Abstract
Recently the tuberous sclerosis complex 2 (TSC2) tumor suppressor gene product has been identified as a negative regulator of protein synthesis upstream of the mTOR and ribosomal S6 kinases. Because of the homology of TSC2 with GTPase-activating proteins for Rap1, we examined whether a Ras/Rap-related GTPase might be involved in this process. TSC2 was found to bind to Rheb-GTP in vitro and to reduce Rheb GTP levels in vivo. Over-expression of Rheb but not Rap1 promoted the activation of S6 kinase in a rapamycin-dependent manner, suggesting that Rheb acts upstream of mTOR. The ability of Rheb to induce S6 phosphorylation was also inhibited by a farnesyl transferase inhibitor, suggesting that Rheb may be responsible for the Ras-independent anti-neoplastic properties of this drug.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Antineoplastic Agents / pharmacology
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Cell Line
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Enzyme Activation
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Gene Expression Regulation, Enzymologic
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Humans
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Immunoblotting
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Monomeric GTP-Binding Proteins / metabolism*
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Neuropeptides / metabolism*
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Phosphorylation
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Plasmids / metabolism
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Protein Binding
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Protein Kinases / metabolism*
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Protein Prenylation
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Ras Homolog Enriched in Brain Protein
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Repressor Proteins / metabolism*
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Ribosomal Protein S6 Kinases / metabolism*
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Sirolimus / pharmacology*
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TOR Serine-Threonine Kinases
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Tuberous Sclerosis Complex 2 Protein
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Tumor Suppressor Proteins
Substances
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Antineoplastic Agents
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Neuropeptides
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RHEB protein, human
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Ras Homolog Enriched in Brain Protein
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Repressor Proteins
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TSC2 protein, human
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Tuberous Sclerosis Complex 2 Protein
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Tumor Suppressor Proteins
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Protein Kinases
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MTOR protein, human
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Ribosomal Protein S6 Kinases
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TOR Serine-Threonine Kinases
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Monomeric GTP-Binding Proteins
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Sirolimus