Human Molecular Genetics, 2002, Vol. 11, No. 5 525-534
© 2002 Oxford University Press
A mouse model of TSC1 reveals sex-dependent lethality from liver hemangiomas, and up-regulation of p70S6 kinase activity in Tsc1 null cells
Genetics Laboratory, Hematology Division, Brigham and Women’s Hospital, Harvard Medical School, 221 Longwood Avenue, LM-302, Boston, MA 02115, USA
Tuberous sclerosis (TSC) is a autosomal dominant genetic disorder caused by mutations in either TSC1 or TSC2, and characterized by benign hamartoma growth. We developed a murine model of Tsc1 disease by gene targeting. Tsc1 null embryos die at mid-gestation from a failure of liver development. Tsc1 heterozygotes develop kidney cystadenomas and liver hemangiomas at high frequency, but the incidence of kidney tumors is somewhat lower than in Tsc2 heterozygote mice. Liver hemangiomas were more common, more severe and caused higher mortality in female than in male Tsc1 heterozygotes. Tsc1 null embryo fibroblast lines have persistent phosphorylation of the p70S6K (S6K) and its substrate S6, that is sensitive to treatment with rapamycin, indicating constitutive activation of the mTOR-S6K pathway due to loss of the Tsc1 protein, hamartin. Hyperphosphorylation of S6 is also seen in kidney tumors in the heterozygote mice, suggesting that inhibition of this pathway may have benefit in control of TSC hamartomas.
+ To whom correspondence should be addressed. Tel: +1 617 278 0384; Fax: +1 617 734 2248; Email: dk@rics.bwh.harvard.edu
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 J C Lewis, H V Thomas, K C Murphy, and J R Sampson Genotype and psychological phenotype in tuberous sclerosis J. Med. Genet., March 1, 2004; 41(3): 203 - 207. [Full Text] [PDF]
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S. Jozwiak, D. Kwiatkowski, K. Kotulska, M. Larysz-Brysz, J. Lewin-Kowalik, W. Grajkowska, and M. Roszkowski Tuberin and Hamartin Expression Is Reduced in the Majority of Subependymal Giant Cell Astrocytomas in Tuberous Sclerosis Complex Consistent With a Two-Hit Model of Pathogenesis J Child Neurol, February 1, 2004; 19(2): 102 - 106. [Abstract] [PDF]
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S. Han, T. M. Santos, A. Puga, J. Roy, E. A. Thiele, M. McCollin, A. Stemmer-Rachamimov, and V. Ramesh Phosphorylation of Tuberin as a Novel Mechanism for Somatic Inactivation of the Tuberous Sclerosis Complex Proteins in Brain Lesions Cancer Res., February 1, 2004; 64(3): 812 - 816. [Abstract] [Full Text] [PDF]
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V. Murthy, S. Han, R. L. Beauchamp, N. Smith, L. A. Haddad, N. Ito, and V. Ramesh Pam and Its Ortholog Highwire Interact with and May Negatively Regulate the TSC1{middle dot}TSC2 Complex J. Biol. Chem., January 9, 2004; 279(2): 1351 - 1358. [Abstract] [Full Text] [PDF]
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 J. M. Ward and D. E. Devor-Henneman Mouse Models of Human Familial Cancer Syndromes Toxicol Pathol, January 1, 2004; 32(1_suppl): 90 - 98. [Abstract] [PDF]
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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]
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 J. Gomez-Cambronero, J. Horn, C. C. Paul, and M. A. Baumann Granulocyte-Macrophage Colony-Stimulating Factor Is a Chemoattractant Cytokine for Human Neutrophils: Involvement of the Ribosomal p70 S6 Kinase Signaling Pathway J. Immunol., December 15, 2003; 171(12): 6846 - 6855. [Abstract] [Full Text] [PDF]
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 T. E. Harris and J. C. Lawrence Jr. TOR Signaling Sci. Signal., December 9, 2003; 2003(212): re15 - re15. [Abstract] [Full Text] [PDF]
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N. El-Hashemite, V. Walker, H. Zhang, and D. J. Kwiatkowski Loss of Tsc1 or Tsc2 Induces Vascular Endothelial Growth Factor Production through Mammalian Target of Rapamycin Cancer Res., September 1, 2003; 63(17): 5173 - 5177. [Abstract] [Full Text] [PDF]
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 B. Govindarajan, M. C. Mizesko, M. S. Miller, H. Onda, M. Nunnelly, K. Casper, D. Brat, C. Cohen, and J. L Arbiser Tuberous Sclerosis-associated Neoplasms Express Activated p42/44 Mitogen-activated Protein (MAP) Kinase, and Inhibition of MAP Kinase Signaling Results in Decreased in Vivo Tumor Growth Clin. Cancer Res., August 1, 2003; 9(9): 3469 - 3475. [Abstract] [Full Text] [PDF]
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 G. A. Finlay, D. S. Hunter, C. L. Walker, K. E. Paulson, and B. L. Fanburg Regulation of PDGF production and ERK activation by estrogen is associated with TSC2 gene expression Am J Physiol Cell Physiol, August 1, 2003; 285(2): C409 - C418. [Abstract] [Full Text] [PDF]
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I. K. Hariharan and D. A. Haber Yeast, Flies, Worms, and Fish in the Study of Human Disease N. Engl. J. Med., June 12, 2003; 348(24): 2457 - 2463. [Full Text] [PDF]
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 L. S. Jefferson and S. R. Kimball Amino Acids as Regulators of Gene Expression at the Level of mRNA Translation J. Nutr., June 1, 2003; 133(6): 2046S - 2051. [Abstract] [Full Text] [PDF]
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H. Nojima, C. Tokunaga, S. Eguchi, N. Oshiro, S. Hidayat, K.-i. Yoshino, K. Hara, N. Tanaka, J. Avruch, and K. Yonezawa The Mammalian Target of Rapamycin (mTOR) Partner, Raptor, Binds the mTOR Substrates p70 S6 Kinase and 4E-BP1 through Their TOR Signaling (TOS) Motif J. Biol. Chem., April 25, 2003; 278(18): 15461 - 15464. [Abstract] [Full Text] [PDF]
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 M. Karbowniczek, A. Astrinidis, B. R. Balsara, J. R. Testa, J. H. Lium, T. V. Colby, F. X. McCormack, and E. P. Henske Recurrent Lymphangiomyomatosis after Transplantation: Genetic Analyses Reveal a Metastatic Mechanism Am. J. Respir. Crit. Care Med., April 1, 2003; 167(7): 976 - 982. [Abstract] [Full Text] [PDF]
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M. Karbowniczek, J. Yu, and E. P. Henske Renal Angiomyolipomas from Patients with Sporadic Lymphangiomyomatosis Contain Both Neoplastic and Non-Neoplastic Vascular Structures Am. J. Pathol., February 1, 2003; 162(2): 491 - 500. [Abstract] [Full Text] [PDF]
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M. Y. Liu, S. Cai, A. Espejo, M. T. Bedford, and C. L. Walker 14-3-3 Interacts with the Tumor Suppressor Tuberin at Akt Phosphorylation Site(s) Cancer Res., November 15, 2002; 62(22): 6475 - 6480. [Abstract] [Full Text] [PDF]
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Y. Li, K. Inoki, R. Yeung, and K.-L. Guan Regulation of TSC2 by 14-3-3 Binding J. Biol. Chem., November 15, 2002; 277(47): 44593 - 44596. [Abstract] [Full Text] [PDF]
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L. A. Haddad, N. Smith, M. Bowser, Y. Niida, V. Murthy, C. Gonzalez-Agosti, and V. Ramesh The TSC1 Tumor Suppressor Hamartin Interacts with Neurofilament-L and Possibly Functions as a Novel Integrator of the Neuronal Cytoskeleton J. Biol. Chem., November 8, 2002; 277(46): 44180 - 44186. [Abstract] [Full Text] [PDF]
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A. Jaeschke, J. Hartkamp, M. Saitoh, W. Roworth, T. Nobukuni, A. Hodges, J. Sampson, G. Thomas, and R. Lamb Tuberous sclerosis complex tumor suppressor-mediated S6 kinase inhibition by phosphatidylinositide-3-OH kinase is mTOR independent J. Cell Biol., October 28, 2002; 159(2): 217 - 224. [Abstract] [Full Text] [PDF]
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H. L. Kenerson, L. D. Aicher, L. D. True, and R. S. Yeung Activated Mammalian Target of Rapamycin Pathway in the Pathogenesis of Tuberous Sclerosis Complex Renal Tumors Cancer Res., October 15, 2002; 62(20): 5645 - 5650. [Abstract] [Full Text] [PDF]
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T. Radimerski, J. Montagne, M. Hemmings-Mieszczak, and G. Thomas Lethality of Drosophila lacking TSC tumor suppressor function rescued by reducing dS6K signaling Genes & Dev., October 15, 2002; 16(20): 2627 - 2632. [Abstract] [Full Text] [PDF]
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A. R. Tee, D. C. Fingar, B. D. Manning, D. J. Kwiatkowski, L. C. Cantley, and J. Blenis Tuberous sclerosis complex-1 and -2 gene products function together to inhibit mammalian target of rapamycin (mTOR)-mediated downstream signaling PNAS, October 15, 2002; 99(21): 13571 - 13576. [Abstract] [Full Text] [PDF]
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M. Nellist, M. A. Goedbloed, C. de Winter, B. Verhaaf, A. Jankie, A. J. J. Reuser, A. M. W. van den Ouweland, P. van der Sluijs, and D. J. J. Halley Identification and Characterization of the Interaction between Tuberin and 14-3-3zeta J. Biol. Chem., October 11, 2002; 277(42): 39417 - 39424. [Abstract] [Full Text] [PDF]
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S. Matsumoto, A. Bandyopadhyay, D. J. Kwiatkowski, U. Maitra, and T. Matsumoto Role of the Tsc1-Tsc2 Complex in Signaling and Transport Across the Cell Membrane in the Fission Yeast Schizosaccharomyces pombe Genetics, July 1, 2002; 161(3): 1053 - 1063. [Abstract] [Full Text] [PDF]
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