Multiple anti-apoptotic pathways stimulated by EGF in cytotrophoblasts
Multiple anti-apoptotic pathways stimulated by EGF in cytotrophoblasts
复制标题
DOI：
10.1016/j.placenta.2004.08.012
复制
发表时间：
2005-08-01
期刊：
影响因子：
3.8
通讯作者：
Guilbert, LJ
中科院分区：
文献类型：
--
作者：
Johnstone, ED;Mackova, M;Guilbert, LJ
表皮生长因子(EGF)通过两条不同的途径减少原代培养的细胞滋养层细胞(CT)的凋亡：细胞外信号相关激酶(ERK)1/2和磷脂酰肌醇3-激酶(PI-3)。目前尚不清楚是否有其他途径参与生存信号的传递。我们发现，c-Jun NH2末端激酶(JNK)和丝裂原激活的激酶(MAPK)p38也被EGF激活，表现为JNK和p38的磷酸化增加。然而，用特异性抑制剂SP600125抑制JNK的磷酸化，以一种不同于加入表皮生长因子的方式增加细胞凋亡，但用其特异性抑制剂SB 203580抑制p38的磷酸化不会增加细胞的凋亡率。EGF还激活鞘氨醇激酶-1(SPHK-1)，将鞘氨醇转化为鞘氨醇-1-磷酸，二甲基鞘氨醇(DMS)的抑制增加了滋养层细胞的死亡。抑制SPHK-1也不影响EGF诱导的PI-3、Akt、ERK1/2或p38的磷酸化，但用特异性抑制剂LY294002抑制PI-3激酶的部分(40%)可抑制EGF诱导的SPHK-1活性的增加。我们的结论是，除了PI-3激酶和ERK1/2通路外，EGF还通过其受体刺激JNK、p38和SPHK-1通路，但参与抑制细胞凋亡的不是p38，而是JNK和SPHK-1。这一信息提供了证据，证明EGF沿着不同于滋养层细胞和其他细胞类型的多种途径刺激生存。
Epidermal growth factor (EGF) reduces apoptosis in primary, cytotrophoblast (CT) in culture through two separate pathways: the extracellular signal related kinase (ERK) 1/2 and phosphatidyl inositol 3-kinase (PI-3 kinase) paths. Whether other pathways are involved in survival signalling is unknown. We here show that the c-Jun NH2 terminal kinase (JNK) and the mitogen activated kinase (MAPK) p38 arc also activated by EGF as seen by increases in JNK and p38 phosphorylation. However, inhibition of JNK phosphorylation with the specific inhibitor SP600125 increases apoptosis in a manner refractory to the addition of EGF but inhibition of p38 phosphorylation with its specific inhibitor SB 203580 does not increase apoptosis. EGF also activates sphingosine kinase-1 (SPHK-1), which converts sphingosine to sphingosine-1-phosphate, and its inhibition with dimethyl sphingosine (DMS) increased trophoblast death. Inhibition of SPHK-1 also did not affect EGF stimulated phosphorylation of PI-3 kinase, Akt, ERK1/2 or p38 but inhibition of PI-3 kinase with a specific inhibitor LY294002 partly (40%) inhibited the EGF-stimulated increase in SPHK-1 activity. We conclude that, in addition to the PI-3 kinase and ERK1/2 pathways, EGF acts through its receptor to stimulate JNK, p38 and SPHK-1 pathways, but that the JNK and SPHK-1, and not the p38, pathways are involved in suppressing apoptosis. This information provides evidence that EGF stimulates survival along multiple pathways that differ in trophoblast and other cell types.