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

TitleELAVL1 regulates alternative splicing of eIF4E transporter to promote postnatal angiogenesis.
Publication TypeJournal Article
Year of Publication2014
AuthorsChang S-H, Elemento O, Zhang J, Zhuang ZW, Simons M, Hla T
JournalProc Natl Acad Sci U S A
Volume111
Issue51
Pagination18309-14
Date Published2014 Dec 23
ISSN1091-6490
KeywordsAlternative Splicing, Animals, ELAV Proteins, ELAV-Like Protein 1, Exons, Mice, Mice, Inbred C57BL, Mice, Knockout, Neovascularization, Physiologic, RNA, Messenger
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.

DOI10.1073/pnas.1412172111
Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID25422430
PubMed Central IDPMC4280608
Grant ListHL49094 / HL / NHLBI NIH HHS / United States
R01 HL049094 / HL / NHLBI NIH HHS / United States
U54 HL117798 / HL / NHLBI NIH HHS / United States
P01 CA077839 / CA / NCI NIH HHS / United States
HL117798 / HL / NHLBI NIH HHS / United States
CA77839 / CA / NCI NIH HHS / United States