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J Biol Chem, Vol. 273, Issue 5, 2931-2938, January 30, 1998

A Role for Nuclear Factor kappa B in the Antiapoptotic Function of Insulin

France Bertrand, Azeddine AtfiDagger , Axelle Cadoret, Gilles L'Allemain, Hélène Robin, Olivier Lascols, Jacqueline Capeau, and Gisèle Cherqui

From INSERM U.402, Institut Fédératif de Recherche 65, Laboratoire de Biologie Cellulaire, Faculté de Médecine Saint-Antoine, 27 rue Chaligny, 75571 Paris, Cedex 12, France, the Dagger  INSERM U.482, Institut Fédératif de Recherche 65, Hôpital Saint-Antoine, 184 rue du Faubourg Saint-Antoine, 75571 Paris, Cedex 12 France, and the  Centre de Biochimie, CNRS, Unité Mixte de Recherche 134, Faculté des Sciences, Parc Valrose, 06108 Nice, Cedex 02, France

We previously reported that insulin activates nuclear factor kappa B (NF-kappa B) in Chinese hamster ovary (CHO)-R cells overexpressing wild-type insulin receptors (IRs) through a pathway requiring IR tyrosine kinase and Raf-1 kinase activities. We now investigated whether the activation of NF-kappa B by insulin could serve an antiapoptotic function. Insulin (10-9-10-7 M) inhibited apoptosis induced by serum withdrawal in CHO-R cells in a concentration-dependent manner. Insulin antiapoptotic signaling: (i) was dependent on IR number and IR tyrosine kinase activity since it was reduced in parental CHO cells and was abolished in CHO-Y2 cells overexpressing IRs mutated at Tyr1162/1163; (ii) was, like insulin activation of NF-kappa B, dependent on Raf-1 but not on mitogen-activated protein kinase activity since both processes were decreased by the dominant-negative Raf-1 mutant Raf-C4 whereas they persisted in mitogen-activated protein kinase-depleted cells; and (iii) required NF-kappa B activation since it was decreased by proteasome inhibitors and the dominant-negative Ikappa B-alpha (A32/36) mutant and was mimicked by overexpression of the NF-kappa B c-Rel subunit. We also show that insulin antiapoptotic signaling but not insulin activation of NF-kappa B involved phosphatidylinositol 3-kinase (PI 3-kinase), as supported by the inhibition of the former but not of the latter process by the PI 3-kinase inhibitor LY294002. Inhibition of both NF-kappa B and PI 3-kinase totally abolished insulin antiapoptotic signaling. Thus insulin exerts a specific antiapoptotic function which is dependent on IR tyrosine kinase activity and is mediated by both a Raf-1-dependent pathway that leads to NF-kappa B activation and a PI 3-kinase-dependent pathway.


Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.
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