-
[show abstract]
[hide abstract]
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.
Genes & Development 09/2008; 22(16):2178-88. · 11.66 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Deregulation of protein translation is a common event in cancer and occurs frequently as a result of mutational activation of the AKT signaling pathway. We had previously reported the in vivo oncogenic activity of the translation initiation factor eIF4E, which acts downstream AKT and mTOR. We now identified an absolute requirement for Ser209 phosphorylation by the MNK1/2 kinases for eIF4E's oncogenic action. MNK1/2 kinases are dispensable for normal development in mammals. This potential difference between normal and cancer cells may provide a therapeutic avenue for targeting translational requirements in cancer.
Cell cycle (Georgetown, Tex.) 04/2008; 7(5):553-5. · 5.36 Impact Factor
-
Hans-Guido Wendel, Ricardo L A Silva,
Abba Malina,
John R Mills,
Hong Zhu,
Takeshi Ueda,
Rie Watanabe-Fukunaga,
Rikiro Fukunaga,
Julie Teruya-Feldstein,
Jerry Pelletier,
Scott W Lowe
[show abstract]
[hide abstract]
ABSTRACT: Genetically engineered mouse models are powerful tools for studying cancer genes and validating targets for cancer therapy. We previously used a mouse lymphoma model to demonstrate that the translation initiation factor eIF4E is a potent oncogene in vivo. Using the same model, we now show that the oncogenic activity of eIF4E correlates with its ability to activate translation and become phosphorylated on Ser 209. Furthermore, constitutively activated MNK1, an eIF4E Ser 209 kinase, promotes tumorigenesis in a manner similar to eIF4E, and a dominant-negative MNK mutant inhibits the in vivo proliferation of tumor cells driven by mutations that deregulate translation. Phosphorylated eIF4E promotes tumorigenesis primarily by suppressing apoptosis and, accordingly, the anti-apoptotic protein Mcl-1 is one target of both phospho-eIF4E and MNK1 that contributes to tumor formation. Our results provide insight into how eIF4E contributes to tumorigenesis and pinpoint a level of translational control that may be suitable for therapeutic intervention.
Genes & Development 01/2008; 21(24):3232-7. · 11.66 Impact Factor
