PUBLICATION
tRNA synthetase counteracts c-Myc to develop functional vasculature
- Authors
- Shi, Y., Xu, X., Zhang, Q., Fu, G., Mo, Z., Wang, G.S., Kishi, S., Yang, X.L.
- ID
- ZDB-PUB-170214-321
- Date
- 2014
- Source
- eLIFE 3: e02349 (Journal)
- Registered Authors
- Kishi, Shuji
- Keywords
- SIRT2, VEGFA, angiogenesis, c-Myc, seryl-tRNA synthetase, vasculature
- MeSH Terms
-
- HEK293 Cells
- Humans
- Protein Conformation
- Promoter Regions, Genetic
- Amino Acid Sequence
- Molecular Sequence Data
- Animals
- Proto-Oncogene Proteins c-myc/genetics*
- Proto-Oncogene Proteins c-myc/metabolism
- Human Umbilical Vein Endothelial Cells/drug effects
- Human Umbilical Vein Endothelial Cells/metabolism
- Epigenesis, Genetic
- Male
- Female
- Cell Line
- Zebrafish
- Vascular Endothelial Growth Factor A/antagonists & inhibitors
- Vascular Endothelial Growth Factor A/genetics
- Vascular Endothelial Growth Factor A/metabolism
- Angiogenesis Inducing Agents/pharmacology
- Gene Silencing
- Sirtuin 2/genetics
- Sirtuin 2/pharmacology
- Serine-tRNA Ligase/genetics*
- Serine-tRNA Ligase/pharmacology
- RNA, Small Interfering/genetics
- RNA, Small Interfering/metabolism
- PubMed
- 24940000 Full text @ Elife
Citation
Shi, Y., Xu, X., Zhang, Q., Fu, G., Mo, Z., Wang, G.S., Kishi, S., Yang, X.L. (2014) tRNA synthetase counteracts c-Myc to develop functional vasculature. eLIFE. 3:e02349.
Abstract
Recent studies suggested an essential role for seryl-tRNA synthetase (SerRS) in vascular development. This role is specific to SerRS among all tRNA synthetases and is independent of its well-known aminoacylation function in protein synthesis. A unique nucleus-directing domain, added at the invertebrate-to-vertebrate transition, confers this novel non-translational activity of SerRS. Previous studies showed that SerRS, in some unknown way, controls VEGFA expression to prevent vascular over-expansion. Using in vitro, cell and animal experiments, we show here that SerRS intervenes by antagonizing c-Myc, the major transcription factor promoting VEGFA expression, through a tandem mechanism. First, by direct head-to-head competition, nuclear-localized SerRS blocks c-Myc from binding to the VEGFA promoter. Second, DNA-bound SerRS recruits the SIRT2 histone deacetylase to erase prior c-Myc-promoted histone acetylation. Thus, vertebrate SerRS and c-Myc is a pair of 'Yin-Yang' transcriptional regulator for proper development of a functional vasculature. Our results also discover an anti-angiogenic activity for SIRT2.DOI: http://dx.doi.org/10.7554/eLife.02349.001.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping