Kim Dong-Seok, Hwang Eui-Soo, Lee Jai-Eun, Kim Sook-Young, Park Kyoung-Chan
Research Division for Human Life Sciences, Seoul National University, Seoul 110-744, South Korea.
Cell Signal. 2003 Oct;15(10):919-26. doi: 10.1016/s0898-6568(03)00055-x.
In this study, we investigated the signalling pathways induced by ultraviolet B (UVB) and the effects of sphingosine-1-phosphate on UVB-induced apoptosis of mouse melanocytes, Mel-Ab, and observed the cytoprotective effects of sphingosine-1-phosphate on UVB-induced apoptosis. Since sphingosine-1-phosphate is a well-known mitogenic agent, we thought it possible that the mitogenic effect of sphingosine-1-phosphate might contribute to cell survival. However, we found that sphingosine-1-phosphate significantly inhibits DNA synthesis. We next examined the regulation of the three major subfamilies of mitogen-activated protein (MAP) kinases and of the Akt pathway by sphingosine-1-phosphate against UVB-induced apoptosis. UVB irradiation resulted in the remarkable and sustained activation of c-Jun N-terminal kinase (JNK), while p38 MAP kinase was only transiently activated. The basal level of extracellular signal-regulated protein kinase (ERK) phosphorylation decreased 30 min after UVB irradiation, whereas the basal level of Akt phosphorylation was unaffected by UVB. We also found that sphingosine-1-phosphate potently stimulates the phosphorylation of both ERK and Akt, which are involved in the cell survival-signalling cascade. Furthermore, the specific inhibition of the ERK and Akt pathways by PD98059 and LY294002, respectively, restored the cytoprotective effect induced by sphingosine-1-phosphate. On the other hand, the p38 inhibitor SB203580 additively enhanced the cytoprotective effect on sphingosine-1-phosphate. Based on these results, we conclude that the activation of p38 MAP kinase plays an important role in UVB-induced apoptosis, and that sphingosine-1-phosphate probably exert its cytoprotective effect in Mel-Ab cells through ERK and Akt activation.
在本研究中，我们探究了紫外线B（UVB）诱导的信号通路以及1-磷酸鞘氨醇对UVB诱导的小鼠黑素细胞Mel-Ab凋亡的影响，并观察了1-磷酸鞘氨醇对UVB诱导凋亡的细胞保护作用。由于1-磷酸鞘氨醇是一种众所周知的促有丝分裂剂，我们认为1-磷酸鞘氨醇的促有丝分裂作用可能有助于细胞存活。然而，我们发现1-磷酸鞘氨醇显著抑制DNA合成。接下来，我们研究了1-磷酸鞘氨醇对UVB诱导凋亡的丝裂原活化蛋白（MAP）激酶三个主要亚家族和Akt信号通路的调节作用。UVB照射导致c-Jun氨基末端激酶（JNK）显著且持续激活，而p38 MAP激酶仅短暂激活。UVB照射30分钟后，细胞外信号调节蛋白激酶（ERK）磷酸化的基础水平下降，而Akt磷酸化的基础水平不受UVB影响。我们还发现1-磷酸鞘氨醇强烈刺激ERK和Akt的磷酸化，二者均参与细胞存活信号级联反应。此外，分别用PD98059和LY294002特异性抑制ERK和Akt信号通路，可恢复1-磷酸鞘氨醇诱导的细胞保护作用。另一方面，p38抑制剂SB203580可增强1-磷酸鞘氨醇的细胞保护作用。基于这些结果，我们得出结论，p38 MAP激酶的激活在UVB诱导的凋亡中起重要作用，并且1-磷酸鞘氨醇可能通过激活ERK和Akt在Mel-Ab细胞中发挥其细胞保护作用。
