Ilana Goldberg-Cohen, Henry Furneauxb §, and Andrew P. Levy ¶

Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Post Office Box 9649, Haifa 31096, Israel, and the
§ Department of Physiology, University of Connecticut Health Center, Farmington, Connecticut 06032

¶ To whom correspondence should be addressed. Tel.: 972-4-8295202; Fax: 972-4-8514103;
E-mail:   alevy@tx.technion.ac.il

VEGF is a critical mediator of hypoxia-induced angiogenesis in numerous physiological and pathophysiological conditions. The hypoxic induction of VEGF is due in large part to an increase in the stability of its mRNA. We recently demonstrated that the stabilization of VEGF mRNA by hypoxia is dependent upon the RNA-binding protein HuR. This report describes the identification of a 40-bp functional HuR binding site in the VEGF mRNA 3'-untranslated region. This element can confer HuR-mediated stabilization of a heterologous gene in vitro and in vivo. Furthermore, the element is sufficient to confer an increase in the hypoxic induction of a heterologous gene. Deletion of the HuR binding site within this 40-bp element as mapped by RNase T1 and lead footprinting uncouples a stabilizing sequence from a destabilizing sequence, thus providing a novel RNA-protein regulatory model that might be exploited to manipulate VEGF expression and hypoxia-induced angiogenesis.

* This work was supported by National Institutes of Health Grant RO1HL58510 (to H. F., and A. P. L.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 

1. Mignone F, Gissi C, Liuni S, and Pesole G, "Untranslated Regions of mRNAs".

2. Eddy SR, "Non-Coding RNA Genes and the Modern RNA World".

3. Frenster JH, "Activation of DNA Transcription within Repressed Chromatin".

4. Frenster JH, "Ultrastructural Probes of Active DNA Sites, and the RNA Activators of DNA" .