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Insulin Induction of Protein Kinase C Expression Is Independent of Insulin Receptor Tyr^1162/1163 Residues and Involves Mitogen-Activated Protein Kinase Kinase 1 and Sustained Activation of Nuclear p44^MAPK1

INSERM U-402, Institut Federatif de Recherche 65, Laboratoire de Biologie Cellulaire, Faculté de Médecine Saint-Antoine, 75571 Paris Cedex 12, France

Address all correspondence and requests for reprints to: Dr. Gisele Cherqui, INSERM U-402, IFR 65, Laboratoire de Biologie Cellulaire, Faculté de Médecine Saint-Antoine, 27 rue Chaligny, 75571 Paris Cedex 12, France. E-mail: cherqui{at}st-antoine.inserm.fr

We examined the effect of insulin on protein kinase C (PKC) expression and the implication of the mitogen-activated protein kinase kinase 1 mitogen-activated protein kinase (MAPK) pathway in this effect. PKC expression was measured by quantitative RT-PCR and Western blotting using Chinese hamster ovary (CHO) cells overexpressing human insulin receptors of the wild type (CHO-R) or insulin receptors mutated at Tyr^1162/1163 autophosphorylation sites (CHO-Y2). In CHO-R cells, insulin caused a time- and concentration-dependent increase in PKC messenger RNA, with a maximum at 6 h and 10^-8 M insulin. This increase involved a transcriptional mechanism, as it was not due to stabilization of PKC messenger RNA and was associated with a similar increase in the immunoreactive PKC level. Insulin induction of PKC expression involved the MEK1-MAPK pathway, as it was 1) almost completely suppressed by the potent MEK1 inhibitor PD98059, 2) mimicked by the dominant-active MEK1 (S218D/S222D) mutant, and 3) associated with sustained MAPK activation. In CHO-Y2 cells in which the early phase of MAPK activation by insulin was lost and only the late and sustained phase of activation was observed, insulin signaling of PKC expression was preserved and again involved the MEK1-MAPK pathway. Moreover, we show that in both CHO-R and CHO-Y2 cells, insulin stimulation of PKC gene expression was associated with prolonged activation of nuclear p44^MAPK. These results indicate that induction of PKC gene expression by insulin is independent of Tyr^1162/1163 autophosphorylation sites and correlates with sustained activation of p44^MAPK at the nuclear level.

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