title: Tsc1 haploinsufficiency without mammalian target of rapamycin activation is sufficient for renal cyst formation in Tsc1+/- mice.
abstract: Tuberous sclerosis complex (TSC) is caused by mutations in either the TSC1 or TSC2 gene. Both genes are generally considered to act as tumor suppressors that fulfill Knudson's "two-hit hypothesis" and that function within the phosphoinositide 3-kinase-Akt-mammalian target of rapamycin (mTOR) pathway. We previously generated Tsc1(+/-) mice that are predisposed to renal cysts, which develop into cystadenomas and renal cell carcinomas. Here, we identified somatic Tsc1 mutations (second hits) in approximately 80% of cystadenomas and renal cell carcinomas, but only 31.6% of cysts from Tsc1(+/-) mice (P < 0.0003), raising the possibility that haploinsufficiency for Tsc1 plays a role in cyst formation. Consistent with this proposal, many cysts showed little or no staining for phosphorylated mTOR (53%) and phosphorylated S6 ribosomal protein (37%), whereas >90% of cystadenomas and renal cell carcinomas showed strong staining for both markers (P < 0.0005). We also sought somatic mutations in renal lesions from Tsc1(+/-) Blm(-/-) mice that have a high frequency of somatic loss of heterozygosity, thereby facilitating the detection of second hits. We also found significantly less somatic mutations in cysts as compared with cystadenomas and renal cell carcinomas from these mice (P = 0.017). Our data indicate that although activation of the mTOR pathway is an important step in Tsc-associated renal tumorigenesis, it may not be the key initiating event in this process.
authors.affiliation: Department of Medical Genetics, Cardiff University, Cardiff, United Kingdom.
authors.forename: Catherine
authors.initials: C
authors.lastname: Wilson
authors.forename: Cleo
authors.initials: C
authors.lastname: Bonnet
authors.forename: Carol
authors.initials: C
authors.lastname: Guy
authors.forename: Shelley
authors.initials: S
authors.lastname: Idziaszczyk
authors.forename: James
authors.initials: J
authors.lastname: Colley
authors.forename: Vikki
authors.initials: V
authors.lastname: Humphreys
authors.forename: Julie
authors.initials: J
authors.lastname: Maynard
authors.forename: Julian R
authors.initials: JR
authors.lastname: Sampson
authors.forename: Jeremy P
authors.initials: JP
authors.lastname: Cheadle
mesh_terms: D000818:Animals; D004247:DNA / Q000235:genetics / Q000302:isolation & purification; D005838:Genotype; D052177:Kidney Diseases, Cystic / Q000235:genetics* / Q000473:pathology*; D007680:Kidney Neoplasms / Q000235:genetics* / Q000473:pathology; D019656:Loss of Heterozygosity; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D010766:Phosphorylation; D011494:Protein Kinases / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins / Q000172:deficiency* / Q000235:genetics*
chemical_list: C000624651:Tsc1 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins; D004247:DNA; D011494:Protein Kinases; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases