Premium
Up‐regulation of p21 CIP1 expression mediated by ERK‐dependent and ‐independent pathways contributes to hepatocyte growth factor‐induced inhibition of HepG2 hepatoma cell proliferation
Author(s) -
Shirako Erika,
Hirayama Naoki,
Tsukada Yuichi,
Tanaka Toshiaki,
Kitamura Naomi
Publication year - 2007
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.21614
Subject(s) - hepatocyte growth factor , mapk/erk pathway , cell growth , microbiology and biotechnology , epidermal growth factor , cdk inhibitor , gene knockdown , cell culture , cancer research , signal transduction , biology , growth factor , kinase , chemistry , cyclin dependent kinase 2 , receptor , protein kinase a , biochemistry , genetics
Strong activation of the ERK signal is required for hepatocyte growth factor (HGF) to inhibit proliferation of the human hepatocellular carcinoma cell line HepG2. However, it is still to be elucidated whether the activation alone is sufficient to induce the inhibitory effect. In this study, we constructed HepG2 cell clones expressing a high level of epidermal growth factor receptor (EGFR), and examined the effect of the strong activation of ERK on the proliferation of the cell clones. EGF treatment of the cell clones induced strong activation of ERK similar to HGF treatment, but did not inhibit cell proliferation. HGF treatment of the cell clones up‐regulated the expression of a Cdk inhibitor p16 INK4a , which has previously been shown to be required to inhibit the proliferation of HepG2 cells, but EGF treatment did not. Furthermore, EGF treatment of the cell clones did not induce the up‐regulation of another Cdk inhibitor p21 CIP1 , whereas HGF treatment did. Knockdown of p21 by siRNA restored the proliferation of HepG2 cells inhibited by HGF, and restored Cdk2 activity suppressed in HGF‐treated HepG2 cells. These results suggest that strong activation of ERK alone is not sufficient, and some other pathway(s), which is activated through the HGF receptor but not through EGFR, is also required to induce the up‐regulation of p16 and p21 expression, and also suggest that in addition to the up‐regulated expression of p16, that of p21 contributes to the suppression of Cdk2 activity leading to the inhibition of proliferation of HGF‐treated HepG2 cells. J. Cell. Biochem. 104: 176–188, 2008. © 2007 Wiley‐Liss, Inc.