMed Central Google Scholar
• Klionsky, D.J. & Ohsumi, Y. Vacuolar import of proteins and organelles from the cytoplasm. Annu. Rev. Cell Dev. Biol. 15, 1–32 (1999).
  CAS PubMed Google Scholar
• Gozuacik, D. & Kimchi, A. Autophagy as a cell death and tumor suppressor mechanism. Oncogene 23, 2891–2906 (2004).
  CAS PubMed Google Scholar
• Kamada, Y., Sekito, T. & Ohsumi, Y. Autophagy in yeast: a TOR-mediated response to nutrient starvation. Curr. Top. Microbiol. Immunol. 279, 73–84 (2004).
  CAS PubMed Google Scholar
• Ravikumar, B. et al. Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat. Genet. 36, 585–595 (2004).
  CAS PubMed Google Scholar
• van der Hoeve, J. Eye symptoms in tuberous sclerosis of the brain. Trans. Ophthalmol. Soc. UK 20, 329–334 (1920).
  Google Scholar
• Tucker, M., Goldstein, A., Dean, M. & Knudson, A. National Cancer Institute Workshop Report: the phakomatoses revisited. J. Natl. Cancer Inst. 92, 530–533 (2000).
  CAS PubMed Google Scholar
• van Slegtenhorst, M. et al. Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. Science 277, 805–808 (1997).
  CAS PubMed Google Scholar
• The European Chromosome 16 Tuberous Sclerosis Consortium. Identification and characterization of the tuberous sclerosis gene on chromosome 16. Cell 75, 1305–1315 (1993).
• Niida, Y. et al. Survey of somatic mutations in tuberous sclerosis complex (TSC) hamartomas suggests different genetic mechanisms for pathogenesis of TSC lesions. Am. J. Hum. Genet. 69, 493–503 (2001).
  CAS PubMed PubMed Central Google Scholar
• Tucker, T. & Friedman, J.M. Pathogenesis of hereditary tumors: beyond the “two-hit” hypothesis. Clin. Genet. 62, 345–357 (2002).
  CAS PubMed Google Scholar
• El-Hashemite, N., Zhang, H., Henske, E.P. & Kwiatkowski, D.J. Mutation in TSC2 and activation of mammalian target of rapamycin signalling pathway in renal angiomyolipoma. Lancet 361, 1348–1349 (2003).
  CAS PubMed Google Scholar
• Kwiatkowski, D.J. Tuberous sclerosis: from tubers to mTOR. Ann. Hum. Genet. 67, 87–96 (2003).
  CAS PubMed Google Scholar
• Sawyers, C.L. Will mTOR inhibitors make it as cancer drugs? Cancer Cell 4, 343–348 (2003).
  CAS PubMed Google Scholar
• Kenerson, H.L., Aicher, L.D., True, L.D. & Yeung, R.S. Activated mammalian target of rapamycin pathway in the pathogenesis of tuberous sclerosis complex renal tumors. Cancer Res. 62, 5645–5650 (2002).
  CAS PubMed Google Scholar
• Eng, C. PTEN: one gene, many syndromes. Hum. Mutat. 22, 183–198 (2003).
  CAS PubMed Google Scholar
• Maehama, T., Taylor, G.S. & Dixon, J.E. PTEN and MYOTUBULARIN: Novel Phosphoinositide Phosphatases. Annu. Rev. Biochem. 70, 247–279 (2001).
  CAS PubMed Google Scholar
• Zhou, X.P. et al. Germline PTEN promoter mutations and deletions in Cowden/Bannayan-Riley-Ruvalcaba syndrome result in aberrant PTEN protein and dysregulation of the phosphoinositol-3-kinase/Akt pathway. Am. J. Hum. Genet. 73, 404–411 (2003).
  CAS PubMed PubMed Central Google Scholar
• Neshat, M.S. et al. Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR. Proc. Natl. Acad. Sci. USA 98, 10314–10319 (2001).
  CAS PubMed PubMed Central Google Scholar
• Majumder, P.K. et al. mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways. Nat. Med. 10, 594–601 (2004).
  CAS PubMed Google Scholar
• Devroede, G., Lemieux, B., Masse, S., Lamarche, J. & Herman, P.S. Colonic hamartomas in tuberous sclerosis. Gastroenterology 94, 182–188 (1988).
  CAS PubMed Google Scholar
• Gomez, M.R., Sampson, J. & Whittemore, V.H. Tuberous Sclerosis Complex 340 (Oxford University Press, Oxford, 1999).
  Google Scholar
• Hernan, I. et al. De novo germline mutation in the serine-threonine kinase STK11/LKB1 gene associated with Peutz-Jeghers syndrome. Clin. Genet. 66, 58–62 (2004).
  CAS PubMed Google Scholar
• Entius, M.M. et al. Molecular genetic alterations in hamartomatous polyps and carcinomas of patients with Peutz-Jeghers syndrome. J. Clin. Pathol. 54, 126–131 (2001).
  CAS PubMed PubMed Central Google Scholar
• Bardeesy, N. et al. Loss of the Lkb1 tumour suppressor provokes intestinal polyposis but resistance to transformation. Nature 419, 162–167 (2002).
  CAS PubMed Google Scholar
• Miyoshi, H. et al. Gastrointestinal hamartomatous polyposis in Lkb1 heterozygous knockout mice. Cancer Res. 62, 2261–2266 (2002).
  CAS PubMed Google Scholar
• Kandt, R.S. Tuberous sclerosis complex and neurofibromatosis type 1: the two most common neurocutaneous diseases. Neurol. Clin. 21, 983–1004 (2003).
  PubMed Google Scholar
• Cichowski, K. & Jacks, T. NF1 tumor suppressor gene function: narrowing the GAP. Cell 104, 593–604 (2001).
  CAS PubMed Google Scholar
• Furuta, S., Hidaka, E., Ogata, A., Yokota, S. & Kamata, T. Ras is involved in the negative control of autophagy through the class I PI3-kinase. Oncogene 23, 3898–3904 (2004).
  CAS PubMed Google Scholar
• Shao, J., Evers, B.M. & Sheng, H. Roles of phosphatidylinositol 3′-kinase and mammalian target of rapamycin/p70 ribosomal protein S6 kinase in K-Ras-mediated transformation of intestinal epithelial cells. Cancer Res. 64, 229–235 (2004).
  CAS PubMed Google Scholar
• Kaelin, W.G. Jr. The von Hippel-Lindau gene, kidney cancer, and oxygen sensing. J. Am. Soc. Nephrol. 14, 2703–2711 (2003).
  PubMed Google Scholar
• El-Hashemite, N., Walker, V., Zhang, H. & Kwiatkowski, D.J. Loss of Tsc1 or Tsc2 induces vascular endothelial growth factor production through mammalian target of rapamycin. Cancer Res. 63, 5173–5177 (2003).
  CAS PubMed Google Scholar
• Brugarolas, J.B., Vazquez, F., Reddy, A., Sellers, W.R. & Kaelin, W.G., Jr. TSC2 regulates VEGF through mTOR-dependent and -independent pathways. Cancer Cell 4, 147–158 (2003).
  CAS PubMed Google Scholar
• Su, L.K. et al. Multiple intestinal neoplasia caused by a mutation in the murine homolog of the APC gene. Science 256, 668–670 (1992).
  CAS PubMed Google Scholar
• Fearnhead, N.S., Britton, M.P. & Bodmer, W.F. The ABC of APC. Hum. Mol. Genet. 10, 721–733 (2001).
  CAS PubMed Google Scholar
• Gera, J.F. et al. AKT activity determines sensitivity to mammalian target of rapamycin (mTOR) inhibitors by regulating cyclin D1 and c-myc expression. J. Biol. Chem. 279, 2737–2746 (2004).
  CAS PubMed Google Scholar
• Mak, B.C., Takemaru, K., Kenerson, H.L., Moon, R.T. & Yeung, R.S. The tuberin-hamartin complex negatively regulates Beta -catenin signaling activity. J. Biol. Chem. 278, 5947–5951 (2003).
  CAS PubMed Google Scholar
• Howe, J.R. et al. Mutations in the SMAD4/DPC4 gene in juvenile polyposis. Science 280, 1086–1088 (1998).
  CAS PubMed Google Scholar
• Zhou, X.P. et al. Germline mutations in BMPR1A/ALK3 cause a subset of cases of juvenile polyposis syndrome and of Cowden and Bannayan-Riley-Ruvalcaba syndromes. Am. J. Hum. Genet. 69, 704–711 (2001).
  CAS PubMed PubMed Central Google Scholar
• Eng, C. Constipation, polyps, or cancer? Let PTEN predict your future. Am. J. Med. Genet. 122A, 315–322 (2003).
  PubMed Google Scholar
• Birchenall-Roberts, M.C. et al. Tuberous sclerosis complex 2 gene product interacts with human SMAD proteins. A molecular link of two tumor suppressor pathways. J. Biol. Chem. 279, 25605–25613 (2004).
  CAS PubMed Google Scholar
• Rajan, P., Panchision, D.M., Newell, L.F. & McKay, R.D. BMPs signal alternately through a SMAD or FRAP-STAT pathway to regulate fate choice in CNS stem cells. J. Cell Biol. 161, 911–921 (2003).
  CAS PubMed PubMed Central Google Scholar
• He, X.C. et al. BMP signaling inhibits intestinal stem cell self-renewal through suppression of Wnt-beta-catenin signaling. Nat. Genet. 36, 1117–1121 (2004).
  CAS PubMed Google Scholar
• Kirschner, L.S. et al. Mutations of the gene encoding the protein kinase A type I-alpha regulatory subunit in patients with the Carney complex. Nat. Genet. 26, 89–92 (2000).
  CAS PubMed Google Scholar
• Stratakis, C.A. Genetics of Peutz-Jeghers syndrome, Carney complex and other familial lentiginoses. Horm. Res. 54, 334–343 (2000).
  CAS PubMed Google Scholar
• Nickerson, M.L. et al. Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with the Birt-Hogg-Dube syndrome. Cancer Cell 2, 157–164 (2002).
  CAS PubMed Google Scholar
• Hancock, E. & Osborne, J. Lymphangioleiomyomatosis: a review of the literature. Respir. Med. 96, 1–6 (2002).
  CAS PubMed Google Scholar
• Pavlovich, C.P. & Schmidt, L.S. Searching for the hereditary causes of renal-cell carcinoma. Nat. Rev. Cancer 4, 381–393 (2004).
  CAS PubMed Google Scholar
• Okimoto, K. et al. A germ-line insertion in the Birt-Hogg-Dube (BHD) gene gives rise to the Nihon rat model of inherited renal cancer. Proc. Natl. Acad. Sci. USA 101, 2023–2027 (2004).
  CAS PubMed PubMed Central Google Scholar
• Harrington, L.S. et al. The TSC1-2 tumor suppressor controls insulin-PI3K signaling via regulation of IRS proteins. J. Cell Biol. 166, 213–223 (2004).
  CAS PubMed PubMed Central Google Scholar
• Shah, O.J., Wang, Z. & Hunter, T. Inappropriate activation of the TSC/Rheb/mTOR/S6K cassette induces IRS1/2 depletion, insulin resistance, and cell survival deficiencies. Curr. Biol. 14, 1650–1656 (2004).
  CAS PubMed Google Scholar
• Um, S.H. et al. Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity. Nature 431, 200–205 (2004).
  CAS PubMed Google Scholar
• Zhang, H. et al. Loss of Tsc1/Tsc2 activates mTOR and disrupts PI3K-Akt signaling through downregulation of PDGFR. J. Clin. Invest. 112, 1223–1233 (2003).
  CAS PubMed PubMed Central Google Scholar
• Shioi, T. et al. Rapamycin attenuates load-induced cardiac hypertrophy in mice. Circulation 107, 1664–1670 (2003).
  CAS PubMed Google Scholar
• Blair, E. et al. Mutations in the gamma(2) subunit of AMP-activated protein kinase cause familial hypertrophic cardiomyopathy: evidence for the central role of energy compromise in disease pathogenesis. Hum. Mol. Genet. 10, 1215–1220 (2001).
  CAS PubMed Google Scholar
• Gollob, M.H. et al. Identification of a gene responsible for familial Wolff-Parkinson-White syndrome. N. Engl. J. Med. 344, 1823–1831 (2001).
  CAS PubMed Google Scholar
• Daniel, T. & Carling, D. Functional analysis of mutations in the gamma 2 subunit of AMP-activated protein kinase associated with cardiac hypertrophy and Wolff-Parkinson-White syndrome. J. Biol. Chem. 277, 51017–51024 (2002).
  CAS PubMed Google Scholar
• Chan, A.Y., Soltys, C.L., Young, M.E., Proud, C.G. & Dyck, J.R. Activation of AMP-activated protein kinase inhibits protein synthesis associated with hypertrophy in the cardiac myocyte. J. Biol. Chem. 279, 32771–32779 (2004).
  CAS PubMed Google Scholar
• Abraham, R.T. & Wiederrecht, G.J. Immunopharmacology of rapamycin. Annu. Rev. Immunol. 14, 483–510 (1996).
  CAS PubMed Google Scholar
• Garza, L., Aude, Y.W. & Saucedo, J.F. Can we prevent in-stent restenosis? Curr. Opin. Cardiol. 17, 518–525 (2002).
  PubMed Google Scholar
• Huang, S. & Houghton, P.J. Targeting mTOR signaling for cancer therapy. Curr. Opin. Pharmacol. 3, 371–377 (2003).
  CAS PubMed Google Scholar
• Bjornsti, M.A. & Houghton, P.J. The TOR pathway: a target for cancer therapy. Nat. Rev. Cancer 4, 335–348 (2004).
  CAS PubMed Google Scholar