We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
Phosphorylation of seryl-tRNA synthetase by ATM/ATR is essential for hypoxia-induced angiogenesis.
- Authors
Shi, Yi; Liu, Ze; Zhang, Qian; Vallee, Ingrid; Mo, Zhongying; Kishi, Shuji; Yang, Xiang-Lei
- Abstract
Hypoxia-induced angiogenesis maintains tissue oxygen supply and protects against ischemia but also enhances tumor progression and malignancy. This is mediated through activation of transcription factors like hypoxia-inducible factor 1 (HIF-1) and c-Myc, yet the impact of hypoxia on negative regulators of angiogenesis is unknown. During vascular development, seryl-tRNA synthetase (SerRS) regulates angiogenesis through a novel mechanism by counteracting c-Myc and transcriptionally repressing vascular endothelial growth factor A (VEGFA) expression. Here, we reveal that the transcriptional repressor role of SerRS is inactivated under hypoxia through phosphorylation by ataxia telangiectasia mutated (ATM) and ataxia telangiectasia mutated and RAD3-related (ATR) at Ser101 and Ser241 to attenuate its DNA binding capacity. In zebrafish, SerRSS101D/S241D, a phosphorylation-mimicry mutant, cannot suppress VEGFA expression to support normal vascular development. Moreover, expression of SerRSS101A/S241A, a phosphorylation-deficient and constitutively active mutant, prevents hypoxia-induced binding of c-Myc and HIF-1 to the VEGFA promoter, and activation of VEGFA expression. Consistently, SerRSS101A/S241A strongly inhibits normal and tumor-derived angiogenesis in mice. Therefore, we reveal a key step regulating hypoxic angiogenesis and highlight the importance of nuclear SerRS in post-developmental angiogenesis regulation in addition to vascular development. The role of nuclear SerRS in inhibiting both c-Myc and HIF-1 may provide therapeutic opportunities to correct dysregulation of angiogenesis in pathological settings.
- Subjects
VASCULAR endothelial growth factors; NEOVASCULARIZATION; ATAXIA telangiectasia; HYPOXIA-inducible factor 1
- Publication
PLoS Biology, 2020, Vol 18, Issue 12, p1
- ISSN
1544-9173
- Publication type
Article
- DOI
10.1371/journal.pbio.3000991