J Biol Chem, Vol. 274, Issue 43, 30596-30602, October 22, 1999

Insulin Antiapoptotic Signaling Involves Insulin Activation of the Nuclear Factor B-dependent Survival Genes Encoding Tumor Necrosis Factor Receptor-associated Factor 2 and Manganese-superoxide Dismutase

France Bertrand, Christèle Desbois-Mouthon, Axelle Cadoret, Céline Prunier^§, Hélène Robin, Jacqueline Capeau, Azeddine Atfi^§, and Gisèle Cherqui

From  INSERM U.402, Faculté de Médecine Saint-Antoine, 27, rue Chaligny and ^§ INSERM U.482, Hôpital Saint-Antoine, 184, rue du Faubourg Saint-Antoine, 75571 Paris Cedex 12, France

We recently showed that the antiapoptotic function of insulin requires nuclear factor B (NF-B) activation (Bertrand, F., Atfi, A., Cadoret, A., L'Allemain, G., Robin, H., Lascols, O., Capeau, J., and Cherqui, G. (1998) J. Biol. Chem. 273, 2931-2938). Here we sought to identify the NF-B-dependent survival genes that are activated by insulin to mediate this function. Insulin increased the expression of tumor necrosis factor receptor-associated factor 2 (TRAF2) mRNA and protein in Chinese hamster ovary cells overexpressing insulin receptors (IRs). This effect required (i) IR activation since it was abrogated by IR mutation at tyrosines 1162 and 1163 and (ii) NF-B activation since it was abolished by overexpression of dominant-negative IB-(A32/36) and mimicked by overexpression of the NF-B c-Rel subunit. TRAF2 contributed to insulin protection against serum withdrawal-induced apoptosis since TRAF2 overexpression mimicked insulin protection, whereas overexpression of dominant-negative TRAF2-(87-501) reduced this process. Along with its protective effect, overexpressed TRAF2 increased basal and insulin-stimulated NF-B activities. All effects were inhibited by IB-(A32/36), suggesting that an amplification loop involving TRAF2 activation of NF-B is implicated in insulin antiapoptotic signaling. We also show that insulin increased manganese-superoxide dismutase (Mn-SOD) mRNA expression through NF-B activation and that Mn-SOD contributed to insulin antiapoptotic signaling since expression of antisense Mn-SOD RNA decreased this process. This study provides the first evidence that insulin activates the NF-B-dependent survival genes encoding TRAF2 and Mn-SOD and thereby clarifies the role of NF-B in the antiapoptotic function of insulin.