Cancer Research CTRC-AACR San Antonio Breast Cancer Symposium Susan G. Komen for the Cure-AACR Outstanding Investigator Award for Breast Cancer Research
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Cell Growth & Differentiation
[Cancer Research 59, 1206-1211, March 1, 1999]
© 1999 American Association for Cancer Research
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Kobayashi, T.
Right arrow Articles by Noda, T.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Kobayashi, T.
Right arrow Articles by Noda, T.
[Cancer Research 59, 1206-1211, March 15, 1999]
© 1999 American Association for Cancer Research

Carcinogenesis

Renal Carcinogenesis, Hepatic Hemangiomatosis, and Embryonic Lethality Caused by a Germ-Line Tsc2 Mutation in Mice1

Toshiyuki Kobayashi, Osamu Minowa, Junko Kuno, Hiroaki Mitani, Okio Hino2 and Tetsuo Noda

Departments of Experimental Pathology [T. K., H. M., O. H.] and Cell Biology [O. M., J. K., T. N.], Cancer Institute, Toshima-ku, Tokyo 170-8455; Department of Molecular Genetics, Tohoku University School of Medicine, Sendai 980-8575 [T. N.]; and CREST, Japan Science and Technology Corporation, Kawaguchi 332-0012 [T. N.], Japan

ABSTRACT

Germ-line mutations of the human TSC2 tumor suppressor gene cause tuberous sclerosis (TSC), a disease characterized by the development of hamartomas in various organs. In the Eker rat, however, a germ-line Tsc2 mutation gives rise to renal cell carcinomas with a complete penetrance. The molecular mechanism for this phenotypic difference between man and rat is currently unknown, and the physiological function of the TSC2/Tsc2 product (tuberin) is not fully understood. To investigate these unsolved problems, we have generated a Tsc2 mutant mouse. Tsc2 heterozygous mutant (Tsc2+/-) mice developed renal carcinomas with a complete penetrance, as seen in the Eker rat, but not the angiomyolipomas characteristic of human TSC, confirming the existence of a species-specific mechanism of tumorigenesis caused by tuberin deficiency. Unexpectedly, ~80% of Tsc2+/- mice also developed hepatic hemangiomas that are not observed in either TSC or the Eker rat. Tsc2 homozygous (Tsc2-/-) mutants died around embryonic day 10.5, indicating an essential function for tuberin in mouse embryonic development. Some Tsc2-/- embryos exhibited an unclosed neural tube and/or thickened myocardium. The latter is associated with increased cell density that may be a reflection of loss of a growth-suppressive function of tuberin. The mouse strain described here should provide a valuable experimental model to analyze the function of tuberin and its association with tumorigenesis.




This article has been cited by other articles:


Home page
 Proc. Natl. Acad. Sci. USAHome page
L. Rachdi, N. Balcazar, F. Osorio-Duque, L. Elghazi, A. Weiss, A. Gould, K. J. Chang-Chen, M. J. Gambello, and E. Bernal-Mizrachi
Disruption of Tsc2 in pancreatic {beta} cells induces {beta} cell mass expansion and improved glucose tolerance in a TORC1-dependent manner
PNAS, July 8, 2008; 105(27): 9250 - 9255.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Cell. Biol.Home page
Y. Shigeyama, T. Kobayashi, Y. Kido, N. Hashimoto, S.-i. Asahara, T. Matsuda, A. Takeda, T. Inoue, Y. Shibutani, M. Koyanagi, et al.
Biphasic Response of Pancreatic {beta}-Cell Mass to Ablation of Tuberous Sclerosis Complex 2 in Mice
Mol. Cell. Biol., May 1, 2008; 28(9): 2971 - 2979.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
Y. Gui, G. H. He, M. P. Walsh, and X.-L. Zheng
Predisposition to tetraploidy in pulmonary vascular smooth muscle cells derived from the Eker rats
Am J Physiol Lung Cell Mol Physiol, September 1, 2007; 293(3): L702 - L711.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
B. Gan, Y. Yoo, and J.-L. Guan
Association of Focal Adhesion Kinase with Tuberous Sclerosis Complex 2 in the Regulation of S6 Kinase Activation and Cell Growth
J. Biol. Chem., December 8, 2006; 281(49): 37321 - 37329.
[Abstract] [Full Text] [PDF]

Home page
 J. Cell Biol.Home page
B. Gan, X. Peng, T. Nagy, A. Alcaraz, H. Gu, and J.-L. Guan
Role of FIP200 in cardiac and liver development and its regulation of TNF{alpha} and TSC-mTOR signaling pathways
J. Cell Biol., October 9, 2006; 175(1): 121 - 133.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
C. Wilson, C. Bonnet, C. Guy, S. Idziaszczyk, J. Colley, V. Humphreys, J. Maynard, J. R. Sampson, and J. P. Cheadle
Tsc1 Haploinsufficiency without Mammalian Target of Rapamycin Activation Is Sufficient for Renal Cyst Formation in Tsc1+/- Mice
Cancer Res., August 15, 2006; 66(16): 7934 - 7938.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Cell. Biol.Home page
C. Thivierge, A. Kurbegovic, M. Couillard, R. Guillaume, O. Cote, and M. Trudel
Overexpression of PKD1 Causes Polycystic Kidney Disease
Mol. Cell. Biol., February 15, 2006; 26(4): 1538 - 1548.
[Abstract] [Full Text] [PDF]

Home page
 Genes Dev.Home page
L. Ma, J. Teruya-Feldstein, N. Behrendt, Z. Chen, T. Noda, O. Hino, C. Cordon-Cardo, and P. P. Pandolfi
Genetic analysis of Pten and Tsc2 functional interactions in the mouse reveals asymmetrical haploinsufficiency in tumor suppression
Genes & Dev., August 1, 2005; 19(15): 1779 - 1786.
[Abstract] [Full Text] [PDF]

Home page
 Genes Dev.Home page
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]

Home page
 Hum Mol GenetHome page
C. Wilson, S. Idziaszczyk, L. Parry, C. Guy, D. F.R. Griffiths, E. Lazda, R. A.L. Bayne, A. J.H. Smith, J. R. Sampson, and J. P. Cheadle
A mouse model of tuberous sclerosis 1 showing background specific early post-natal mortality and metastatic renal cell carcinoma
Hum. Mol. Genet., July 1, 2005; 14(13): 1839 - 1850.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
B. Govindarajan, D. J. Brat, M. Csete, W. D. Martin, E. Murad, K. Litani, C. Cohen, F. Cerimele, M. Nunnelley, B. Lefkove, et al.
Transgenic Expression of Dominant Negative Tuberin through a Strong Constitutive Promoter Results in a Tissue-specific Tuberous Sclerosis Phenotype in the Skin and Brain
J. Biol. Chem., February 18, 2005; 280(7): 5870 - 5874.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
L. Meikle, J. R. McMullen, M. C. Sherwood, A. S. Lader, V. Walker, J. A. Chan, and D. J. Kwiatkowski
A mouse model of cardiac rhabdomyoma generated by loss of Tsc1 in ventricular myocytes
Hum. Mol. Genet., February 1, 2005; 14(3): 429 - 435.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
K. J. Sales, S. Battersby, A. R. W. Williams, R. A. Anderson, and H. N. Jabbour
Prostaglandin E2 Mediates Phosphorylation and Down-Regulation of the Tuberous Sclerosis-2 Tumor Suppressor (Tuberin) in Human Endometrial Adenocarcinoma Cells via the Akt Signaling Pathway
J. Clin. Endocrinol. Metab., December 1, 2004; 89(12): 6112 - 6118.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
M. Cully, A. Elia, S.-H. Ong, V. Stambolic, T. Pawson, M.-S. Tsao, and T. W. Mak
grb2 heterozygosity rescues embryonic lethality but not tumorigenesis in pten+/- mice
PNAS, October 26, 2004; 101(43): 15358 - 15363.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
W. G. Kaelin Jr.
The Von Hippel-Lindau Tumor Suppressor Gene and Kidney Cancer
Clin. Cancer Res., September 15, 2004; 10(18): 6290S - 6295S.
[Abstract] [Full Text] [PDF]

Home page
 J Child NeurolHome page
K.-S. Au, A. T. Williams, M. J. Gambello, and H. Northrup
Molecular Genetic Basis of Tuberous Sclerosis Complex: From Bench to Bedside
J Child Neurol, September 1, 2004; 19(9): 699 - 709.
[Abstract] [PDF]

Home page
 J Child NeurolHome page
D. K. Scheidenhelm and D. H. Gutmann
Mouse Models of Tuberous Sclerosis Complex
J Child Neurol, September 1, 2004; 19(9): 726 - 733.
[Abstract] [PDF]

Home page
 CarcinogenesisHome page
E. Kleymenova, J. I. Everitt, L. Pluta, M. Portis, J. R. Gnarra, and C. L. Walker
Susceptibility to vascular neoplasms but no increased susceptibility to renal carcinogenesis in Vhl knockout mice
Carcinogenesis, March 1, 2004; 25(3): 309 - 315.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
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]

Home page
 Mol Hum ReprodHome page
M. Tachataki, R. M.L. Winston, and D. M. Taylor
Quantitative RT-PCR reveals tuberous sclerosis gene, TSC2, mRNA degradation following cryopreservation in the human preimplantation embryo
Mol. Hum. Reprod., October 1, 2003; 9(10): 593 - 601.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
W. Ma, L. Tessarollo, S.-B. Hong, M. Baba, E. Southon, T. C. Back, S. Spence, C. G. Lobe, N. Sharma, G. W. Maher, et al.
Hepatic Vascular Tumors, Angiectasis in Multiple Organs, and Impaired Spermatogenesis in Mice with Conditional Inactivation of the VHL Gene
Cancer Res., September 1, 2003; 63(17): 5320 - 5328.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
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]

Home page
 Cancer Res.Home page
M. Y. Liu, L. Poellinger, and C. L. Walker
Up-Regulation of Hypoxia-inducible Factor 2{alpha} in Renal Cell Carcinoma Associated with Loss of Tsc-2 Tumor Suppressor Gene
Cancer Res., May 15, 2003; 63(10): 2675 - 2680.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Pathol.Home page
D. M. Hockenbery
Nailing Down a Link between Tuberin and Renal Cysts
Am. J. Pathol., February 1, 2003; 162(2): 369 - 371.
[Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
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]

Home page
 J. Cell Biol.Home page
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]

Home page
 Toxicol PatholHome page
K. S. Mcdorman and D. C. Wolf
Use of the Spontaneous Tsc2 Knockout (Eker) Rat Model of Hereditary Renal Cell Carcinoma for the Study of Renal Carcinogens
Toxicol Pathol, October 1, 2002; 30(6): 675 - 680.
[Abstract] [PDF]

Home page
 J. Med. Genet.Home page
L Khare, A Astrinidis, W Senapedis, P D Adams, and E P. Henske
Expression of wild type and mutant TSC2, but not TSC1, causes an increase in the G1 fraction of the cell cycle in HEK293 cells
J. Med. Genet., September 1, 2002; 39(9): 676 - 680.
[Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
E. A. Goncharova, D. A. Goncharov, A. Eszterhas, D. S. Hunter, M. K. Glassberg, R. S. Yeung, C. L. Walker, D. Noonan, D. J. Kwiatkowski, M. M. Chou, et al.
Tuberin Regulates p70 S6 Kinase Activation and Ribosomal Protein S6 Phosphorylation. A ROLE FOR THE TSC2 TUMOR SUPPRESSOR GENE IN PULMONARY LYMPHANGIOLEIOMYOMATOSIS (LAM)
J. Biol. Chem., August 16, 2002; 277(34): 30958 - 30967.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Renal Physiol.Home page
H.-S. Yoon, T. J. Monks, J. I. Everitt, C. L. Walker, and S. S. Lau
Cell proliferation is insufficient, but loss of tuberin is necessary, for chemically induced nephrocarcinogenicity
Am J Physiol Renal Physiol, August 1, 2002; 283(2): F262 - F270.
[Abstract] [Full Text] [PDF]

Home page
 Circ. Res.Home page
K. B.S. Pasumarthi and L. J. Field
Cardiomyocyte Cell Cycle Regulation
Circ. Res., May 31, 2002; 90(10): 1044 - 1054.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
D. J. Kwiatkowski, H. Zhang, J. L. Bandura, K. M. Heiberger, M. Glogauer, N. el-Hashemite, and H. Onda
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., March 1, 2002; 11(5): 525 - 534.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
J. YU, A. ASTRINIDIS, and E. P. HENSKE
Chromosome 16 Loss of Heterozygosity in Tuberous Sclerosis and Sporadic Lymphangiomyomatosis
Am. J. Respir. Crit. Care Med., October 15, 2001; 164(8): 1537 - 1540.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Pathol.Home page
J. L. Arbiser, R. Yeung, S. W. Weiss, Z. K. Arbiser, M. B. Amin, C. Cohen, D. Frank, S. Mahajan, G. S. Herron, J. Yang, et al.
The Generation and Characterization of a Cell Line Derived from a Sporadic Renal Angiomyolipoma : Use of Telomerase to Obtain Stable Populations of Cells from Benign Neoplasms
Am. J. Pathol., August 1, 2001; 159(2): 483 - 491.
[Abstract] [Full Text]

Home page
 Proc. Natl. Acad. Sci. USAHome page
T. Kobayashi, O. Minowa, Y. Sugitani, S. Takai, H. Mitani, E. Kobayashi, T. Noda, and O. Hino
A germ-line Tsc1 mutation causes tumor development and embryonic lethality that are similar, but not identical to, those caused by Tsc2 mutation in mice
PNAS, June 28, 2001; (2001) 151033798.
[Abstract] [Full Text] [PDF]

Home page
 Genes Dev.Home page
X. Gao and D. Pan
TSC1 and TSC2 tumor suppressors antagonize insulin signaling in cell growth
Genes & Dev., June 1, 2001; 15(11): 1383 - 1392.
[Abstract] [Full Text] [PDF]

Home page
 Circ. Res.Home page
K. B. S. Pasumarthi, H. Nakajima, H. O. Nakajima, S. Jing, and L. J. Field
Enhanced Cardiomyocyte DNA Synthesis During Myocardial Hypertrophy in Mice Expressing a Modified TSC2 Transgene
Circ. Res., May 26, 2000; 86(10): 1069 - 1077.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Renal Physiol.Home page
V. Murthy, L. A. Haddad, N. Smith, D. Pinney, R. Tyszkowski, D. Brown, and V. Ramesh
Similarities and differences in the subcellular localization of hamartin and tuberin in the kidney
Am J Physiol Renal Physiol, May 1, 2000; 278(5): F737 - F746.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
D. M. Juriloff and M. J. Harris
Mouse models for neural tube closure defects
Hum. Mol. Genet., March 1, 2000; 9(6): 993 - 1000.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
T. Kobayashi, O. Minowa, Y. Sugitani, S. Takai, H. Mitani, E. Kobayashi, T. Noda, and O. Hino
A germ-line Tsc1 mutation causes tumor development and embryonic lethality that are similar, but not identical to, those caused by Tsc2 mutation in mice
PNAS, July 17, 2001; 98(15): 8762 - 8767.
[Abstract] [Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Cell Growth & Differentiation
Copyright © 1999 by the American Association for Cancer Research.