Hepatocyte growth factor induces redistribution of p21CIP1 and p27KIP1 through ERK-dependent p16INK4a up-regulation, leading to cell cycle arrest at G1 in HepG2 hepatoma cells
Hepatocyte growth factor induces redistribution of p21CIP1 and p27KIP1 through ERK-dependent p16INK4a up-regulation, leading to cell cycle arrest at G1 in HepG2 hepatoma cells
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DOI：
10.1074/jbc.m503431200
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发表时间：
2005-09-09
影响因子：
4.8
通讯作者：
Tanaka, T
中科院分区：
文献类型：
--
作者：
Han, JH;Tsukada, Y;Tanaka, T
肝细胞生长因子（HGF）对多种类型的肿瘤细胞系和体内肿瘤具有抗增殖作用。我们之前发现，HepG2 肝癌细胞中 HGF 诱导的增殖的抑制是由高强度 ERK 信号导致细胞周期停滞在 G(1) 引起的，该信号抑制 Cdk2 活性。为了进一步研究 HGF 阻滞 G(1) 的机制，我们分析了 Cdk 抑制剂 p16(INK4a)，它通过将细胞周期阻滞在 G1 具有抗增殖功能。我们发现 HGF 治疗显着增加了内源性 p16 水平。用小干扰RNA敲低p16可逆转这种停滞，表明HGF对G(1)的停滞需要诱导p16。对人类 p16 基因启动子的分析确定了近端 Ets 结合位点是 HGF 的响应元件，并且这对高强度 ERK 信号作出响应。 HGF 处理细胞导致 p21(CIP1) 和 p27(KIP1) 从 Cdk4 重新分配到 Cdk2。这种重新分布被小干扰RNA敲除p16所阻断，从而恢复了被HGF抑制的Cdk2活性，这表明p16诱导对于Cdk2活性的重新分布和最终抑制是必需的。我们的结果揭示了 HGF 诱导的 G(1) 阻滞的信号通路。
Hepatocyte growth factor (HGF) has an anti-proliferative effect on many types of tumor cell lines and tumors in vivo. We found previously that inhibition of HGF-induced proliferation in HepG2 hepatoma cells is caused by cell cycle arrest at G(1) through a high intensity ERK signal, which represses Cdk2 activity. To examine further the mechanisms of G(1) arrest by HGF, we analyzed the Cdk inhibitor p16(INK4a), which has an anti-proliferative function through cell cycle arrest at G1. We found that HGF treatment drastically increased endogenous p16 levels. Knockdown of p16 with small interfering RNA reversed the arrest, indicating that the induction of p16 is required for G(1) arrest by HGF. Analysis of the promoter of the human p16 gene identified the proximal Ets-binding site as a responsive element for HGF, and this responded to the high intensity ERK signal. HGF treatment of the cells led to a redistribution of p21(CIP1) and p27(KIP1) from Cdk4 to Cdk2. The redistribution was blocked by the knockdown of p16 with small interfering RNA, which restored the Cdk2 activity repressed by HGF, demonstrating the requirement of p16 induction for the redistribution and eventual repression of Cdk2 activity. Our results reveal a signaling pathway for G(1) arrest induced by HGF.