Insulin Signal Transduction Pathways and Insulin-induced Gene Expression

Abstract

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 immediateearly 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.

Regulation of Microsomal Triglyceride Transfer Protein Gene by Insulin in HepG2 Cells

“…Second, such a cross-talk might represent an important mechanism for the fine-tuning of the transcription of the MTP gene in response to a diverse set of environmental stimuli, including growth factors and other stresses. Indeed, this notion gained support from a recent report showing that insulin-activated MAPK erk could be attenuated by MAPK p38 (40 plicated in the apoptosis of the ␤-cell of islets (42) and the oxidized LDL-induced oxidative stress in glomerular injury (43). Both contribute to the aggravation of the symptoms of diabetes.…”

Promotion of Cancer Cell Migration

“…One explanation is that constitutive ERK1/2 activation in these cells is necessary but not sufficient for IGFBP-6-dependent migration as has been suggested previously for H-ras-induced migration (49). Constitutive ERK1/2 activation may result in downstream cross-talk with IGFBP-6-induced p38 MAPK activation thereby resulting in the migration response (52)(53)(54)(55). Alternatively, MAPK kinase may also activate kinases other than ERK1/2 and mediate alternative signaling pathways (56,57).…”

The immediate early gene Ier2 promotes tumor cell motility and metastasis, and predicts poor survival of colorectal cancer patients

“…Although little is known about the function of Ier2, its expression has been shown to be induced in a wide range of biological contexts. It is activated upon stimulation of quiescent fibroblasts, T cells and other cell types with serum, 12-O-tetradecanoylphorbol-13-acetate (TPA) or growth factors (Charles et al, 1990;Coleclough et al, 1990;Scott et al, 1994;Fambrough et al, 1999;Keeton et al, 2002). Ier2 is also associated with apoptosis, as its expression is induced in neurons after N-methyl-Daspartic acid (NMDA) administration in vivo, and in fibroblasts after anisomycin treatment (Chung et al, 2000a(Chung et al, , 2000b.…”