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A Role for Nuclear Factor κB in the Antiapoptotic Function of Insulin*

F. Bertrand,A. Atfi,A. Cadoret,G. l'Allemain,Hélène Robin,O. Lascols,J. Capeau,G. Cherqui

Published 1998 in Journal of Biological Chemistry

ABSTRACT

We previously reported that insulin activates nuclear factor κB (NF-κB) 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-κB 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-κB, 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-κB activation since it was decreased by proteasome inhibitors and the dominant-negative IκB-α (A32/36) mutant and was mimicked by overexpression of the NF-κB c-Rel subunit. We also show that insulin antiapoptotic signaling but not insulin activation of NF-κB 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-κB 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-κB activation and a PI 3-kinase-dependent pathway.

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