PUBLICATION

Aminoacyl-Transfer RNA Synthetase Deficiency Promotes Angiogenesis via the Unfolded Protein Response Pathway

Authors
Castranova, D., Davis, A.E., Lo, B.D., Miller, M.F., Paukstelis, P.J., Swift, M.R., Pham, V.N., Torres-Vázquez, J., Bell, K., Shaw, K.M., Kamei, M., Weinstein, B.M.
ID
ZDB-PUB-160130-9
Date
2016
Source
Arteriosclerosis, Thrombosis, and Vascular Biology   36(4): 655-62 (Journal)
Registered Authors
Castranova, Dan, Davis, Andrew, Kamei, Makoto, Lo, Brigid, Miller, Mayumi, Pham, Van, Swift, Matthew Russell, Weinstein, Brant M.
Keywords
endoplasmic reticulum, protein kinases, unfolded protein response, vascular endothelial growth factor A, zebrafish
MeSH Terms
  • Threonine-tRNA Ligase/deficiency*
  • Threonine-tRNA Ligase/genetics
  • Vascular Endothelial Growth Factor A/genetics
  • Vascular Endothelial Growth Factor A/metabolism
  • Endoplasmic Reticulum Stress
  • Zebrafish
  • Animals, Genetically Modified
  • Zebrafish Proteins/deficiency*
  • Zebrafish Proteins/genetics
  • Isoleucine-tRNA Ligase/deficiency*
  • Isoleucine-tRNA Ligase/genetics
  • Mutation
  • Transcription Factors/genetics
  • Transcription Factors/metabolism
  • Unfolded Protein Response*
  • Gene Expression Regulation, Developmental
  • Activating Transcription Factor 4/genetics
  • Activating Transcription Factor 4/metabolism
  • X-Box Binding Protein 1
  • Signal Transduction
  • Activating Transcription Factor 6/genetics
  • Activating Transcription Factor 6/metabolism
  • Neovascularization, Physiologic*
  • DNA-Binding Proteins/genetics
  • DNA-Binding Proteins/metabolism
  • Phenotype
  • Endoplasmic Reticulum/metabolism
  • Regulatory Factor X Transcription Factors
  • Animals
  • Genotype
(all 30)
PubMed
26821951 Full text @ Arterio., Thromb., and Vas. Bio.
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.
Approach and 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.
Genes / Markers
Figures
No images available
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Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Target Reagent Reagent Type
atf4aMO1-atf4aMRPHLNO
iars1MO1-iars1MRPHLNO
tars1MO2-tars1MRPHLNO
1 - 3 of 3
Show
Fish
Antibodies
Orthology
Engineered Foreign Genes
Marker Marker Type Name
EGFPEFGEGFP
GFPEFGGFP
1 - 2 of 2
Show
Mapping
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Citation
Castranova, D., Davis, A.E., Lo, B.D., Miller, M.F., Paukstelis, P.J., Swift, M.R., Pham, V.N., Torres-Vázquez, J., Bell, K., Shaw, K.M., Kamei, M., Weinstein, B.M. (2016) Aminoacyl-Transfer RNA Synthetase Deficiency Promotes Angiogenesis via the Unfolded Protein Response Pathway. Arteriosclerosis, Thrombosis, and Vascular Biology. 36(4):655-62.