title: Renal carcinogenesis, hepatic hemangiomatosis, and embryonic lethality caused by a germ-line Tsc2 mutation in mice.
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, approximately 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.
authors: Department of Experimental Pathology, Cancer Institute, Tokyo, Japan.
authors: T
authors: T
authors: Kobayashi
authors: O
authors: O
authors: Minowa
authors: J
authors: J
authors: Kuno
authors: H
authors: H
authors: Mitani
authors: O
authors: O
authors: Hino
authors: T
authors: T
authors: Noda
mesh_terms: D000818:Animals; D002292:Carcinoma, Renal Cell / Q000235:genetics*; D005314:Embryonic and Fetal Development / Q000235:genetics; D016147:Genes, Tumor Suppressor; D018095:Germ-Line Mutation; D006391:Hemangioma / Q000235:genetics*; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics*; D008113:Liver Neoplasms / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D051381:Rats; D012097:Repressor Proteins / Q000235:genetics / Q000502:physiology*; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins
chemical_list: D012097:Repressor Proteins; C000624653:TSC2 protein, human; C000624654:Tsc2 protein, mouse; C000624655:Tsc2 protein, rat; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins