Involvement of Down-Regulation of Cdk2 Activity in Hepatocyte Growth Factor-Induced Cell Cycle Arrest at G1 in the Human Hepatocellular Carcinoma Cell Line HepG2
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概要
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Hepatocyte growth factor (HGF) induces growth stimulation of a variety of cell types, but it also induces growth inhibition of several types of tumor cell lines. We previously investigated the intracellular signaling pathway involved in the antiproliferative effect of HGF on the human hepatocellular carcinoma cell line HepG 2. The results suggested that the HGF-induced proliferation inhibition is caused by cell cycle arrest, which results from the retinoblastoma tumor suppressor gene product pRb being maintained in its active hypophosphorylated form via a high-intensity ERK signal. In this study, we examined the molecular mechanism of the HGF-induced cell cycle arrest in HepG2 cells. Cyclin A/Cdk2 complexes phosphorylated serine residues on pRb crucial for the G1 to S phase transition in proliferating HepG2 cells, and HGF treatment inhibited the phosphorylation. The expression of cyclin A was decreased and the expression of a Cdk inhibitor p21Cip1 was increased in HGF-treated HepG2 cells, and these changes were prevented by pretreatment with a low concentration of a MEK inhibitor. These results suggest that the decrease in cyclin A expression and increase in p21Cip1 expression through a high-intensity ERK signal by HGF lead to suppression of the phosphorylation of pRb by Cdk2, which contributes to the cell cycle arrest at G 1 in HepG2 cells by HGF. Furthermore, the expression of E2F-1, a member of the E2F transcription factor family, was decreased in HGF-treated HepG2 cells, suggesting that the decrease in E2F-1 expression may also contribute to the cell cycle arrest at G1.
- 社団法人 日本生化学会の論文
著者
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Tanaka Toshiaki
Department Of Applied Chemistry Tokyo Institute Of Technology
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Miyazawa Keiji
Department Of Biochemistry Interdisciplinary Graduate School Of Medicine And Engineering University
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Tsukada Yu-ichi
Department Of Biological Sciences Graduate School Of Bioscience And Biotechnology Tokyo Institute Of
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KITAMURA NAOMI
Department of Biological Science, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology
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