Protein kinase C mediates basic fibroblast growth factor protection of endothelial cells against radiation-induced apoptosis.
Protein kinase C mediates basic fibroblast growth factor protection of endothelial cells against radiation-induced apoptosis.
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发表时间：
1994-05
期刊：
影响因子：
11.2
通讯作者：
A. Haimovitz-Friedman;Naomi Balaban;M. McLoughlin;Desiree Ehleiter;Joseph Michaeli;Israel Vlodavsky;Zvi Fuks
中科院分区：
文献类型：
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作者：
A. Haimovitz-Friedman;Naomi Balaban;M. McLoughlin;Desiree Ehleiter;Joseph Michaeli;Israel Vlodavsky;Zvi Fuks
碱性成纤维细胞生长因子（bFGF）被认为是保护牛主动脉内皮细胞免受电离辐射的致死效应，通过抑制程序性细胞死亡（凋亡）在这些细胞中诱导的辐射暴露。bFGF受体酪氨酸激酶参与此功能的表现为通过bFGF受体酪氨酸激酶的特异性抑制剂tyrphostin AG 213消除bFGF的辐射保护作用。牛主动脉内皮细胞中bFGF受体酪氨酸激酶刺激后的下游信号传导涉及胞质蛋白激酶C（PKC）的α同种型易位到膜中，并在bFGF刺激后30 s内激活。PKC参与bFGF所赋予的辐射防护作用，这一点是通过证明短期（30分钟）暴露于佛波酯，12-O-十四烷酰基佛波醇-13-乙酸酯（TPA; 30 ng/ml）的非特异性PKC活化模拟bFGF的辐射防护作用而提出的。此外，用PKC抑制剂1-（5-异喹啉磺酰基）-2-甲基哌嗪（20 μ M）处理细胞可消除bFGF的辐射防护作用，这与用高剂量TPA（200 nM）过夜预孵育细胞PKC耗尽后观察到的结果相同。琼脂糖凝胶电泳显示，TPA（30 ng/ml; 30分钟）和bFGF（1 ng/ml）抑制辐射暴露（500 cGy）诱导的这些细胞中的DNA的凋亡降解。bFGF和TPA介导的细胞凋亡抑制都可以被PKC抑制剂1-（5-异喹啉磺酰基）-2-甲基哌嗪（20 μ M）逆转。这些数据表明PKC参与了碱性成纤维细胞生长因子对辐射诱导的细胞凋亡的抑制，并将内皮细胞从这种辐射诱导的细胞死亡模式中拯救出来。
Basic fibroblast growth factor (bFGF) was found to protect bovine aortic endothelial cells against the lethal effects of ionizing radiation by inhibiting the programmed cell death (apoptosis) induced in these cells by radiation exposure. The involvement of the bFGF receptor tyrosine kinase in this function was demonstrated by abrogation of the radioprotective effect of bFGF by a specific inhibitor of the bFGF receptor tyrosine kinase, the tyrphostin AG213. The downstream signaling after stimulation of the bFGF receptor tyrosine kinase in bovine aortic endothelial cells involved translocation of the alpha isotype of cytoplasmic protein kinase C (PKC) into the membrane and its activation within 30 s after bFGF stimulation. The involvement of PKC in the radioprotective effect conferred by bFGF was suggested by the demonstration that nonspecific PKC activation by short-term exposure (30 min) to the phorbol ester, 12-O-tetradecanoylphorbol-13-acetate (TPA; 30 ng/ml) mimicked the radioprotective effect of bFGF. Furthermore, treatment of the cells with the PKC inhibitor 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (20 microM) abrogated the radioprotective effect of bFGF, as was observed after the depletion of cellular PKC by overnight preincubation with high-dose TPA (200 nM). Agarose gel electrophoresis of DNA extracted from irradiated bovine aortic endothelial cells showed that both TPA (30 ng/ml; 30 min) and bFGF (1 ng/ml) inhibited the apoptotic degradation of DNA induced in these cells by radiation exposure (500 cGy). Both the bFGF- and the TPA-mediated inhibition of apoptosis could be reversed by the PKC inhibitor 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (20 microM). These data demonstrate the involvement of PKC in the inhibition of radiation-induced apoptosis by bFGF and the rescue of endothelial cells from this mode of radiation-induced cell death.