Cell cycle regulation of astrocytes by extracellular nucleotides and fibroblast growth factor-2.
Cell cycle regulation of astrocytes by extracellular nucleotides and fibroblast growth factor-2.
复制标题
细胞周期通过细胞外核苷酸和成纤维细胞生长因子2调节星形胶质细胞。
DOI：
10.1007/s11302-005-8075-y
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发表时间：
2005-12
影响因子：
3.5
通讯作者：
Shi, You-Fang
中科院分区：
文献类型：
--
作者：
Neary, Joseph T;Kang, Yuan;Shi, You-Fang
细胞外ATP增强星形胶质细胞中成纤维细胞生长因子-2（FGF 2）的促有丝分裂活性，但这种协同作用的分子机制尚不清楚。为了确定细胞外ATP的增强作用是否涉及细胞周期控制机制，我们测量了在大鼠皮质星形胶质细胞的原代培养物中细胞周期的不同阶段诱导的细胞周期蛋白的表达。我们发现，ATP增强了FGF 2刺激细胞周期蛋白D1（细胞周期进入的调节因子）和细胞周期蛋白A（DNA复制的调节因子）表达的能力。由于FGF 2和P2嘌呤能受体与细胞外信号调节蛋白激酶（ERK）偶联，ERK是调节增殖的信号级联的关键成员，因此我们还研究了ERK在调节FGF 2和ATP诱导的细胞周期蛋白表达中的作用。我们发现ATP对细胞周期蛋白表达的增强作用被ERK上游激活剂MEK的抑制剂U 0126显著降低。P2受体激动剂研究表明，UTP增强FGF 2诱导的细胞周期蛋白表达和有丝分裂，而2-methylthioADP是无效的。相反，2-3-O-（4-苯甲酰基）-苯甲酰基-ATP显著抑制FGF 2诱导的有丝分裂。与P2 Y和P2 X受体对有丝分裂的相反作用一致，UTP刺激了ERK的短暂激活，而BzATP刺激了更持续的ERK信号。这些发现表明，P2 Y受体的信号传导，最有可能的嘌呤/嘧啶亚型，增强FGF 2的能力，刺激进入一个新的细胞周期，以及DNA复制，通过ERK依赖性机制，而P2 X受体的信号传导，可能P2 X7亚型，抑制FGF 2诱导的星形胶质细胞有丝分裂。P2 Y，P2 X和多肽生长因子信号通路之间的相互作用可能对CNS发育以及损伤和修复具有重要意义。
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.