The tuberous sclerosis proteins regulate formation of the primary cilium via a rapamycin-insensitive and polycystin 1-independent pathway
Open Access
- 9 October 2008
- journal article
- research article
- Published by Oxford University Press (OUP) in Human Molecular Genetics
- Vol. 18 (1), 151-163
- https://doi.org/10.1093/hmg/ddn325
Abstract
Tuberous sclerosis complex (TSC) is a tumor suppressor gene syndrome in which severe renal cystic disease can occur. Many renal cystic diseases, including autosomal dominant polycystic kidney disease (ADPKD), are associated with absence or dysfunction of the primary cilium. We report here that hamartin (TSC1) localizes to the basal body of the primary cilium, and that Tsc1−/− and Tsc2−/− mouse embryonic fibroblasts (MEFs) are significantly more likely to contain a primary cilium than wild-type controls. In addition, the cilia of Tsc1−/− and Tsc2−/− MEFs are 17–27% longer than cilia from wild-type MEFs. These data suggest a novel type of ciliary disruption in TSC, associated with enhanced cilia development. The TSC1 and TSC2 proteins function as a heterodimer to inhibit the activity of the mammalian target of rapamycin complex 1 (TORC1). The enhanced ciliary formation in the Tsc1−/− and Tsc2−/− MEFs was not abrogated by rapamycin, which indicates a TORC1-independent mechanism. Polycystin 1 (PC1), the product of the PKD1 gene, has been found to interact with TSC2, but Pkd1−/− MEFs did not have enhanced ciliary formation. Furthermore, while activation of mTOR has been observed in renal cysts from ADPKD patients, Pkd1−/− MEFs did not have evidence of constitutive mTOR activation, thereby underscoring the independent functions of the TSC proteins and PC1 in regulation of primary cilia and mTOR. Our data link the TSC proteins with the primary cilium and reveal a novel phenotype of enhanced ciliary formation in a cyst-associated disease.Keywords
This publication has 97 references indexed in Scilit:
- Identification of CC2D2A as a Meckel Syndrome Gene Adds an Important Piece to the Ciliopathy PuzzleAmerican Journal of Human Genetics, 2008
- HEF1-Dependent Aurora A Activation Induces Disassembly of the Primary CiliumCell, 2007
- pVHL and GSK3β are components of a primary cilium-maintenance signalling networkNature, 2007
- The von Hippel-Lindau tumor suppressor protein controls ciliogenesis by orienting microtubule growthThe Journal of cell biology, 2006
- Activity of TSC2 is inhibited by AKT-mediated phosphorylation and membrane partitioningThe Journal of cell biology, 2006
- Rheb is a direct target of the tuberous sclerosis tumour suppressor proteinsNature, 2003
- Rheb is an essential regulator of S6K in controlling cell growth in DrosophilaNature, 2003
- mTOR Interacts with Raptor to Form a Nutrient-Sensitive Complex that Signals to the Cell Growth MachineryCell, 2002
- Regulation of cell size in growth, development and human disease: PI3K, PKB and S6KBioEssays, 2002
- A germline insertion in the tuberous sclerosis (Tsc2) gene gives rise to the Eker rat model of dominantly inherited cancerNature Genetics, 1995