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PMID: 8887686 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

Translational control of programmed cell death: eukaryotic translation initiation factor 4E blocks apoptosis in growth-factor-restricted fibroblasts with physiologically expressed or deregulated Myc.

Molecular and cellular biology ·Vol. 16 ·No. 11 ·1996-11-00 ·Pages 6573-81

Polunovsky VA, Rosenwald IB, Tan AT, White J, Chiang L, Sonenberg N, Bitterman PB

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.

MeSH Terms
3T3 Cells Animals Animals, Newborn Apoptosis Becaplermin Biomarkers Cell Cycle Cell Division/drug effects Cell Survival/drug effects Cells, Cultured Eukaryotic Initiation Factor-4E Fibroblasts/cytology,physiology Growth Substances/pharmacology Insulin-Like Growth Factor I/pharmacology Lung Mice Mice, Inbred BALB C Peptide Initiation Factors/biosynthesis,metabolism Platelet-Derived Growth Factor/pharmacology Protein Biosynthesis Proto-Oncogene Proteins/biosynthesis Proto-Oncogene Proteins c-bcl-2/biosynthesis Proto-Oncogene Proteins c-myc/biosynthesis,physiology Proto-Oncogene Proteins c-sis Recombinant Proteins/metabolism Signal Transduction Time Factors bcl-X Protein
Chemicals
Bcl2l1 protein, mouse Biomarkers Eukaryotic Initiation Factor-4E Growth Substances Peptide Initiation Factors Platelet-Derived Growth Factor Proto-Oncogene Proteins Proto-Oncogene Proteins c-bcl-2 Proto-Oncogene Proteins c-myc Proto-Oncogene Proteins c-sis Recombinant Proteins bcl-X Protein Becaplermin Insulin-Like Growth Factor I
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Polunovsky V A
Pulmonary and Critical Care Division, Department of Medicine, University of Minnesota Medical School, Minneapolis 55455, USA.
Rosenwald I B
Tan A T
White J
Chiang L
Sonenberg N
Bitterman P B
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.16.11.6573
Published
1996-11-00
Pages
6573-81
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC231659
Subset
IM
Grants
NHLBI NIH HHS · 1-P50 HL50152-01 · United States
External Links
PubMed source DOI: 10.1128/MCB.16.11.6573 PMC Full Text View journal details
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