Williamson Andrew J K, Dibling Benjamin C, Boyne James R, Selby Peter, Burchill Susan A
Candlelighter's Children's Cancer Research Laboratory, Cancer Research UK Clinical Centre, St. James's University Hospital, Leeds LS9 7TF, United Kingdom.
J Biol Chem. 2004 Nov 12;279(46):47912-28. doi: 10.1074/jbc.M409035200. Epub 2004 Aug 13.
Basic fibroblast growth factor (bFGF) induces cell death in cells of the Ewing's sarcoma family of tumors in vivo and in vitro. In this study we demonstrate that this is dependent on the rapid and sustained activation of p38(MAPK), in contrast to the transient activation of p38(MAPK) associated with bFGF-induced cell proliferation. Stem cell factor-induced survival of TC-32 cells was also associated with transient activation of p38(MAPK). Inhibition of p38(MAPK) by SB202190 and p38(MAPK) small interfering RNA reduces bFGF-induced death in TC-32 cells, consistent with the hypothesis that activation of p38(MAPK) is essential for induction of death by bFGF. This appears to be dependent on sustained activation of p38(MAPK), demonstrated by inhibition of bFGF-induced cell death following addition of SB202190 to TC-32 cells 5 min after exposure to bFGF (20 ng/ml) and activation of p38(MAPK). Prolonged activation of p38(MAPK) is accompanied by a rapid and sustained phosphorylation of Ras and ERK; inhibition of ERK phosphorylation using the MEK-1 inhibitor PD98059 rescued approximately 30% of cells from bFGF-induced death suggesting ERK plays a secondary role in the induction of death. This hypothesis is supported by observations in the A673 cell line; bFGF induced sustained activation of ERK and transient activation of p38(MAPK), which was not associated with cell death. These data demonstrate that sustained activation of p38(MAPK) is essential for activation of the death cascade following exposure of Ewing's sarcoma family of tumors cells to bFGF and provide evidence that activation of p38(MAPK) results in an up-regulation of the death receptor p75(NTR).
碱性成纤维细胞生长因子（bFGF）在体内和体外均可诱导尤因肉瘤家族肿瘤细胞死亡。在本研究中，我们证明这依赖于p38（丝裂原活化蛋白激酶）的快速持续激活，这与bFGF诱导细胞增殖时p38（丝裂原活化蛋白激酶）的短暂激活形成对比。干细胞因子诱导的TC-32细胞存活也与p38（丝裂原活化蛋白激酶）的短暂激活相关。SB202190和p38（丝裂原活化蛋白激酶）小干扰RNA对p38（丝裂原活化蛋白激酶）的抑制作用可降低bFGF诱导的TC-32细胞死亡，这与p38（丝裂原活化蛋白激酶）的激活对于bFGF诱导死亡至关重要的假说一致。这似乎依赖于p38（丝裂原活化蛋白激酶）的持续激活，在将SB202190添加到暴露于bFGF（20 ng/ml）5分钟后的TC-32细胞中，并激活p38（丝裂原活化蛋白激酶）后，bFGF诱导的细胞死亡受到抑制，这证明了这一点。p38（丝裂原活化蛋白激酶）的长期激活伴随着Ras和ERK的快速持续磷酸化；使用MEK-1抑制剂PD98059抑制ERK磷酸化可使约30%的细胞从bFGF诱导的死亡中获救，这表明ERK在死亡诱导中起次要作用。A673细胞系中的观察结果支持了这一假说；bFGF诱导ERK的持续激活和p38（丝裂原活化蛋白激酶）的短暂激活，这与细胞死亡无关。这些数据表明，p38（丝裂原活化蛋白激酶）的持续激活对于尤因肉瘤家族肿瘤细胞暴露于bFGF后死亡级联反应的激活至关重要，并提供了证据表明p38（丝裂原活化蛋白激酶）的激活导致死亡受体p75（神经营养因子受体）上调。
