title: 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.
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 Ca(2+) 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.
authors.affiliation: Institut für Neurobiochemie, Medizinische Fakultät, Otto-von-Guericke-Universität Magdeburg, Leipziger Straße 44, Magdeburg 39120, Germany.
authors.forename: Zhihui
authors.initials: Z
authors.lastname: Zhu
authors.affiliation: Institut für Neurobiochemie, Medizinische Fakultät, Otto-von-Guericke-Universität Magdeburg, Leipziger Straße 44, Magdeburg 39120, Germany. Electronic address: georg.reiser@med.ovgu.de.
authors.forename: Georg
authors.initials: G
authors.lastname: Reiser
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D019938:Cyclin D1 / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000187:drug effects*; D061251:Primary Cell Culture; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D044463:Receptor, PAR-1 / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects*; D013917:Thrombin / Q000494:pharmacology*
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017382:Reactive Oxygen Species; D044463:Receptor, PAR-1; D019938:Cyclin D1; D013917:Thrombin; D005947:Glucose; D002118:Calcium
keywords: Astrocytes; Glucose uptake; HIF-1α; Proliferation; ROS; Thrombin