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-X L . 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.Normal diploid fibroblasts deprived of serum or polypeptide growth factors exit the cell cycle and persist in a quiescent state. When quiescent cells are stimulated to enter the cell cycle by viral oncogenes (31) or by enforced expression of cellular growth-promoting proteins such as c-Myc (2, 8; reviewed in reference 38), E2F (1, 17, 68), or cyclin A (18, 35), they do not progress toward mitosis but undergo programmed cell death. Similarly, the relaxation of negative growth control that occurs during preneoplastic progression of fibroblasts toward immortalization (42, 62) or by decreased retinoblastoma protein expression (1, 57) leads to apoptosis in response to growth factor withdrawal. Along these lines, peptide growth factors such as platelet-derived growth factor (PDGF) and epidermal growth factor can signal both cell cycle entry and apoptosis in fibroblasts deprived of progression-type growth factors (24). These findings support the idea that cell cycle transit is a potentially lethal condition unless specific rescue factors prevent this fate (20,43,44). Therefore, a mitogenic stimulus must coordinately activate metabolic pathways directing both proliferation and survival in order to result in cell division without death. While recent advances in our understanding of the cell division cycle reveal how cells integrate proliferative signals with the cell cycle machinery, the molecular mechanisms and regulatory pathways involved in growth factor survival signaling remain uncertain.The quiescent state is characterize...
Activated Ras has been shown to provide powerful antiapoptotic signals to cells through well defined transcriptional and post-translational pathways, whereas translational control as a mechanism of Ras survival signaling remains unexplored. Here we show a direct relationship between assembly of the cap-dependent translation initiation apparatus and suppression of apoptosis by oncogenic Ras in vitro and in vivo. Decreasing protein synthesis with rapamycin, which is known to inhibit cap-dependent translation, increases the susceptibility of Ras-transformed fibroblasts to cytostatic drug-induced apoptosis. In contrast, suppressing global protein synthesis with equipotent concentrations of cycloheximide actually prevents apoptosis. Enforced expression of the cap-dependent translational repressor, the eukaryotic translation initiation factor (eIF) 4E-binding protein (4E-BPI), sensitizes fibroblasts to apoptosis in a manner strictly dependent on its ability to sequester eIF4E from a translationally active complex with eIF4GI and the co-expression of oncogenic Ras. Ectopic expression of 4E-BP1 also promotes apoptosis of Ras-transformed cells injected into immunodeficient mice and markedly diminishes their tumorigenicity. These results establish that eIF4E-dependent protein synthesis is essential for survival of fibroblasts bearing oncogenic Ras and support the concept that activation of cap-dependent translation by extracellular ligands or intrinsic survival signaling molecules suppresses apoptosis, whereas synthesis of proteins mediating apoptosis can occur independently of the cap.Extracellular survival factors suppress the intrinsic apoptotic apparatus through cognate receptor kinases at the cell surface, which activate the proto-oncogene ras and a number of pleiotropic transcriptional and post-translational effector pathways (1). A major effector of Ras survival signaling is the serine/threonine protein kinase, Akt (2, 3). Transcriptional control is exerted by Akt-mediated phosphorylation of the Forkhead1 family transcription factor FKHRL1(4) and the transcription factor nuclear factor-B (5), which alter expression of apoptosis-related genes. Akt-mediated phosphorylation of the Bcl-2 family member Bad (6) and the cell death protease caspase-9 (7) is implicated in post-translational suppression of the intrinsic apoptotic machinery. Akt also regulates the FK506 binding-protein 12 (FKBP12)-rapamycin-associated protein/mammalian target of rapamycin (FRAP/mTOR), 1 a kinase which functions in the control of translation by activating two components of the protein synthesis apparatus: (i) the initiation complex binding the 5Ј-mRNA cap and (ii) the 40 S ribosomal protein S6 kinase, p70 s6k (8 -11). However, data examining the importance of translational control in the mechanism of Ras survival signaling are lacking.Translational control is usually exerted at the initiation step. In eukaryotes, the 5Ј-mRNA cap is bound by the eukaryotic translation initiation complex eIF4F, which consists of a bidirectional RNA helicase eIF4...
The Gait Outcomes Assessment List (GOAL) can discriminate between Gross Motor Function Classification System levels. The GOAL correlates with standard functional assessments and gait analysis. Used with gait analysis, the GOAL provides comprehensive assessment across all International Classification of Functioning, Disability and Health domains.
Ectopically expressed eukaryotic translation initiation factor 4E (eIF4E) stimulates cell proliferation, suppresses apoptosis in growth factor restricted cells, and induces malignant transformation in primary rodent ®broblasts when coexpressed with protooncogene myc. We report here that eIF4E rescued rat embryo ®broblasts ectopically expressing c-Myc ( signi®cantly increased chemosensitivity; either soluble antisense cyclin D1 oligomers or transfection with a dominant negative cyclin D1 mutant that prevents translocation of cyclin D-dependent kinases to the nucleus, signi®cantly blunted the antiapoptotic e ect of eIF4E. These data directly link eIF4E rescue from cytostatic drugs to cyclin D1. Since overexpression of eIF4E and cyclin D1 is observed in many aggressive forms of chemoresistant cancers, these ®ndings provide insight into possible mechanisms responsible for this biological behavior.
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