title: Aminoacyl-Transfer RNA Synthetase Deficiency Promotes Angiogenesis via the Unfolded Protein Response Pathway.
abstract: OBJECTIVE
  Understanding the mechanisms regulating normal and pathological angiogenesis is of great scientific and clinical interest. In this report, we show that mutations in 2 different aminoacyl-transfer RNA synthetases, threonyl tRNA synthetase (tars(y58)) or isoleucyl tRNA synthetase (iars(y68)), lead to similar increased branching angiogenesis in developing zebrafish.
  
  
  RESULTS
  The unfolded protein response pathway is activated by aminoacyl-transfer RNA synthetase deficiencies, and we show that unfolded protein response genes atf4, atf6, and xbp1, as well as the key proangiogenic ligand vascular endothelial growth factor (vegfaa), are all upregulated in tars(y58) and iars(y68) mutants. Finally, we show that the protein kinase RNA-like endoplasmic reticulum kinase-activating transcription factor 4 arm of the unfolded protein response pathway is necessary for both the elevated vegfaa levels and increased angiogenesis observed in tars(y58) mutants.
  
  
  CONCLUSIONS
  Our results suggest that endoplasmic reticulum stress acts as a proangiogenic signal via unfolded protein response pathway-dependent upregulation of vegfaa.
authors.affiliation: From the Program in Genomics of Differentiation, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD (D.C., A.E.D., B.D.L., M.F.M., M.R.S., V.N.P., J.T.-V., K.B., K.M.S., M.K., B.M.W.); and Department of Chemistry and Biochemistry, College of Computer, Mathematical, and Natural Sciences, University of Maryland, College Park (P.J.P.).
authors.forename: Daniel
authors.initials: D
authors.lastname: Castranova
authors.affiliation: From the Program in Genomics of Differentiation, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD (D.C., A.E.D., B.D.L., M.F.M., M.R.S., V.N.P., J.T.-V., K.B., K.M.S., M.K., B.M.W.); and Department of Chemistry and Biochemistry, College of Computer, Mathematical, and Natural Sciences, University of Maryland, College Park (P.J.P.).
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Davis
authors.affiliation: From the Program in Genomics of Differentiation, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD (D.C., A.E.D., B.D.L., M.F.M., M.R.S., V.N.P., J.T.-V., K.B., K.M.S., M.K., B.M.W.); and Department of Chemistry and Biochemistry, College of Computer, Mathematical, and Natural Sciences, University of Maryland, College Park (P.J.P.).
authors.forename: Brigid D
authors.initials: BD
authors.lastname: Lo
authors.affiliation: From the Program in Genomics of Differentiation, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD (D.C., A.E.D., B.D.L., M.F.M., M.R.S., V.N.P., J.T.-V., K.B., K.M.S., M.K., B.M.W.); and Department of Chemistry and Biochemistry, College of Computer, Mathematical, and Natural Sciences, University of Maryland, College Park (P.J.P.).
authors.forename: Mayumi F
authors.initials: MF
authors.lastname: Miller
authors.affiliation: From the Program in Genomics of Differentiation, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD (D.C., A.E.D., B.D.L., M.F.M., M.R.S., V.N.P., J.T.-V., K.B., K.M.S., M.K., B.M.W.); and Department of Chemistry and Biochemistry, College of Computer, Mathematical, and Natural Sciences, University of Maryland, College Park (P.J.P.).
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Paukstelis
authors.affiliation: From the Program in Genomics of Differentiation, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD (D.C., A.E.D., B.D.L., M.F.M., M.R.S., V.N.P., J.T.-V., K.B., K.M.S., M.K., B.M.W.); and Department of Chemistry and Biochemistry, College of Computer, Mathematical, and Natural Sciences, University of Maryland, College Park (P.J.P.).
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Swift
authors.affiliation: From the Program in Genomics of Differentiation, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD (D.C., A.E.D., B.D.L., M.F.M., M.R.S., V.N.P., J.T.-V., K.B., K.M.S., M.K., B.M.W.); and Department of Chemistry and Biochemistry, College of Computer, Mathematical, and Natural Sciences, University of Maryland, College Park (P.J.P.).
authors.forename: Van N
authors.initials: VN
authors.lastname: Pham
authors.affiliation: From the Program in Genomics of Differentiation, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD (D.C., A.E.D., B.D.L., M.F.M., M.R.S., V.N.P., J.T.-V., K.B., K.M.S., M.K., B.M.W.); and Department of Chemistry and Biochemistry, College of Computer, Mathematical, and Natural Sciences, University of Maryland, College Park (P.J.P.).
authors.forename: Jesús
authors.initials: J
authors.lastname: Torres-Vázquez
authors.affiliation: From the Program in Genomics of Differentiation, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD (D.C., A.E.D., B.D.L., M.F.M., M.R.S., V.N.P., J.T.-V., K.B., K.M.S., M.K., B.M.W.); and Department of Chemistry and Biochemistry, College of Computer, Mathematical, and Natural Sciences, University of Maryland, College Park (P.J.P.).
authors.forename: Kameha
authors.initials: K
authors.lastname: Bell
authors.affiliation: From the Program in Genomics of Differentiation, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD (D.C., A.E.D., B.D.L., M.F.M., M.R.S., V.N.P., J.T.-V., K.B., K.M.S., M.K., B.M.W.); and Department of Chemistry and Biochemistry, College of Computer, Mathematical, and Natural Sciences, University of Maryland, College Park (P.J.P.).
authors.forename: Kenna M
authors.initials: KM
authors.lastname: Shaw
authors.affiliation: From the Program in Genomics of Differentiation, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD (D.C., A.E.D., B.D.L., M.F.M., M.R.S., V.N.P., J.T.-V., K.B., K.M.S., M.K., B.M.W.); and Department of Chemistry and Biochemistry, College of Computer, Mathematical, and Natural Sciences, University of Maryland, College Park (P.J.P.).
authors.forename: Makoto
authors.initials: M
authors.lastname: Kamei
authors.affiliation: From the Program in Genomics of Differentiation, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD (D.C., A.E.D., B.D.L., M.F.M., M.R.S., V.N.P., J.T.-V., K.B., K.M.S., M.K., B.M.W.); and Department of Chemistry and Biochemistry, College of Computer, Mathematical, and Natural Sciences, University of Maryland, College Park (P.J.P.). bw96w@nih.gov.
authors.forename: Brant M
authors.initials: BM
authors.lastname: Weinstein
mesh_terms: D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism; D051702:Activating Transcription Factor 6 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D030801:Animals, Genetically Modified; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress; D018507:Gene Expression Regulation, Developmental; D005838:Genotype; D007533:Isoleucine-tRNA Ligase / Q000172:deficiency* / Q000235:genetics; D009154:Mutation; D018919:Neovascularization, Physiologic; D010641:Phenotype; D000071701:Regulatory Factor X Transcription Factors; D015398:Signal Transduction; D013914:Threonine-tRNA Ligase / Q000172:deficiency* / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D056811:Unfolded Protein Response; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D000071717:X-Box Binding Protein 1; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000172:deficiency* / Q000235:genetics
chemical_list: D051702:Activating Transcription Factor 6; D004268:DNA-Binding Proteins; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; D029961:Zebrafish Proteins; D051701:Activating Transcription Factor 4; D013914:Threonine-tRNA Ligase; D007533:Isoleucine-tRNA Ligase
keywords: endoplasmic reticulum; pathologic neovascularization; protein kinases; unfolded protein response; vascular endothelial growth factor A; zebrafish
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