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J. Biol. Chem., Vol. 280, Issue 22, 20945-20953, June 3, 2005

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Internal Translation Initiation Mediated by the Angiogenic Factor Tie2^*

Eun-Hee Park, Joseph M. Lee, Jaime D. Blais¶, John C. Bell¶, and Jerry Pelletier||**

From the Department of Biochemistry and ^||McGill Cancer Center, McGill University, Montreal, Quebec H3G 1Y6, Canada and the ^¶Ottawa Regional Cancer Centre Research Laboratories, Ottawa, Ontario K1H 8L6, Canada

Tie2 is an endothelium-specific receptor tyrosine kinase required for normal blood vessel maturation. We report that Tie2 mRNA translation is maintained under hypoxic conditions. To identify the mechanism responsible for this, we undertook structure/function analysis of the Tie2 5'-untranslated region (UTR). Transcription start site mapping indicates the existence of a several mRNA isoforms containing unusually long 5'-UTRs (>350 nucleotides) with five upstream open reading frames. We find internal ribosome binding activity that allows the Tie2 mRNA to initiate in a cap-independent fashion. Our data provide a framework for understanding how Tie2 mRNA is translated despite a cumbersome structured 5'-UTR and how its production is secured under unfavorable environmental conditions.

Received for publication, November 10, 2004 , and in revised form, March 8, 2005.

^* This work was supported by Grant MOP-11354 from the Canadian Institutes of Health Research (CIHR) (to J. P.). 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.

Supported by a K. M. Hunter/CIHR doctoral research award.

^** CIHR Senior Investigator. To whom correspondence should be addressed: McIntyre Medical Sciences Bldg., Rm. 810, 3655 Promenade Sir William Osler, McGill University, Montreal, Quebec H3G 1Y6, Canada. Tel.: 514-398-2323; Fax: 514-398-7384; E-mail: jerry.pelletier{at}mcgill.ca.

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