題名:Inhibition of the ERK phosphorylation plays a role in terbinafine-induced p21 up-regulation and DNA synthesis inhibition in human vascular endothelial cells
作者:何元順; 梁有志
Ho; Pei-Yin; Hsu Sung-Po; Liang; Yu-Chih; Kuo; Min-Liang; Ho; Yuan-Soo; Lee; Wen-Sen
貢獻者:醫學檢驗暨生物技術學系 上傳時間:2009-08-25T02:38:33Z
摘要:Abstract
Previously, we showed that terbinafine (TB) induces cell-cycle arrest in cultured human umbilical vein endothelial cells (HUVEC) through an upregulation of the p21 protein. The aim of this study is to
delineate the molecular mechanisms underlying TB-induced increase of p21 protein. RT-PCR
analysis demonstrated that the mRNA levels of p21 and p53 were increased in the TB-treated HUVEC. The p21 promoter activity was also increased by
TB treatment. Transfection of HUVEC with p53 dominant negative (DN) abolished the TB-induced increases of p21 promoter activity and protein level,
suggesting that the TB-induced increase of p21 is p53-dependent. Western blot analysis demonstrated that TB decreased the levels of phosphorylated
extracellular signal-regulated kinase (ERK).
Over-expression of mitogen-activated protein kinase (MEK)-1, the immediate upstream activator kinase of
ERK, abolished the TB-induced increases of p21 and p53 protein and decrease of thymidine incorporation. The ERK inhibitor (PD98059) enhanced the
TB-induced inhibition of thymidine incorporation into HUVEC. Taken together, these data suggest that the decrease of ERK activity plays a role in the
TB-induced up-regulation of p21 inHUVEC.On the other hand, pretreatment of the cells with geranylgeraniol (GGOH), farnesol (FOH), or Ras inhibitor
peptide did not affect the TB-induced decrease of thymidine incorporation. Taken together, our results suggest that TB might cause a decrease of MEK,
which in turn up-regulates p53 through the inhibition of ERK phosphorylation, and finally causes an increase of p21 expression and cell-cycle arrest.
