![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
Vol. 16, No. 20, pp. 2627-2632, October 15, 2002
1 Friedrich Miescher Institute for Biomedical Research,
CH-4058, Basel, Switzerland; 2 Novartis Pharma AG,
CH-4056 Basel, Switzerland
Tuberous sclerosis complex (TSC) is a genetic disorder caused by
mutations in one of two tumor suppressor genes, TSC1 and TSC2. Here, we show that absence of Drosophila Tsc1/2
leads to constitutive dS6K activation and inhibition of dPKB, the
latter effect being relieved by loss of dS6K. In contrast, the dPTEN tumor suppressor, a negative effector of PI3K, has little effect on
dS6K, but negatively regulates dPKB. More importantly, we demonstrate that reducing dS6K signaling rescues early larval lethality associated with loss of dTsc1/2 function, arguing that the S6K pathway is a
promising target for the treatment of TSC.
[Key Words: growth; TSC; S6K; TOR; PTEN; PKB]
CiteULike 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
This article has been cited by other articles:
|
|
 |
|
  H. McNeill, G. M. Craig, and J. M. Bateman Regulation of Neurogenesis and Epidermal Growth Factor Receptor Signaling by the Insulin Receptor/Target of Rapamycin Pathway in Drosophila Genetics, June 1, 2008; 179(2): 843 - 853. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Juhasz, J. H. Hill, Y. Yan, M. Sass, E. H. Baehrecke, J. M. Backer, and T. P. Neufeld The class III PI(3)K Vps34 promotes autophagy and endocytosis but not TOR signaling in Drosophila J. Cell Biol., May 19, 2008; 181(4): 655 - 666. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Johansson, Y. Y. Mahller, M. H. Collins, M.-O. Kim, T. Nobukuni, J. Perentesis, T. P. Cripe, H. A. Lane, S. C. Kozma, G. Thomas, et al. Effective in vivo targeting of the mammalian target of rapamycin pathway in malignant peripheral nerve sheath tumors Mol. Cancer Ther., May 1, 2008; 7(5): 1237 - 1245. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. F. Harvey, J. Mattila, A. Sofer, F. C. Bennett, M. R. Ramsey, L. W. Ellisen, O. Puig, and I. K. Hariharan FOXO-regulated transcription restricts overgrowth of Tsc mutant organs J. Cell Biol., February 25, 2008; 180(4): 691 - 696. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. D. Antion, M. Merhav, C. A. Hoeffer, G. Reis, S. C. Kozma, G. Thomas, E. M. Schuman, K. Rosenblum, and E. Klann Removal of S6K1 and S6K2 leads to divergent alterations in learning, memory, and synaptic plasticity Learn. Mem., January 3, 2008; 15(1): 29 - 38. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Tremblay, S. Brule, S. Hee Um, Y. Li, K. Masuda, M. Roden, X. J. Sun, M. Krebs, R. D. Polakiewicz, G. Thomas, et al. Identification of IRS-1 Ser-1101 as a target of S6K1 in nutrient- and obesity-induced insulin resistance PNAS, August 28, 2007; 104(35): 14056 - 14061. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Wang, X. Mao, L. Wang, M. Liu, M. D. Wetzel, K.-L. Guan, L. Q. Dong, and F. Liu Adiponectin Sensitizes Insulin Signaling by Reducing p70 S6 Kinase-mediated Serine Phosphorylation of IRS-1 J. Biol. Chem., March 16, 2007; 282(11): 7991 - 7996. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Q. Yang, K. Inoki, T. Ikenoue, and K.-L. Guan Identification of Sin1 as an essential TORC2 component required for complex formation and kinase activity. Genes & Dev., October 15, 2006; 20(20): 2820 - 2832. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. J. Shah and T. Hunter Turnover of the Active Fraction of IRS1 Involves Raptor-mTOR- and S6K1-Dependent Serine Phosphorylation in Cell Culture Models of Tuberous Sclerosis. Mol. Cell. Biol., September 1, 2006; 26(17): 6425 - 6434. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D.-H. Cho, Y. J. Choi, S. A. Jo, J. Ryou, J. Y. Kim, J. Chung, and I. Jo Troglitazone acutely inhibits protein synthesis in endothelial cells via a novel mechanism involving protein phosphatase 2A-dependent p70 S6 kinase inhibition Am J Physiol Cell Physiol, August 1, 2006; 291(2): C317 - C326. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. S. Klos, S. L. Wyszomierski, M. Sun, M. Tan, X. Zhou, P. Li, W. Yang, G. Yin, W. N. Hittelman, and D. Yu ErbB2 Increases Vascular Endothelial Growth Factor Protein Synthesis via Activation of Mammalian Target of Rapamycin/p70S6K Leading to Increased Angiogenesis and Spontaneous Metastasis of Human Breast Cancer Cells Cancer Res., February 15, 2006; 66(4): 2028 - 2037. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Zhang, C. J. Billington Jr., D. Pan, and T. P. Neufeld Drosophila Target of Rapamycin Kinase Functions as a Multimer Genetics, January 1, 2006; 172(1): 355 - 362. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. KARBOWNICZEK and E. P. HENSKE The Role of Tuberin in Cellular Differentiation: Are B-Raf and MAPK Involved? Ann. N.Y. Acad. Sci., November 1, 2005; 1059(1): 168 - 173. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Diao, Z. Asghar, C. B. Chan, and M. B. Wheeler Glucose-regulated Glucagon Secretion Requires Insulin Receptor Expression in Pancreatic {alpha}-Cells J. Biol. Chem., September 30, 2005; 280(39): 33487 - 33496. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. D. Manning, M. N. Logsdon, A. I. Lipovsky, D. Abbott, D. J. Kwiatkowski, and L. C. Cantley Feedback inhibition of Akt signaling limits the growth of tumors lacking Tsc2 Genes & Dev., August 1, 2005; 19(15): 1773 - 1778. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. C. I. Goberdhan, D. Meredith, C. A. R. Boyd, and C. Wilson PAT-related amino acid transporters regulate growth via a novel mechanism that does not require bulk transport of amino acids Development, May 15, 2005; 132(10): 2365 - 2375. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. D. Sarbassov, D. A. Guertin, S. M. Ali, and D. M. Sabatini Phosphorylation and Regulation of Akt/PKB by the Rictor-mTOR Complex Science, February 18, 2005; 307(5712): 1098 - 1101. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. H. Reiling and E. Hafen The hypoxia-induced paralogs Scylla and Charybdis inhibit growth by down-regulating S6K activity upstream of TSC in Drosophila Genes & Dev., December 1, 2004; 18(23): 2879 - 2892. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. D. Manning Balancing Akt with S6K: implications for both metabolic diseases and tumorigenesis J. Cell Biol., November 8, 2004; 167(3): 399 - 403. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Dong and D. Pan Tsc2 is not a critical target of Akt during normal Drosophila development Genes & Dev., October 15, 2004; 18(20): 2479 - 2484. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Kapahi and B. Zid TOR Pathway: Linking Nutrient Sensing to Life Span Sci. Aging Knowl. Environ., September 8, 2004; 2004(36): pe34 - pe34. [Abstract] [Full Text]
|
|
|
|
 |
|
 A. Astrinidis and E. Petri Henske Aberrant Cellular Differentiation and Migration in Renal and Pulmonary Tuberous Sclerosis Complex J Child Neurol, September 1, 2004; 19(9): 710 - 715. [Abstract] [PDF]
|
|
|
|
|
|
L. S. Harrington, G. M. Findlay, A. Gray, T. Tolkacheva, S. Wigfield, H. Rebholz, J. Barnett, N. R. Leslie, S. Cheng, P. R. Shepherd, et al. The TSC1-2 tumor suppressor controls insulin-PI3K signaling via regulation of IRS proteins J. Cell Biol., July 19, 2004; 166(2): 213 - 223. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Karbowniczek, T. Cash, M. Cheung, G. P. Robertson, A. Astrinidis, and E. P. Henske Regulation of B-Raf Kinase Activity by Tuberin and Rheb Is Mammalian Target of Rapamycin (mTOR)-independent J. Biol. Chem., July 16, 2004; 279(29): 29930 - 29937. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. R. McMullen, T. Shioi, L. Zhang, O. Tarnavski, M. C. Sherwood, A. L. Dorfman, S. Longnus, M. Pende, K. A. Martin, J. Blenis, et al. Deletion of Ribosomal S6 Kinases Does Not Attenuate Pathological, Physiological, or Insulin-Like Growth Factor 1 Receptor-Phosphoinositide 3-Kinase-Induced Cardiac Hypertrophy Mol. Cell. Biol., July 15, 2004; 24(14): 6231 - 6240. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. van Slegtenhorst, E. Carr, R. Stoyanova, W. D. Kruger, and E. P. Henske Tsc1+ and tsc2+ Regulate Arginine Uptake and Metabolism in Schizosaccharomyces pombe J. Biol. Chem., March 26, 2004; 279(13): 12706 - 12713. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Astrinidis, W. Senapedis, T. R. Coleman, and E. P. Henske Cell Cycle-regulated Phosphorylation of Hamartin, the Product of the Tuberous Sclerosis Complex 1 Gene, by Cyclin-dependent Kinase 1/Cyclin B J. Biol. Chem., December 19, 2003; 278(51): 51372 - 51379. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Miron, P. Lasko, and N. Sonenberg Signaling from Akt to FRAP/TOR Targets both 4E-BP and S6K in Drosophila melanogaster Mol. Cell. Biol., December 15, 2003; 23(24): 9117 - 9126. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. M. Hannan, Y. Brandenburger, A. Jenkins, K. Sharkey, A. Cavanaugh, L. Rothblum, T. Moss, G. Poortinga, G. A. McArthur, R. B. Pearson, et al. mTOR-Dependent Regulation of Ribosomal Gene Transcription Requires S6K1 and Is Mediated by Phosphorylation of the Carboxy-Terminal Activation Domain of the Nucleolar Transcription Factor UBF{dagger} Mol. Cell. Biol., December 1, 2003; 23(23): 8862 - 8877. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. L. Edinger, C. M. Linardic, G. G. Chiang, C. B. Thompson, and R. T. Abraham Differential Effects of Rapamycin on Mammalian Target of Rapamycin Signaling Functions in Mammalian Cells Cancer Res., December 1, 2003; 63(23): 8451 - 8460. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. C.I. Goberdhan and C. Wilson PTEN: tumour suppressor, multifunctional growth regulator and more Hum. Mol. Genet., October 15, 2003; 12(90002): R239 - 248. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. H. Patel, N. Thapar, L. Guo, M. Martinez, J. Maris, C.-L. Gau, J. A. Lengyel, and F. Tamanoi Drosophila Rheb GTPase is required for cell cycle progression and cell growth J. Cell Sci., September 1, 2003; 116(17): 3601 - 3610. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. F. Castro, J. F. Rebhun, G. J. Clark, and L. A. Quilliam Rheb Binds Tuberous Sclerosis Complex 2 (TSC2) and Promotes S6 Kinase Activation in a Rapamycin- and Farnesylation-dependent Manner J. Biol. Chem., August 29, 2003; 278(35): 32493 - 32496. [Abstract] [Full Text] [PDF]
|
|
