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Molecular and Cellular Biology, January 2008, p. 772-783, Vol. 28, No. 2
0270-7306/08/$08.00+0     doi:10.1128/MCB.02078-06
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Double-Stranded RNA-Binding Protein Regulates Vascular Endothelial Growth Factor mRNA Stability, Translation, and Breast Cancer Angiogenesis{triangledown}

Frank Vumbaca, Kathryn N. Phoenix, Daniel Rodriguez-Pinto,{dagger} David K. Han, and Kevin P. Claffey*

Center for Vascular Biology, University of Connecticut Health Center, Farmington, Connecticut 06030-3501

Received 7 November 2006/ Returned for modification 4 December 2006/ Accepted 1 November 2007

Vascular endothelial growth factor (VEGF) is a key angiogenic factor expressed under restricted nutrient and oxygen conditions in most solid tumors. The expression of VEGF under hypoxic conditions requires transcription through activated hypoxia-inducible factor 1 (HIF-1), increased mRNA stability, and facilitated translation. This study identified double-stranded RNA-binding protein 76/NF90 (DRBP76/NF90), a specific isoform of the DRBP family, as a VEGF mRNA-binding protein which plays a key role in VEGF mRNA stability and protein synthesis under hypoxia. The DRBP76/NF90 protein binds to a human VEGF 3' untranslated mRNA stability element. RNA interference targeting the DRBP76/NF90 isoform limited hypoxia-inducible VEGF mRNA and protein expression with no change in HIF-1-dependent transcriptional activity. Stable repression of DRBP76/NF90 in MDA-MB-435 breast cancer cells demonstrated reduced polysome-associated VEGF mRNA levels under hypoxic conditions and reduced mRNA stability. Transient overexpression of the DRBP76/NF90 protein increased both VEGF mRNA and protein levels synthesized under normoxic and hypoxic conditions. Cells with stable repression of the DRBP76/NF90 isoform showed reduced tumorigenic and angiogenic potential in an orthotopic breast tumor model. These data demonstrate that the DRBP76/NF90 isoform facilitates VEGF expression by promoting VEGF mRNA loading onto polysomes and translation under hypoxic conditions, thus promoting breast cancer growth and angiogenesis in vivo.

* Corresponding author. Mailing address: Center for Vascular Biology, EM028, University of Connecticut Health Center, 263 Farmington Ave., Farmington, CT 06030-3501. Phone: (860) 679-8713. Fax: (860) 679-1201. E-mail: claffey{at}nso2.uchc.edu

{triangledown} Published ahead of print on 26 November 2007.

{dagger} Present address: The Feinstein Institute for Medical Research, Autoimmune Disease Center, 350 Community Drive, Manhasset, NY 11030.

Molecular and Cellular Biology, January 2008, p. 772-783, Vol. 28, No. 2
0270-7306/08/$08.00+0     doi:10.1128/MCB.02078-06
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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