Platelet-derived growth factor-mediated signal transduction underlying astrocyte proliferation: Site of ethanol action
Platelet-derived growth factor-mediated signal transduction underlying astrocyte proliferation: Site of ethanol action
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DOI：
10.1523/jneurosci.19-22-10014.1999
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发表时间：
1999-11-15
影响因子：
5.3
通讯作者：
Miller, MW
中科院分区：
文献类型：
--
作者：
Luo, J;Miller, MW
血小板衍生生长因子（PDGF）是细胞增殖的关键调节因子。由于乙醇抑制细胞增殖在体内和体外，我们假设，乙醇诱导的抑制结果从差异干扰与PDGF激活的信号转导通路。培养的皮质星形胶质细胞用于检查乙醇对PDGF介导的信号转导、对两个PDGF单体（A链和B链）的表达以及对两个PDGF受体亚基（PDGF α r和PDGF β r）的表达的影响。PDGF-B链同源二聚体（PDGF-BB）和较小程度的PDGF-A链同源二聚体（PDGF-AA）刺激无血清培养基中培养的星形胶质细胞增殖。乙醇以浓度依赖性方式减弱这些作用。乙醇抑制PDGF-AA-和PDGF-BB-介导的PDGF α r磷酸化，但对PDGF β r自身磷酸化几乎没有影响。同样地，乙醇可阻断PDGF α r与Ras GTP酶激活蛋白（Ras GAP）的结合，但不影响Ras GAP与PDGF β r的结合。PDGF以蛋白激酶C（PKC）非依赖和依赖的方式刺激丝裂原活化蛋白激酶（MAPK）活性。乙醇抑制PKC非依赖性的MAPK急性激活，但刺激PKC依赖性的MAPK持续激活。乙醇处理3d后，两种配体的表达均未发生改变。此外，这种治疗以浓度依赖性方式特异性上调PDGF α r表达。然而，它并不影响任一受体的结合亲和力。因此，由PDGF-AA和PDGF-BB启动的信号转导途径受到乙醇的不同影响。这种差异的脆弱性是由于乙醇对PDGF α r自磷酸化的优先作用。因此，乙醇诱导的改变通过促有丝分裂生长因子的特异性受体转导。
Platelet-derived growth factor (PDGF) is a critical regulator of cell proliferation. Because ethanol inhibits cell proliferation in vivo and in vitro, we hypothesize that ethanol-induced inhibition results from differential interference with signal transduction pathways activated by PDGF. Cultured cortical astrocytes were used to examine the effects of ethanol on PDGF-mediated signal transduction, on the expression of two PDGF monomers (A- and B-chains), and on the expression of two PDGF receptor subunits (PDGF alpha r and PDGF beta r). PDGF-B chain homodimer (PDGF-BB), and to a lesser extent PDGF-A chain homodimer (PDGF-AA), stimulated the proliferation of astrocytes raised in a serum-free medium. Ethanol attenuated these actions in a concentration-dependent manner. Ethanol inhibited both PDGF-AA- and PDGF-BB- mediated phosphorylation of PDGF alpha r, but it had little effect on PDGF beta r autophosphorylation. Likewise, ethanol abolished the association of PDGF alpha r to Ras GTPase-activating protein (Ras-GAP), but it did not affect the binding of Ras-GAP to PDGF beta r. PDGF stimulated the activities of mitogen-activated protein kinase (MAPK) in protein kinase C (PKC) independent and dependent manners. Ethanol inhibited the PKC-independent, acute activation of MAPK; however, it stimulated the PKC-dependent, sustained activation of MAPK. The expression of neither ligand was altered by exposure to ethanol for 3 d. Moreover, such treatment specifically upregulated PDGF alpha r expression in a concentration-dependent manner. It did not, however, affect the binding affinity of either receptor. Thus, the signal transduction pathways initiated by PDGF-AA and PDGF-BB were differentially affected by ethanol. This differential vulnerability resulted from the preferential effects of ethanol on PDGF alpha r autophosphorylation. Hence, ethanol-induced alterations are transduced through specific receptors of mitogenic growth factors.