Hypoxic Stabilization of Vascular Endothelial Growth Factor mRNA by the RNA-binding Protein HuR*
- From the ‡Cardiology Division, Georgetown University Medical Center, Washington, D. C. 20007 and the §Program in Molecular Pharmacology and Therapeutics, Memorial Sloan Kettering Cancer Center, New York, New York 10021
Abstract
Vascular endothelial growth factor (VEGF) is a potent angiogenic factor whose expression is dramatically induced by hypoxia due in large part to an increase in the stability of its mRNA. Here we show that HuR binds with high affinity and specificity to the element that regulates VEGF mRNA stability by hypoxia. Inhibition of HuR expression abrogates the hypoxia-mediated increase in VEGF mRNA stability. Overexpression of HuR increases the stability of VEGF mRNA. However, this only occurs efficiently in hypoxic cells. We further show that the stabilization of VEGF mRNA can be recapitulated in vitro. Using an S-100 extract, we show that the addition of recombinant HuR stabilizes VEGF mRNA markedly. These data support the critical role of HuR in mediating the hypoxic stabilization of VEGF mRNA by hypoxia.
Footnotes
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↵* This work was supported by Grants NS29682 (to H. F.) and 1K08HL03405-02 (to A. P. L.) from the National Institutes of Health, a grant from the Byrne fund (to H. F.), Core Grant P30-CA08748 from the NCI, National Institutes of Health, and a grant-in-aid from the American Heart Association (to 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.
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↵¶ Present address: Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, P. O. Box 9649, Haifa, Israel 31096. To whom correspondence should be sent. Tel.: 972-4-829-5202; Fax: 972-4-852-0089; E-mail: alevy{at}tx.technion.ac.il.
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↵1 The abbreviations used are: VEGF, vascular endothelial growth factor; UTR, untranslated region; AU, adenylate-uridylate; VRS, VEGF regulatory segment; GST, glutathioneS-transferase; HIF, hypoxia-inducible factor.
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↵2 G. B. Aranda-Abreu, S. Chung, H. Furneaux, and I. Ginzburg, submitted for publication.
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- Received May 7, 1997.
- Revision received December 6, 1997.
- The American Society for Biochemistry and Molecular Biology, Inc.
