Signaling mechanism of protease activated receptor 1-induced proliferation of astrocytes: Stabilization of hypoxia inducible factor-1α triggers glucose metabolism and accumulation of cyclin D1 |
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| Institution: | 1. IHU Liryc, Electrophysiology and Heart Modeling Institute, fondation Bordeaux Université, F-33600 Pessac-Bordeaux, France;2. Bordeaux University Hospital (CHU), Cardio-Thoracic Unit, F-33600 Pessac, France;3. Maastricht University Medical Center, Cardiovascular Research Institute Maastricht, Maastricht, the Netherlands;1. U1022 INSERM, UMR8258 CNRS, Unité de Technologies Chimiques et Biologiques pour la Santé, Chimie ParisTech, Faculté de Pharmacie, 4 Avenue de l''Observatoire, 75006 Paris, France;2. V-SAT, UMR7199 CNRS, Université de Strasbourg, Faculté de Pharmacie, 67401 Illkirch Cedex, France;3. UPR4301 CNRS, rue Charles Sadron, 45071 Orléans Cedex 02, France;1. Department of Anatomy, National University of Singapore, Singapore 119260;2. Division of Neurology, National Neuroscience Institute, Singapore General Hospital Campus, Singapore 169608;3. Department of Neurosurgery, Cedars-Sinai Medical Center, Advanced Health Sciences Pavilion, Los Angeles, CA 90048, USA;4. Neurobiology and Ageing Research Programme, National University of Singapore, Singapore 119260;1. Department of Clinical Neurosciences, John van Geest Centre for Brain Repair, University of Cambridge, Cambridge CB2 0PY, UK;2. School of Clinical Medicine, University of Cambridge, Addenbrooke''s Hospital, Cambridge CB2 0SP, UK;3. Neuroscience Research Institute, Gachon University, Incheon 405-760, Republic of Korea;4. Department of Neurology, Addenbrooke''s Hospital, Cambridge CB2 0QQ, UK |
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| Abstract: | Thrombin was found to stimulate astrocytes proliferation. In this study, we want to clarify whether thrombin-activated protease-activated receptor will affect the glucose metabolism signaling pathways to accelerate the proliferation of astrocytes. In addition, we study if thrombin has effects on cell cycle transition to promote astrocytes proliferation. We firstly observed that thrombin activated protease-activated receptor 1 (PAR-1) inducing the increases of intracellular Ca2+ and ROS production, which contribute to the astrocytes' proliferation. We further confirmed that ROS stabilized HIF-1α, the latter subsequently accelerated glucose uptake in astrocytes. On the other hand, we demonstrated that thrombin triggered PI3K/Akt/cyclin D1 signal transduction, which may promote the cell cycle transition to enhance astrocytes proliferation. As a result, we discovered three signaling pathways mainly accounting for cell proliferation induced by thrombin: (1) thrombin-stimulated ERK, JNK/ROS/HIF-1α and (2) PI3K/Akt/ROS/HIF-1α pathways to increase expression of hexokinase 2 which mediated glucose metabolism in astrocytes, and (3) thrombin stimulates PAR-1/PI3K/Akt/cyclin D1 to promote the cell cycle transition and finally to increase cell proliferation. |
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