Terrein inhibits keratinocyte proliferation via ERK inactivation and G2/M cell cycle arrest
Terrein inhibits keratinocyte proliferation via ERK inactivation and G2/M cell cycle arrest
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DOI：
10.1111/j.1600-0625.2007.00646.x
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发表时间：
2008-04-01
影响因子：
3.6
通讯作者：
Park, Kyoung-Chan
中科院分区：
文献类型：
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作者：
Kim, Dong-Seok;Lee, Hyun-Kyung;Park, Kyoung-Chan
Terrein是一种真菌代谢物，最近已被证明对皮肤等效物具有强烈的抗增殖作用。在本研究中，我们进一步研究了terrein对细胞外信号调节蛋白激酶（ERK）和Akt通路的调节，terrein对可能参与人表皮角质形成细胞生长抑制的信号通路的影响。观察到ERK被terrein灭活，角质形成细胞增殖受到抑制，而Akt不受影响。U 0126（一种特异性ERK抑制剂）对ERK通路的抑制作用也对人角质形成细胞具有剂量依赖性抗增殖作用。这些结果表明ERK抑制参与terrein对角质形成细胞生长的抑制。此外，流式细胞术分析表明，terrein抑制DNA合成，如S期细胞周期的减少和G（2）/M期细胞周期的增加所证明的。因此，我们接下来研究了G（2）/M细胞周期相关蛋白表达的变化。发现Terrein下调细胞周期蛋白B-1和Cdc 2，而不磷酸化Cdc 2，但上调p27（KIP 1）（p27），一种已知的细胞周期蛋白依赖性激酶抑制剂。这些结果表明，terrein通过抑制ERK和降低cyclin B-1和Cdc 2复合物的表达来降低人角质形成细胞的增殖。
Terrein, a fungal metabolite, has been recently shown to have a strong antiproliferative effect on skin equivalents. In the present study, we further investigated the effects of terrein on the possible signalling pathways involved in the growth inhibition of human epidermal keratinocytes by examining the regulations of extracellular signal-regulated protein kinase (ERK) and of the Akt pathway by terrein. It was observed that ERK was inactivated by terrein and that keratinocyte proliferation was inhibited, whereas Akt was unaffected. The inhibition of the ERK pathway by U0126 (a specific ERK inhibitor) also had a dose-dependent antiproliferative effect on human keratinocytes. These results indicate that ERK inhibition is involved in keratinocyte growth inhibition by terrein. Moreover, flow cytometric analysis showed that terrein inhibits DNA synthesis, as evidenced by a reduction in the S phase and an increase in the G(2)/M phase of the cell cycle. Thus, we next examined changes in the expressions of G(2)/M cell cycle-related proteins. Terrein was found to downregulate cyclin B-1 and Cdc2 without Cdc2 phosphorylation, but upregulated p27(KIP1) (p27), a known inhibitor of cyclin-dependent kinase. These results suggest that terrein reduces human keratinocyte proliferation by inhibiting ERK and by decreasing the expressions of cyclin B-1 and Cdc2 complex.