The mammalian target of rapamycin, mTOR, regulates cell growth and proliferation. Here we show that the initiation factor of translation (eIF-4E), a downstream effector of mTOR, has oncogenic effects in vivo and cooperates with c-Myc in B-cell lymphomagenesis. We found that c-Myc overrides eIF-4E-induced cellular senescence, whereas eIF-4E antagonizes c-Myc-dependent apoptosis in vivo. Our results implicate activation of eIF-4E as a key event in oncogenic transformation by phosphoinositide-3 kinase and Akt.

The DKC1 gene encodes a pseudouridine synthase that modifies ribosomal RNA (rRNA). DKC1 is mutated in people with X-linked dyskeratosis congenita (X-DC), a disease characterized by bone marrow failure, skin abnormalities, and increased susceptibility to cancer. How alterations in ribosome modification might lead to cancer and other features of the disease remains unknown. Using an unbiased proteomics strategy, we discovered a specific defect in IRES (internal ribosome entry site)-dependent translation in Dkc1(m) mice and in cells from X-DC patients. This defect results in impaired translation of messenger RNAs containing IRES elements, including those encoding the tumor suppressor p27(Kip1) and the antiapoptotic factors Bcl-xL and XIAP (X-linked Inhibitor of Apoptosis Protein). Moreover, Dkc1(m) ribosomes were unable to direct translation from IRES elements present in viral messenger RNAs. These findings reveal a potential mechanism by which defective ribosome activity leads to disease and cancer.

Proton and electron currents in human eosinophils were studied using the permeabilized‐patch voltage‐clamp technique, with an applied NH4+ gradient to control pHi. Voltage‐gated proton channels in unstimulated human eosinophils studied with the permeabilized‐patch approach had properties similar to those reported in whole‐cell studies. Superoxide anion (O2−) release assessed by cytochrome c reduction was compared in human eosinophils and neutrophils stimulated by phorbol myristate acetate (PMA). PMA‐stimulated O2 release was more transient and the maximum rate was three times greater in eosinophils. In PMA‐activated eosinophils, the H+ current amplitude (IH) at +60 mV increased 4.7‐fold, activation was 4.0 times faster, deactivation (tail current decay) was 5.4 times slower, the H+ conductance‐voltage (gH‐V) relationship was shifted ‐43 mV, and diphenylene iodinium (DPI)‐inhibitable inward current reflecting electron flow through NADPH oxidase was activated. The data reveal that PMA activates the H+ efflux during the respiratory burst by modulating the properties of H+ channels, not simply as a result of NADPH oxidase activity. The electrophysiological response of eosinophils to PMA resembled that reported in human neutrophils, but PMA activated larger proton and electron currents in eosinophils and the response was more transient. ZnCl2 slowed the activation of H+ currents and shifted the gH‐V relationship to more positive voltages. These effects occurred at similar ZnCl2 concentrations in eosinophils before and after PMA stimulation. These data are compatible with the existence of a single type of H+ channel in eosinophils that is modulated during the respiratory burst.

1. Effects of arachidonic acid (AA) on proton and electron currents in human eosinophils were studied using the permeabilized-patch voltage-clamp technique, using an applied NH 4 + gradient to control pH i .2. Superoxide anion (O 2 _ ) release was assessed by cytochrome c reduction in human eosinophils. Significant O 2 _ release was stimulated by 5-10 µM AA.3. AA activated diphenylene iodinium (DPI)-inhibitable inward current reflecting electron efflux through NADPH oxidase. These electron currents (I e ) were elicited in human eosinophils at AA concentrations (3-10 µM) similar to those that induced O 2 _ release.4. The voltage-gated proton conductance (g H ) in eosinophils stimulated with AA was profoundly enhanced: H + current amplitude (I H ) increased 4.6 times, activation was 4 times faster, and the H + conductance-voltage (g H -V) relationship was shifted to substantially more negative voltages. The electrophysiological effects of AA resembled those reported for PMA, except that AA did not consistently slow r tail (deactivation of H + currents).5. The stimulation of both proton and electron currents by AA was reversible upon washout. Repeated exposure elicited repeated responses. The activation of H + currents by AA was dissociable from its activation of NADPH oxidase; H + currents were enhanced at low concentrations of AA that did not elicit detectable I e or when NADPH oxidase was inhibited by DPI.6. Most of the effects of AA on H + currents qualitatively resemble those reported in whole-cell studies, reflecting a more direct action than PMA. The results are compatible with AA being an immediate activator of both NADPH oxidase and proton channels in human eosinophils.