Phosphorylation of seryl-tRNA synthetase by ATM/ATR is essential for hypoxia-induced angiogenesis
| العنوان: | Phosphorylation of seryl-tRNA synthetase by ATM/ATR is essential for hypoxia-induced angiogenesis |
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| المؤلفون: | Ingrid Vallee, Yi Shi, Qian Zhang, Zhongying Mo, Xiang-Lei Yang, Shuji Kishi, Ze Liu |
| المصدر: | PLoS Biology, Vol 18, Iss 12, p e3000991 (2020) PLoS Biology |
| بيانات النشر: | Public Library of Science (PLoS), 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | Vascular Endothelial Growth Factor A, 0301 basic medicine, Pulmonology, Physiology, Angiogenesis, Ataxia Telangiectasia Mutated Proteins, Cardiovascular Physiology, Biochemistry, Animals, Genetically Modified, Neovascularization, Mice, 0302 clinical medicine, Breast Tumors, Medicine and Health Sciences, Phosphorylation, Post-Translational Modification, Biology (General), Hypoxia, Zebrafish, Statistical Data, Neovascularization, Pathologic, General Neuroscience, Statistics, Precipitation Techniques, Cell biology, Vascular endothelial growth factor A, Oncology, 030220 oncology & carcinogenesis, Physical Sciences, Female, medicine.symptom, General Agricultural and Biological Sciences, Angiogenesis Inducing Agents, Research Article, Serine-tRNA Ligase, QH301-705.5, Mice, Nude, Biology, Transfection, Research and Analysis Methods, General Biochemistry, Genetics and Molecular Biology, Cell Line, Ataxia Telangiectasia, 03 medical and health sciences, Medical Hypoxia, Breast Cancer, medicine, Animals, Humans, Immunoprecipitation, Molecular Biology Techniques, Molecular Biology, Transcription factor, General Immunology and Microbiology, HEK 293 cells, Biology and Life Sciences, Proteins, Cancers and Neoplasms, Cell Biology, Zebrafish Proteins, Hypoxia-Inducible Factor 1, alpha Subunit, Xenograft Model Antitumor Assays, HEK293 Cells, 030104 developmental biology, Tumor progression, Mathematics, Transcription Factors, Developmental Biology |
| الوصف: | 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. |
| تدمد: | 1545-7885 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::58595ff695f73e1c43c01ebebb54d41dTest https://doi.org/10.1371/journal.pbio.3000991Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....58595ff695f73e1c43c01ebebb54d41d |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15457885 |
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