Individuals affected with tuberous sclerosis complex (TSC) develop subependymal giant cell astrocytomas, suggesting that the TSC gene products, hamartin and tuberin, function as a negative growth regulators for astrocytes. In this proposal, we plan to critically test the hypothesis that hamartin and tuberin regulate astrocyte growth and prevent astrocytoma formation. Previously, we have demonstrated that loss of tuberin is associated with brain tumor formation and that both reduced expression of tuberin and hamartin result in increased astrocyte growth in vivo. Specifically, we plan to determine whether (1) absent TSC expression is astrocytes results in increased astrocyte proliferation and tumor formation in vitro and in vivo and (2) tuberin and hamartin regulate astrocyte cell growth in a rap 1- and p27-Kipl-dependent fashion. These studies are aimed at understanding how tuberin and hamartin function as growth regulators for astrocytes relevant to tumor formation.
| Uhlmann, Erik J; Li, Wen; Scheidenhelm, Danielle K et al. (2004) Loss of tuberous sclerosis complex 1 (Tsc1) expression results in increased Rheb/S6K pathway signaling important for astrocyte cell size regulation. Glia 47:180-8 |
| Wong, Michael; Ess, Kevin C; Uhlmann, Erik J et al. (2003) Impaired glial glutamate transport in a mouse tuberous sclerosis epilepsy model. Ann Neurol 54:251-6 |
| Tabancay Jr, Angel P; Gau, Chia-Ling; Machado, Iara M P et al. (2003) Identification of dominant negative mutants of Rheb GTPase and their use to implicate the involvement of human Rheb in the activation of p70S6K. J Biol Chem 278:39921-30 |
