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J. Biol. Chem., Vol. 283, Issue 24, 16309-16319, June 13, 2008

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Hypoxia-mediated Selective mRNA Translation by an Internal Ribosome Entry Site-independent Mechanism^*

Regina M. Young, Shang-Jui Wang, John D. Gordan, Xinjun Ji, Stephen A. Liebhaber, and M. Celeste Simon^¶1

From the Abramson Family Cancer Research Institute, Departments of Genetics and Medicine, University of Pennsylvania School of Medicine, and ^¶Howard Hughes Medical Institute, University of Pennsylvania, Philadelphia Pennsylvania 19104

Although it is advantageous for hypoxic cells to inhibit protein synthesis and conserve energy, it is also important to translate mRNAs critical for adaptive responses to hypoxic stress. Because internal ribosome entry sites (IRES) have been postulated to mediate this preferential synthesis, we analyzed the 5 '-untranslated regions from a panel of stress-regulated mRNAs for m⁷GTP cap-independent translation and identified putative IRES elements in encephalomyocarditis virus, vascular endothelial growth factor, hypoxia-inducible factors (HIFs) 1 and 2, glucose transporter-like protein 1, p57^Kip2, La, BiP, and triose phosphate isomerase transcripts. However, when capped and polyadenylated dicistronic RNAs were synthesized in vitro and transfected into cells, cellular IRES-mediated translation accounted for less than 1% that of the level of cap-dependent translation. Moreover, hypoxic stress failed to activate cap-independent synthesis, indicating that it is unlikely that this is the primary mechanism for the maintenance of the translation of these mRNAs under low O₂. Furthermore, although HIF-1 is frequently cited as an example of an mRNA that is preferentially translated, we demonstrate that under different levels and durations of hypoxic stress, changes in newly synthesized HIF-1 and β-actin protein levels mirror alterations in corresponding mRNA abundance. In addition, our data suggest that cyclin-dependent kinase inhibitor p57^Kip2 and vascular endothelial growth factor mRNAs are selectively translated by an IRES-independent mechanism under hypoxic stress.

Received for publication, December 11, 2007 , and in revised form, March 28, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants P01 CA104838 (NCI, to M. S. C.), CA1048387-03S1 (to R. M. Y.), and R37 HL65449 (MERIT; to S. A. L.). This work was also supported by the Howard Hughes Medical Institute and the Abramson Family Cancer Research Institute. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1 and 2.

¹ An Investigator of the Howard Hughes Medical Institute. To whom correspondence should be addressed: 421 Curie Blvd., Philadelphia, PA 19104. Tel.: 215-746-5532; Fax: 215-746-5511; E-mail: celeste2{at}mail.med.upenn.edu.

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