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Nucleic Acids Research Advance Access originally published online on August 26, 2006
Nucleic Acids Research 2006 34(16):4375-4386; doi:10.1093/nar/gkl558
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Nucleic Acids Research, 2006, Vol. 34, No. 16 4375-4386
© 2006 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Molecular Biology

Apoptosis resistance downstream of eIF4E: posttranscriptional activation of an anti-apoptotic transcript carrying a consensus hairpin structure

Ola Larsson*, David M. Perlman, Danhua Fan, Cavan S. Reilly1, Mark Peterson, Cecilia Dahlgren2, Zicai Liang2, Shunan Li, Vitaly A. Polunovsky, Claes Wahlestedt3 and Peter B. Bitterman*

Department of Medicine, University of Minnesota MMC 276, USA Minneapolis, MN 55455, USA 1 School of Public Health Division of Biostatistics, University of Minnesota Minneapolis, MN 55455, USA 2 Department of Cell and Molecular Biology (CMB), Programme for Genomics and Bioinformatics, Karolinska Institutet Berzelius väg 35, 171 77 Stockholm, Sweden 3 Scripps Florida, 5353 Parkside Drive RF2, Jupiter, FL 33458, USA

*To whom correspondence should be addressed. Tel: +1 612 626 6848; Fax: +1 612 625 2174; Email: larss004{at}tc.umn.edu

Received April 25, 2006. Revised July 7, 2006. Accepted July 18, 2006.

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.

*Correspondence may also be addressed to Peter Bitterman. Tel: +1 612 624 5175; Fax: +1 612 625 2174; Email: bitte001{at}umn.edu

The authors wish it to be known that, in their opinion, the second and third authors should be regarded as joint Second Authors

Gene expression Omnibus accession no. GSE 2094


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