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(Received for publication, January 30, 1997)
From the Department of Genetic and Cellular Toxicology, Merck
Research Laboratories, West Point, Pennsylvania 19486
Peroxisome proliferators (PPs) are a class of
nongenotoxic carcinogens in the rodent liver. The induction of
immediate-early gene expression in immortalized mouse liver cells by
the PPs Wy-14,643, monoethylhexyl phthalate, ciprofibrate ethyl ester,
and clofibrate suggested that they may be activating growth-regulatory
signal transduction pathways. We report that incubation of quiescent ML457 cells with Wy-14,643 resulted in the appearance of two
tyrosine-phosphorylated bands of approximately 44 and 42 kDa with
maximal phosphorylation at 20 min. These two proteins were identified
as extracellular signal-regulated kinases (ERKs) ERK1 and ERK2 (also
known as mitogen-activated protein kinases, or MAPKs). Stimulation of
quiescent ML457 cells with monoethylhexyl phthalate, ciprofibrate ethyl
ester, and clofibrate also resulted in tyrosine phosphorylation of ERK1
and ERK2; however, the steroid PP dehydroepiandrosterone sulfate, which
does not induce immediate-early gene expression, did not induce
phosphorylation of ERK1 and ERK2. Kinase activity of ERK1 and ERK2 was
stimulated by the PPs, consistent with their phosphorylation. The PPs
also induced phosphorylation of the upstream regulator MAPK/ERK kinase (MEK). Preincubation of quiescent cells with MEK inhibitor PD98059 blocked activation of ERK1 and ERK2 by the PPs, implicating MEK activation as a requirement for PP-induced ERK activation. In addition,
pretreatment with PD98059 greatly reduced the PP-induced expression of
immediate-early genes c-fos, egr-1, and to a
lesser extent junB. Induction of ERK phosphorylation and
junB expression by Wy-14,643 was also seen in rat
hepatocytes. These results attribute many of the effects of PPs on
immediate-early gene expression to the activation of the MEK/ERK signal
transduction pathway and add the PPs to the growing number of tumor
promoters that modulate signaling proteins.
Volume 272, Number 20,
Issue of May 16, 1997
pp. 13452-13457
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.
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