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Terrein inhibits keratinocyte proliferation via ERK inactivation and G 2 /Mcell cycle arrest
Author(s) -
Kim DongSeok,
Lee HyunKyung,
Park SeoHyoung,
Lee Sangku,
Ryoo InJa,
Kim WonGon,
Yoo IckDong,
Na JungIm,
Kwon SunBang,
Park KyoungChan
Publication year - 2008
Publication title -
experimental dermatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.108
H-Index - 96
eISSN - 1600-0625
pISSN - 0906-6705
DOI - 10.1111/j.1600-0625.2007.00646.x
Subject(s) - mapk/erk pathway , cyclin dependent kinase 1 , keratinocyte , protein kinase b , kinase , cell growth , cyclin b1 , cell cycle , microbiology and biotechnology , cyclin a , chemistry , cyclin d , biology , phosphorylation , cyclin d1 , biochemistry , cell , in vitro
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.