title: ELAVL1 regulates alternative splicing of eIF4E transporter to promote postnatal angiogenesis.
abstract: 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.
authors.affiliation: Center for Vascular Biology, Department of Pathology and Laboratory Medicine, and tih2002@med.cornell.edu sch2002@med.cornell.edu.
authors.forename: Sung-Hee
authors.initials: SH
authors.lastname: Chang
authors.affiliation: Institute for Computational Biomedicine, Department of Physiology and Biophysics, Weill Cornell Medical College, Cornell University, New York, NY 10065; and.
authors.forename: Olivier
authors.initials: O
authors.lastname: Elemento
authors.affiliation: Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT 06520.
authors.forename: Jiasheng
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT 06520.
authors.forename: Zhen W
authors.initials: ZW
authors.lastname: Zhuang
authors.affiliation: Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT 06520.
authors.forename: Michael
authors.initials: M
authors.lastname: Simons
authors.affiliation: Center for Vascular Biology, Department of Pathology and Laboratory Medicine, and tih2002@med.cornell.edu sch2002@med.cornell.edu.
authors.forename: Timothy
authors.initials: T
authors.lastname: Hla
mesh_terms: D017398:Alternative Splicing / Q000502:physiology*; D000818:Animals; D051959:ELAV Proteins / Q000502:physiology*; D000067780:ELAV-Like Protein 1; D005091:Exons; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; C098770:ELAVL1 protein, human; D012333:RNA, Messenger
keywords: RNA binding protein; alternative splicing; angiogenesis; eIF4e transporter; tumor angiogenesis