Mavrakis, K. J., Zhu, H., Silva, R. L., Mills, J. R., Teruya-Feldstein, J., Lowe, S. W., Tam, W., Pelletier, J., Wendel, H. G. (August 2008) Tumorigenic activity and therapeutic inhibition of Rheb GTPase. Genes Dev, 22 (16). pp. 2178-88.
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Abstract
The AKT-mTOR pathway harbors several known and putative oncogenes and tumor suppressors. In a phenotypic screen for lymphomagenesis, we tested candidate genes acting upstream of and downstream from mTOR in vivo. We find that Rheb, a proximal activator of mTORC1, can produce rapid development of aggressive and drug-resistant lymphomas. Rheb causes mTORC1-dependent effects on apoptosis, senescence, and treatment responses that resemble those of Akt. Moreover, Rheb activity toward mTORC1 requires farnesylation and is readily blocked by a pharmacological inhibitor of farnesyltransferase (FTI). In Pten-deficient tumor cells, inhibition of Rheb by FTI is responsible for the drug's anti-tumor effects, such that a farnesylation-independent mutant of Rheb renders these tumors resistant to FTI therapy. Notably, RHEB is highly expressed in some human lymphomas, resulting in mTORC1 activation and increased sensitivity to rapamycin and FTI. Downstream from mTOR, we examined translation initiation factors that have been implicated in transformation in vitro. Of these, only eIF4E was able to enhance lymphomagenesis in vivo. In summary, the Rheb GTPase is an oncogenic activity upstream of mTORC1 and eIF4E and a direct therapeutic target of farnesyltransferase inhibitors in cancer.
| Item Type: | Paper |
|---|---|
| Uncontrolled Keywords: | Animals Antibiotics, Antineoplastic/pharmacology Blotting, Western Cell Aging Cell Transformation, Neoplastic/*pathology Cells, Cultured Doxorubicin/pharmacology Eukaryotic Initiation Factor-4E/*metabolism Farnesyltranstransferase/*antagonists & inhibitors/metabolism Female Fibroblasts/cytology/metabolism Gene Dosage Humans Immunophenotyping Immunosuppressive Agents/pharmacology Lymphoma/metabolism/*pathology Mice Mice, Inbred C57BL Mice, Knockout Monomeric GTP-Binding Proteins/*antagonists & inhibitors/metabolism Neuropeptides/*antagonists & inhibitors/metabolism PTEN Phosphohydrolase/physiology Phosphorylation Piperidines/pharmacology Proto-Oncogene Proteins c-akt/metabolism Proto-Oncogene Proteins c-myc/physiology Pyridines/pharmacology RNA, Messenger/genetics/metabolism Reverse Transcriptase Polymerase Chain Reaction Signal Transduction Sirolimus/pharmacology Transcription Factors/*metabolism Tumor Suppressor Protein p53/physiology |
| Subjects: | diseases & disorders > cancer diseases & disorders bioinformatics > genomics and proteomics > genetics & nucleic acid processing bioinformatics > genomics and proteomics bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification |
| CSHL Authors: | |
| Communities: | CSHL labs > Lowe lab |
| Depositing User: | Matt Covey |
| Date: | 15 August 2008 |
| Date Deposited: | 22 Feb 2013 19:25 |
| Last Modified: | 03 Nov 2017 20:17 |
| PMCID: | PMC2518821 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/27636 |
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