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Translational control of programmed cell death: eukaryotic translation initiation factor 4E blocks apoptosis in
V A Polunovsky1, I B Rosenwald, A T Tan
1Pulmonary and Critical Care Division, Department of Medicine, University of Minnesota Medical School, Minneapolis 55455, USA.
Abstract:
There is increasing evidence that cell cycle transit is potentially lethal, with survival depending on the activation of metabolic pathways which block apoptosis. However, the identities of those pathways coupling cell cycle transit to survival remain undefined. Here we show that the eukaryotic translation initiation factor 4E (eIF4E) can mediate both proliferative and survival signaling. Overexpression of eIF4E completely substituted for serum or individual growth factors in preserving the viability of established NIH 3T3 fibroblasts. An eIF4E mutant (Ser-53 changed to Ala) defective in mediating its growth-factor-regulated functions was also defective in its survival signaling. Survival signaling by enforced expression of eIF4E did not result from autocrine release of survival factors, nor did it lead to increased expression of the apoptosis antagonists Bcl-2 and Bcl-XL. In addition, the execution apparatus of the apoptotic response in eIF4E-overexpressing cells was found to be intact. Increased expression of eIF4E was sufficient to inhibit apoptosis in serum-restricted primary fibroblasts with enforced expression of Myc. In contrast, activation of Ha-Ras, which is required for eIF4E proliferative signaling, did not suppress Myc-induced apoptosis. These data suggest that the eIF4E-activated pathways leading to survival and cell cycle progression are distinct. This dual signaling of proliferation and survival might be the basis for the potency of eIF4E as an inducer of neoplastic transformation.
Insights
The eukaryotic translation initiation factor 4E (eIF4E) promotes cell survival and proliferation by distinct pathways. This dual signaling role of eIF4E may explain its potent ability to induce cancer.
Area of Science:
- Cell Biology
- Molecular Biology
- Cancer Research
Background:
- Cell cycle progression can be lethal, necessitating metabolic pathways that block apoptosis.
- The specific pathways linking cell cycle transit to cell survival are not fully understood.
Purpose of the Study:
- To investigate the role of eukaryotic translation initiation factor 4E (eIF4E) in mediating cell survival and proliferation.
- To determine if eIF4E's proliferative and survival signaling pathways are distinct.
Main Methods:
- Overexpression of eIF4E and a mutant form in NIH 3T3 fibroblasts and primary fibroblasts.
- Assessing cell viability under serum-restricted conditions.
- Evaluating apoptosis markers and signaling pathways, including Myc and Ha-Ras activation.
Main Results:
- Overexpressed eIF4E rescued NIH 3T3 fibroblasts from serum deprivation-induced death, acting similarly to growth factors.
- An eIF4E mutant (Ser-53 Ala) impaired in growth factor signaling also failed in survival signaling.
- eIF4E overexpression inhibited Myc-induced apoptosis in primary fibroblasts, whereas Ha-Ras activation did not.
- eIF4E-mediated survival did not involve autocrine factor release or increased Bcl-2/Bcl-XL expression.
Conclusions:
- eIF4E mediates distinct signaling pathways for cell survival and proliferation.
- The dual role of eIF4E in promoting both survival and cell cycle progression contributes to its oncogenic potential.