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

Junhong Han, Yuichi Tsukada, Eiji Hara, Naomi Kitamura, Toshiaki Tanaka

Research output: Contribution to journalArticle

49 Citations (Scopus)

Abstract

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 G1 through a high intensity ERK signal, which represses Cdk2 activity. To examine further the mechanisms of G1 arrest by HGF, we analyzed the Cdk inhibitor p16INK4a, 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 G1 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 p21CIP1 and p27KIP1 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 G1 arrest induced by HGF.

Original languageEnglish
Pages (from-to)31548-31556
Number of pages9
JournalJournal of Biological Chemistry
Volume280
Issue number36
DOIs
Publication statusPublished - Sep 9 2005
Externally publishedYes

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G1 Phase Cell Cycle Checkpoints
Hepatocyte Growth Factor
Hep G2 Cells
Hepatocellular Carcinoma
Up-Regulation
Cells
Small Interfering RNA
Tumors
p16 Genes
Tumor Cell Line
Genes
Binding Sites

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

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. / Han, Junhong; Tsukada, Yuichi; Hara, Eiji; Kitamura, Naomi; Tanaka, Toshiaki.

In: Journal of Biological Chemistry, Vol. 280, No. 36, 09.09.2005, p. 31548-31556.

Research output: Contribution to journalArticle

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