Up-regulation of p21CIP1 expression mediated by ERK-dependent and -independent pathways contributes to hepatocyte growth factor-induced inhibition of HepG2 hepatoma cell proliferation

Activation of the extracellular signal-regulated kinase (ERK) pathway is a key factor in the regulation of cell proliferation by growth factors. Hepatocyte growth factor (HGF)-induced cell cycle arrest in the human hepatocellular carcinoma cell line HepG2 requires strong activation of the ERK pathway. In this study, we investigated the molecular mechanism of the activation. We constructed a chimeric receptor composed of the extracellular domain of the NGF receptor and the cytoplasmic domain of the HGF receptor (c-Met) and introduced a point mutation (N1358H) into the chimeric receptor, which specifically abrogates the direct binding of Grb2 to c-Met. The mutant chimeric receptor failed to mediate the strong activation of ERK, up-regulation of the expression of a Cdk inhibitor p16INK4a and inhibition of HepG2 cell proliferation by ligand stimulation. Moreover, the mutant receptor did not induce tyrosine phosphorylation of the docking protein Gab1. Knockdown of Gab1 using siRNA suppressed the HGF-induced strong activation of ERK and inhibition of HepG2 cell proliferation. These results suggest that coupling of Grb2 to Gab1 mediates the HGF-induced strong activation of the ERK pathway, which is required for the inhibition of HepG2 cell proliferation.

Download Full-text

Hepatocyte Growth Factor Overexpression in the Islet of Transgenic Mice Increases Beta Cell Proliferation, Enhances Islet Mass, and Induces Mild Hypoglycemia

Journal of Biological Chemistry ◽

10.1074/jbc.275.2.1226 ◽

2000 ◽

Vol 275 (2) ◽

pp. 1226-1232 ◽

Cited By ~ 163

Author(s):

Adolfo Garcia-Ocaña ◽

Karen K. Takane ◽

Mushtaq A. Syed ◽

William M. Philbrick ◽

Rupangi C. Vasavada ◽

...

Keyword(s):

Cell Proliferation ◽

Growth Factor ◽

Transgenic Mice ◽

Hepatocyte Growth Factor ◽

Beta Cell ◽

Beta Cell Proliferation ◽

Islet Mass ◽

Hepatocyte Growth

Download Full-text

Monocyte activation state regulates monocyte-induced endothelial proliferation through Met signaling

Blood ◽

10.1182/blood-2009-02-207340 ◽

2010 ◽

Vol 115 (16) ◽

pp. 3407-3412 ◽

Cited By ~ 10

Author(s):

Shai Y. Schubert ◽

Alejandro Benarroch ◽

Juan Monter-Solans ◽

Elazer R. Edelman

Keyword(s):

Cell Proliferation ◽

Endothelial Cells ◽

Endothelial Cell ◽

Growth Factor ◽

Hepatocyte Growth Factor ◽

Direct Interaction ◽

Endothelial Cell Proliferation ◽

Specific Cell ◽

Mrna Levels ◽

Hepatocyte Growth

Abstract Direct interaction of unactivated primary monocytes with endothelial cells induces a mitogenic effect in subconfluent, injured endothelial monolayers through activation of endothelial Met. We now report that monocytes' contact-dependent mitogenicity is controlled by activation-mediated regulation of hepatocyte growth factor. Direct interaction of unactivated monocytes with subconfluent endothelial cells for 12 hours resulted in 9- and 120-fold increase in monocyte tumor necrosis factor-α (TNFα) and interleukin-1β (IL-1β) mRNA levels and bitemporal spike in hepatocyte growth factor that closely correlates with endothelial Met and extracellular signal-related kinase (ERK) phosphorylation. Once activated, monocytes cannot induce a second wave of endothelial cell proliferation and endothelial Met phosphorylation and soluble hepatocyte growth factor levels fall off. Monocyte-induced proliferation is dose dependent and limited to the induction of a single cell cycle. Monocytes retain their ability to activate other endothelial cells for up to 8 hours after initial interaction, after which they are committed to the specific cell. There is therefore a profoundly sophisticated mode of vascular repair. Confluent endothelial cells ensure vascular quiescence, whereas subconfluence promotes vessel activation. Simultaneously, circulating monocytes stimulate endothelial cell proliferation, but lose this potential once activated. Such a system provides for the fine balance that can restore vascular and endothelial homeostasis with minimal overcompensation.

Download Full-text