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Toxicol Appl Pharmacol. 1999 Sep 1;159(2):125-33.

The extracellular signal-regulated kinase pathway contributes to mitogenic and antiapoptotic effects of peroxisome proliferators in vitro.

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Molecular Biosciences Department, Pacific Northwest National Laboratory, Richland, Washington 99352, USA.


Peroxisome proliferators are a class of nongenotoxic rodent hepatocarcinogens thought to induce tumors by altering the balance between mitosis and apoptosis. Previous studies suggest mitogenic growth factors that act through the extracellular signal-regulated kinase (ERK) pathway, including insulin and epidermal growth factor (EGF), modulate peroxisome proliferator-activated receptor alpha activation as well as the mitogenic activity of peroxisome proliferators. We have investigated whether the ERK pathway plays a role in regulating the growth and survival altering properties of peroxisome proliferators in primary mouse hepatocytes. Exposure of hepatocytes to Wy-14,643 and trichloroacetate resulted in a dose-dependent phosphorylation and activation of ERK. Peroxisome proliferator-induced ERK phosphorylation was blocked when cells were pretreated with the MEK (ERK kinase) inhibitor, PD098059, or the phosphatidyl-inositol 3-kinase (PI3K) inhibitors, LY294002 and apigenin, suggesting that both MEK and PI3K are involved in the initial response. The pathway leading to peroxisome proliferator-induced ERK activation is different than that induced by phorbol ester or EGF, since the PI3K inhibitors had no effect on ERK phosphorylation induced by these agents. Under defined culture conditions, Wy-14,643 increased the level of BrdU incorporation in primary hepatocytes and suppressed the incidence of apoptosis induced by transforming growth factor beta 1. In contrast, concentrations of PD098059 that block Wy-14,643-induced ERK phosphorylation also blocked the stimulation of DNA replicative synthesis and suppression of apoptosis by Wy-14,643. These studies indicate that activation of the ERK pathway through a PI3K-dependent mechanism may play a significant role in the tumor-promoting properties of peroxisome proliferators.

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