Loss of function mutations in the Tuberous Sclerosis Complex 2 gene (TSC2) result in Tuberous Sclerosis Complex (TSC), a disease characterized by the development of tumors in many tissues.TSC2 is in a pathway that integrates extracellular signals from growth factors and nutrients with the protein translation apparatus but the contribution of this pathway to its tumor suppression function is unclear. Similarities between the cancer prone syndromes TSC and von Hippel-Lindau (resulting from mutations in the VHL tumor suppressor gene), led me to hypothesize the existence of a functional link between TSC2 and pVHL. I have now demonstrated that loss of TSC2, like loss of pVHL, results in the activation of a program of gene expression conferring a selective growth advantage to cells that is regulated by the transcription factor Hypoxia-lnducible Factor (HIF) (Brugarolas et al., 2003). TSC2 inactivation is sufficient to upregulate HIF and reconstitution of TSC2-deficient cells with a TSC2 disease-associated mutant, unlike with wild-type TSC2, fails to restore HIF regulation suggesting that this function is important for tumor suppression. Because HIF levels are normally regulated by changes in oxygen tension and this response is impaired in TSC2-deficient cells, I hypothesized that TSC2 function might also be regulated by changes in oxygen levels. Indeed, while wild-type cells downregulate mammalian Target of Rapamycin (mTOR) function in response to hypoxia, TSC2 deficient cells fail to do so, suggesting that TSC2 is required for mTOR inhibition under these conditions. Furthermore, exposure to hypoxia results in the rapid phosphorylation of TSC2. The experiments outlined in this proposal aim to unravel the mechanism whereby TSC2 function is regulated by hypoxia. A greater understanding of TSC2 regulation by hypoxia might provide insight into its function as a tumor suppressor.
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