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J. Biol. Chem., Vol. 277, Issue 50, 48565-48573, December 13, 2002
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From the Department of Pathology, Division of Molecular and
Cellular Pathology, University of Alabama,
Birmingham, Alabama 35294
Insulin regulates metabolic activity, gene
transcription, and cell growth by modulating the activity of several
intracellular signaling pathways. Insulin activation of one
mitogen-activated protein kinase cascade, the MEK/ERK kinase
cascade, is well described. However, the effect of insulin on the
parallel p38 pathway is less well understood. The present work examines
the effect of inhibiting the p38 signaling pathway by use of specific
inhibitors, either alone or in combination with insulin, on the
activation of ERK1/2 and on the regulation of gene transcription in rat
hepatoma cells. Activation of ERK1/2 was induced by insulin and was
dependent on the activation of MEK1, the kinase upstream of ERK in this pathway. Treatment of cells with p38 inhibitors also induced ERK1/2 activation/phosphorylation. The addition of p38 inhibitors followed by
insulin addition resulted in a greater than additive activation of
ERK1/2. The two genes studied, c-Fos and Pip92, are immediate-early genes that are dependent on the ERK1/2 pathway for insulin-regulated induction because the insulin effect was inhibited by pretreatment with
a MEK1 inhibitor. The addition of p38 inhibitors induced transcription
of both genes in a dose-dependent manner, and insulin stimulation of both genes was enhanced by prior treatment with p38
inhibitors. The ability of the p38 inhibitors to induce ERK1/2 and gene
transcription, both alone and in combination with insulin, was
abolished by prior inhibition of MEK1. These data suggest possible
cross-talk between the p38 and ERK1/2 signaling pathways and a
potential role of p38 in insulin signaling.
Insulin Signal Transduction Pathways and Insulin-induced Gene
Expression*
*
This work was supported by a grant from the American
Diabetes Association and by National Institutes of Health Grant DK40456 (to J. L. M.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Dept. of Pathology,
Div. of Molecular and Cellular Pathology, Volker Hall, G019, 1670 University Blvd., University of Alabama at Birmingham, Birmingham, AL
35294-0019. Tel.: 205-934-4921; Fax: 205-934-1775; E-mail: messina@path.uab.edu.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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