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Sphingosine-1-phosphate promotes mouse melanocyte survival via ERK and Akt activation
Dong-Seok Kim1, Eui-Soo Hwang, Jai-Eun Lee
1Research Division for Human Life Sciences, Seoul National University, Seoul 110-744, South Korea.
Abstract:
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.
Insights
Sphingosine-1-phosphate protects mouse melanocytes from ultraviolet B (UVB) damage by activating ERK and Akt pathways, despite inhibiting DNA synthesis. This highlights a novel mechanism against UVB-induced apoptosis.
Area of Science:
- Cell Biology
- Molecular Biology
- Dermatology
Background:
- Ultraviolet B (UVB) radiation induces significant cellular damage, particularly in melanocytes.
- Understanding the signaling pathways involved in UVB-induced apoptosis is crucial for developing cytoprotective strategies.
- Sphingosine-1-phosphate (S1P) is known for its mitogenic effects, but its role in UVB-induced apoptosis was unclear.
Purpose of the Study:
- To investigate the signaling pathways activated by UVB radiation.
- To determine the effects of sphingosine-1-phosphate (S1P) on UVB-induced apoptosis in mouse melanocytes (Mel-Ab).
- To elucidate the role of mitogen-activated protein (MAP) kinases and the Akt pathway in S1P's cytoprotective effects against UVB.
Main Methods:
- UVB irradiation of Mel-Ab cells.
- Assessment of apoptosis and DNA synthesis.
- Analysis of mitogen-activated protein (MAP) kinase (JNK, p38, ERK) and Akt pathway activation via phosphorylation.
- Pharmacological inhibition of specific signaling pathways (ERK, Akt, p38) using PD98059, LY294002, and SB203580, respectively.
Main Results:
- UVB irradiation robustly activated c-Jun N-terminal kinase (JNK) and transiently activated p38 MAP kinase.
- UVB irradiation decreased extracellular signal-regulated protein kinase (ERK) phosphorylation but did not affect Akt phosphorylation.
- Sphingosine-1-phosphate (S1P) demonstrated significant cytoprotective effects against UVB-induced apoptosis, despite inhibiting DNA synthesis.
- S1P potently stimulated ERK and Akt phosphorylation, key components of cell survival signaling.
- Inhibition of ERK and Akt pathways reversed S1P's cytoprotective effect, while p38 inhibition enhanced it.
Conclusions:
- p38 MAP kinase activation plays a critical role in UVB-induced apoptosis.
- Sphingosine-1-phosphate (S1P) likely exerts its cytoprotective effects in Mel-Ab cells by activating the ERK and Akt signaling pathways.
- These findings reveal a novel mechanism for S1P in mitigating UVB-induced cellular damage in melanocytes.