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[Cancer Research 59, 1206-1211, March 1, 1999]
© 1999 American Association for Cancer Research
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[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.




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