Journal
NUCLEIC ACIDS RESEARCH
Volume 34, Issue 16, Pages 4375-4386Publisher
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkl558
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Funding
- NHLBI NIH HHS [R01 HL076779, T32 HL07741, T32 HL007741, HL076779, R01 HL073719, P50 HL50152, K08 HL074058, HL073719, 1K08-HL074058-01] Funding Source: Medline
- NIAID NIH HHS [P01 AI50162, P01 AI050162] Funding Source: Medline
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Aberrant activation of the translation initiation machinery is a common property of malignant cells, and is essential for breast carcinoma cells to manifest a malignant phenotype. How does sustained activation of the rate limiting step in protein synthesis so fundamentally alter a cell? In this report, we test the post transcriptional operon theory as a possible mechanism, employing a model system in which apoptosis resistance is conferred on NIH 3T3 cells by ectopic expression of eIF4E. We show (i) there is a set of 255 transcripts that manifest an increase in translational efficiency during eIF4E-mediated escape from apoptosis; (ii) there is a novel prototype 55 nt RNA consensus hairpin structure that is overrepresented in the 5'-untranslated region of translationally activated transcripts; (iii) the identified consensus hairpin structure is sufficient to target a reporter mRNA for translational activation under pro-apoptotic stress, but only when eIF4E is deregulated; and (iv) that osteopontin, one of the translationally activated transcripts harboring the identified consensus hairpin structure functions as one mediator of the apoptosis resistance seen in our model. Our findings offer genome-wide insights into the mechanism of eIF4E-mediated apoptosis resistance and provide a paradigm for the systematic study of posttranscriptional control in normal biology and disease.
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