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: Catherine Wilson, Cleo Bonnet, Carol Guy, Shelley Idziaszczyk, James Colley, Vikki Humphreys, Julie Maynard, Julian R Sampson, Jeremy P Cheadle
• Journal: Cancer research (Cancer Res) Vol. 66 Issue 16 Pg. 7934-8 (Aug 15 2006) ISSN: 1538-7445 [Electronic] United States
• PMID: 16912167 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Tsc1 protein, mouse
• Tuberous Sclerosis Complex 1 Protein
• Tumor Suppressor Proteins
• DNA
• Protein Kinases
• mTOR protein, mouse
• TOR Serine-Threonine Kinases

Topics

• Animals
• DNA (genetics, isolation & purification)
• Genotype
• Kidney Diseases, Cystic (genetics, pathology)
• Kidney Neoplasms (genetics, pathology)
• Loss of Heterozygosity
• Mice
• Mice, Knockout
• Mutation
• Phosphorylation
• Protein Kinases (physiology)
• TOR Serine-Threonine Kinases
• Tuberous Sclerosis Complex 1 Protein
• Tumor Suppressor Proteins (deficiency, genetics)