[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. DOI:10.1101/gad.1690808 · 12.64 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The emergence of dengue hemorrhagic fever in Sri Lanka in 1989 correlated with the appearance of a genetic variant of Dengue 3 virus (DENV-3) subtype III (group B), closely related to the endemic group A variant. We studied the 5' and 3' non-coding regions (NCRs) of 15 DENV-3 subtype III isolates from Sri Lanka, Nicaragua and Martinique and found variability in the 3' NCRs. This included an 11-nucleotide insertion common to all isolates examined and two nucleotide differences that segregated viruses geographically into an American and a Sri Lankan group. Comparisons also identified three nucleotide differences shared by all group A Sri Lankan DENV-3 III isolates linked to mild disease epidemics but not group B Sri Lankan and group B-associated American isolates linked to severe disease epidemics. Clustering of the Latin American/Caribbean isolates with Sri Lankan group B DENV-3 in phylogenetic analyses supports the proposed common East African origin for all these strains and confirms the use of the 3' NCR for molecular epidemiologic studies of DENV-3. The differences in the 3' NCRs reported here, as well as potential alterations in the structural and non-structural coding genes, may contribute to the increased pathogenicity of group B DENV-3.
Virus Research 09/2008; 135(2):320-5. DOI:10.1016/j.virusres.2008.03.007 · 2.83 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.
[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. DOI:10.1101/gad.1604407 · 12.64 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Arf is a key mammalian tumor suppressor gene known to be activated in response to aberrant mitogenic signals leading to both p53-dependent and -independent effects. We recently uncovered a new and somewhat unexpected function for mouse Arf as a regulator of mural cell accumulation within an ocular vascular bed destined to regress in the postnatal period. We found that the Arf gene product, p19(Arf), blocks mural cell proliferation driven by Platelet-derived growth factor receptor beta (Pdgfrbeta) in the developing vitreous. In vivo studies and analyses of cultured cells indicate that p19(Arf) dampens the expression of Pdgfrbeta. In cultured mouse embryo fibroblasts, p19(Arf) accomplishes this independently of two established effectors - Mdm2 and p53. Our findings indicating that p19(Arf) responds to specific developmental cues to disrupt Pdgfrbeta signaling in the developing eye extend existing paradigms for Arf tumor suppressor gene biology.
[Show abstract][Hide abstract] ABSTRACT: We have established that the Arf tumor suppressor gene regulates mural cell biology in the hyaloid vascular system (HVS) of the developing eye. In the absence of Arf, perivascular cells accumulate within the HVS and prevent its involution. We now demonstrate that mural cell accumulation evident at embryonic day (E) 13.5 in Arf(-/-) mice was driven by excess proliferation at E12.5, when Arf expression was detectable in vitreous pericyte-like cells. Their expression of Arf overlapped with Pdgf receptor beta (Pdgfrbeta), which is essential for pericyte accumulation in the mouse. In cultured cells, p19Arf decreased Pdgfrbeta and blocked Pdgf-B-driven proliferation independently of Mdm2 and p53. The presence of a normal Arf allele correlated with decreased Pdgfrbeta in the embryonic vitreous. Pdgfrbeta was required for vitreous cell accumulation in the absence of Arf. Our findings demonstrate a novel, p53- and Mdm2-independent function for p19Arf. Instead of solely sensing excessive mitogenic stimuli, developmental cues induce Arf to block Pdgfrbeta-dependent signals and prevent the accumulation of perivascular cells selectively in a vascular bed destined to regress.
The EMBO Journal 09/2005; 24(15):2803-14. DOI:10.1038/sj.emboj.7600751 · 10.75 Impact Factor