High Intensity ERK Signal Mediates Hepatocyte Growth Factor-induced Proliferation Inhibition of the Human Hepatocellular Carcinoma Cell Line HepG2

Yu Ichi Tsukada, Keiji Miyazawa, Naomi Kitamura

Research output: Contribution to journalArticle

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Abstract

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. The molecular mechanism of the HGF-induced growth inhibition of tumor cells remains obscure. We have investigated the intracellular signaling pathway involved in the antiproliferative effect of HGF on the human hepatocellular carcinoma Cell line HepG2. HGF induced strong activation of ERK in HepG2 cells. Although the serum-dependent proliferation of HepG2 cells was inhibited by the MEK inhibitor PD98059 in a dose-dependent manner, 10 μM PD98059 reduced the HGF-induced strong activation of ERK to a weak activation; and as a result, the proliferation inhibited by HGF was completely restored. Above or below this specific concentration, the restoration was incomplete. Expression of constitutively activated Ha-Ras, which induces strong activation of ERK, led to the proliferation inhibition of HepG2 cells, as was observed in HGF-treated HepG2 cells. This inhibition was suppressed by the MEK inhibitor. Furthermore, HGF treatment and expression of constitutively activated Ha-Ras changed the hyperphosphorylated form of the retinoblastoma tumor suppressor gene product pRb to the hypophosphorylated form. This change was inhibited by the same concentration of MEK inhibitor needed to suppress the proliferation inhibition. These results suggest that ERK activity is required for both the stimulation and inhibition of proliferation of HepG2 cells; that the level of ERK activity determines the opposing proliferation responses; and that HGF-induced proliferation inhibition is caused by cell cycle arrest, which results from pRb being maintained in its active hypophosphorylated form via a high-intensity ERK signal in HepG2 cells.

Original languageEnglish
Pages (from-to)40968-40976
Number of pages9
JournalJournal of Biological Chemistry
Volume276
Issue number44
DOIs
Publication statusPublished - Nov 2 2001
Externally publishedYes

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Hepatocyte Growth Factor
Hepatocellular Carcinoma
Hep G2 Cells
Cells
Cell Line
Mitogen-Activated Protein Kinase Kinases
Chemical activation
Tumors
Growth
Retinoblastoma
Cell Cycle Checkpoints
Tumor Cell Line
Tumor Suppressor Genes
Restoration
Genes
Serum

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

High Intensity ERK Signal Mediates Hepatocyte Growth Factor-induced Proliferation Inhibition of the Human Hepatocellular Carcinoma Cell Line HepG2. / Tsukada, Yu Ichi; Miyazawa, Keiji; Kitamura, Naomi.

In: Journal of Biological Chemistry, Vol. 276, No. 44, 02.11.2001, p. 40968-40976.

Research output: Contribution to journalArticle

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