Tuberous sclerosis complex (TSC) is a genetic disease caused by mutations in either the TSC1 or TSC2 tumor suppressor gene. TSC is characterized by hamartoma formation in a wide range of tissues with the most severe clinical problems in brain and kidney. The TSC2 tumor suppressor protein has a conserved GTPase activating protein (GAP) domain and plays a key role in regulation of protein synthesis and cell size. The major cellular function of TSC2 is to decrease the phosphorylation of S6K (ribosomal S6 kinase) and 4EBP1 (eukaryotic initiation factor 4E binding protein), possibly by inhibiting mTOR (mammalian target of rapamycin). Rheb (Ras homology enriched in brain) is a Ras family small GTPase whose physiological function was previously unknown. Recently, it has been demonstrated that TSC2 directly stimulates the GTP hydrolysis of Rheb. Furthermore, Rheb can stimulate phosphorylation of both S6K and 4EBP1. These observations suggest that Rheb may function between TSC2 and mTOR to regulate cell growth. The long term objectives of this project are to elucidate the physiological functions of Rheb and to demonstrate that Rheb acts downstream of TSC2 and upstream of mTOR to regulate cell growth, cell size, and cell survival.
The specific aims for this proposal are: ? 1. To perform biochemical and functional characterizations of TSC2 GAP and Rheb GTPase activity. ? 2. To investigate the mechanism of Rheb in mTOR regulation. ? 3. To elucidate the function of Rheb in TSC2 signaling, cell size control, cellular energy response, and cell survival. ? 4. To demonstrate Rheb as a key cellular target of FTI (famesyl transferase inhibitor) in cell growth inhibition. ? 5. To identify and characterize Rheb interacting proteins. ? ?
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