Kinome Sirna Screen Identifies SMG-1 as a Negative Regulator of Hypoxia-inducible Factor-1α in Hypoxia*
| العنوان: | Kinome Sirna Screen Identifies SMG-1 as a Negative Regulator of Hypoxia-inducible Factor-1α in Hypoxia* |
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| المؤلفون: | Jiing Dwan Lee, Colleen Fearns, Run-qiang Chen, Vasco A. Oliveira, William S. Dalton, Yan-ling Chen, Qingkai Yang |
| المصدر: | The Journal of Biological Chemistry |
| بيانات النشر: | American Society for Biochemistry and Molecular Biology, 2009. |
| سنة النشر: | 2009 |
| مصطلحات موضوعية: | MAPK/ERK pathway, Vascular Endothelial Growth Factor A, Proteome, MAP Kinase Signaling System, Protein Array Analysis, Biology, Protein Serine-Threonine Kinases, Biochemistry, 03 medical and health sciences, Phosphatidylinositol 3-Kinases, 0302 clinical medicine, Molecular Basis of Cell and Developmental Biology, stomatognathic system, Epidermal growth factor, Antigens, Neoplasm, Cell Movement, Cell Line, Tumor, medicine, Humans, Kinase activity, RNA, Small Interfering, Carbonic Anhydrase IX, Molecular Biology, PI3K/AKT/mTOR pathway, 030304 developmental biology, Carbonic Anhydrases, Gene Library, Phosphoinositide-3 Kinase Inhibitors, 0303 health sciences, Kinase, Cell Biology, Hypoxia (medical), Hypoxia-Inducible Factor 1, alpha Subunit, Cell Hypoxia, Cell biology, Vascular endothelial growth factor A, Hypoxia-inducible factors, 030220 oncology & carcinogenesis, medicine.symptom, HeLa Cells |
| الوصف: | Hypoxia-inducible factor-1 (HIF-1) plays a central role in tumor progression by regulating genes involved in proliferation, glycolysis, angiogenesis, and metastasis. To improve our understanding of HIF-1 regulation by kinome, we screened a kinase-specific small interference RNA library using a hypoxia-response element (HRE) luciferase reporter assay under hypoxic conditions. This screen determined that depletion of cellular SMG-1 kinase most significantly modified cellular HIF-1 activity in hypoxia. SMG-1 is the newest and least studied member of the phosphoinositide 3-kinase-related kinase family, which consists of ATM, ATR, DNA-PKcs, mTOR, and SMG-1. We individually depleted members of the phosphoinositide 3-kinase-related kinase family, and only SMG-1 deficiency significantly augmented HIF-1 activity in hypoxia. We subsequently discovered that SMG-1 kinase activity was activated by hypoxia, and depletion of SMG-1 up-regulated MAPK activity under low oxygen. Suppressing cellular MAPK by silencing ERK1/2 or by treatment with U0126, a MAPK inhibitor, partially blocked the escalation of HIF-1 activity resulting from SMG-1 deficiency in hypoxic cells. Increased expression of SMG-1 but not kinase-dead SMG-1 effectively inhibited the activity of HIF-1alpha. In addition, cellular SMG-1 deficiency increased secretion of the HIF-1alpha-regulated angiogenic factor, vascular epidermal growth factor, and survival factor, carbonic anhydrase IX (CA9), as well as promoted the hypoxic cell motility. Taken together, we discovered that SMG-1 negatively regulated HIF-1alpha activity in hypoxia, in part through blocking MAPK activation. |
| اللغة: | English |
| تدمد: | 1083-351X 0021-9258 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::b7ca104c37947d7c909f4f2341b963ad http://europepmc.org/articles/PMC2719310 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....b7ca104c37947d7c909f4f2341b963ad |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 1083351X 00219258 |
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