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Proc Natl Acad Sci U S A. 2014 Dec 23;111(51):18309-14. doi: 10.1073/pnas.1412172111. Epub 2014 Nov 24.

ELAVL1 regulates alternative splicing of eIF4E transporter to promote postnatal angiogenesis.

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Center for Vascular Biology, Department of Pathology and Laboratory Medicine, and
Institute for Computational Biomedicine, Department of Physiology and Biophysics, Weill Cornell Medical College, Cornell University, New York, NY 10065; and.
Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT 06520.


Posttranscriptional RNA regulation is important in determining the plasticity of cellular phenotypes. However, mechanisms of how RNA binding proteins (RBPs) influence cellular behavior are poorly understood. We show here that the RBP embryonic lethal abnormal vision like 1 (ELAVL1, also know as HuR) regulates the alternative splicing of eukaryotic translation initiation factor 4E nuclear import factor 1 (Eif4enif1), which encodes an eukaryotic translation initiation factor 4E transporter (4E-T) protein and suppresses the expression of capped mRNAs. In the absence of ELAVL1, skipping of exon 11 of Eif4enif1 forms the stable, short isoform, 4E-Ts. This alternative splicing event results in the formation of RNA processing bodies (PBs), enhanced turnover of angiogenic mRNAs, and suppressed sprouting behavior of vascular endothelial cells. Further, endothelial-specific Elavl1 knockout mice exhibited reduced revascularization after hind limb ischemia and tumor angiogenesis in oncogene-induced mammary cancer, resulting in attenuated blood flow and tumor growth, respectively. ELAVL1-regulated alternative splicing of Eif4enif1 leading to enhanced formation of PB and mRNA turnover constitutes a novel posttranscriptional mechanism critical for pathological angiogenesis.


RNA binding protein; alternative splicing; angiogenesis; eIF4e transporter; tumor angiogenesis

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