Cell cycle regulation of astrocytes by extracellular nucleotides and fibroblast growth factor-2 |
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Authors: | Email author" target="_blank">Joseph?T?NearyEmail author Yuan?Kang You-Fang?Shi |
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Institution: | (1) Research Service, Miami VA Medical Center, Departments of Pathology and Biochemistry & Molecular Biology, and Neuroscience Program, University of Miami School of Medicine, Miami, Florida, USA;(2) Research Service 151, VA Medical Center, 1201 NW 16th Street, Miami, FL 33215, USA |
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Abstract: | Extracellular ATP enhances the mitogenic activity of fibroblast growth factor-2 (FGF2) in astrocytes, but the molecular mechanism
underlying this synergistic interaction is not known. To determine whether the potentiating effect of extracellular ATP involves
cell cycle control mechanisms, we have measured the expression of cyclins that are induced in different phases of the cell
cycle in primary cultures of rat cortical astrocytes. We found that ATP potentiated the ability of FGF2 to stimulate expression
of cyclin D1, a regulator of cell cycle entry, as well as cyclin A, a regulator of DNA replication. Because FGF2 and P2 purinergic
receptors are coupled to extracellular signal regulated protein kinase (ERK), a key member of a signaling cascade that regulates
proliferation, we also investigated the role of ERK in regulating cyclin expression induced by FGF2 and ATP. We found that
the potentiating effect of ATP on cyclin expression was significantly reduced by U0126, an inhibitor of MEK, the upstream
activator of ERK. P2 receptor agonist studies revealed that UTP enhanced FGF2-induced cyclin expression and mitogenesis whereas
2-methylthioADP was ineffective. By contrast, 2′,3′-O-(4-benzoyl)-benzoyl-ATP markedly inhibited FGF2-induced mitogenesis. Consistent with opposing effects of P2Y and P2X receptors
on mitogenesis, UTP stimulated a transient activation of ERK whereas BzATP stimulated a more sustained ERK signal. These findings
suggest that signaling by P2Y receptors, most likely of the purine/pyrimidine subtype, enhance the ability of FGF2 to stimulate
entry into a new cell cycle, as well as DNA replication, by an ERK-dependent mechanism, whereas signaling by P2X receptors,
possibly the P2X7 subtype, inhibits FGF2-induced mitogenesis in astrocytes. Interactions between P2Y, P2X and polypeptide
growth factor signaling pathways may have important implications for CNS development as well as injury and repair. |
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Keywords: | astrocytes cell cycle CNS injury ERK extracellular ATP gliosis P2 purinergic receptors proliferation |
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