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J Biol Chem, Vol. 273, Issue 5, 2931-2938, January 30, 1998
A Role for Nuclear Factor B in the Antiapoptotic Function
of Insulin
France
Bertrand,
Azeddine
Atfi ,
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
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 B (NF- 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- 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- 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- B activation since it was decreased by proteasome
inhibitors and the dominant-negative I B- (A32/36) mutant and was
mimicked by overexpression of the NF- B c-Rel subunit. We also show
that insulin antiapoptotic signaling but not insulin activation of
NF- 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- 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- 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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Copyright © 1998 by the American Society for Biochemistry and Molecular Biology.
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