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Oxidative, multistep activation of the noncanonical NF-B pathway via disulfide Bcl-3/p50 complex

Silvia Cristofanon^*,, Franck Morceau^*, A. Ivana Scovassi, Mario Dicato^*, Lina Ghibelli^,1 and Marc Diederich^*,1

^* Laboratoire de Biologie Moléculaire et Cellulaire du Cancer, Fondation Recherche sur le Cancer et les Maladies du Sang, Hôpital Kirchberg, Luxembourg;

Dipartimento di Biologia, Università di Roma "Tor Vergata," Rome, Italy; and

Istituto di Genetica Molecolare Consiglio Nazionale delle Ricerche, Pavia, Italy

¹ Correspondence: L.G., Dipartimento di Biologia, Università di Roma "Tor Vergata," Via della Ricerca Scientifica, 00133 Rome, Italy. E-mail: ghibelli{at}uniroma2.it; M.D., Laboratoire de Biologie Moléculaire et Cellulaire du Cancer, Fondation Recherche sur le Cancer et les Maladies du Sang, Hôpital Kirchberg, 9, rue Edward Steichen, L-2540 Luxembourg. E-mail: marc.diederich{at}lbmcc.lu

Buthionine sulfoximine (BSO) is a well-known inhibitor of glutathione synthesis, producing slow glutathione (GSH) depletion and oxidative stress; some "responder" cells avoid BSO-induced death by trans-activating the prosurvival protein Bcl-2. Here we show that BSO activates a noncanonical, inhibitory NF-B- and p65-independent NF-B pathway via a multistep process leading to the up-regulation of Bcl-2. The slow BSO-induced GSH depletion allows separation of two redox-related phases, namely, early thiol disequilibrium and late frank oxidative stress; each phase contributes to the progressive activation of a p50-p50 homodimer. The early phase, coinciding with substantial thiol depletion, produces a cytosolic preparative complex, consisting of p50 and its interactor Bcl-3 linked by interprotein disulfide bridges. The late phase, coinciding with reactive oxygen species production, is responsible, probably via p38 activation, for nuclear targeting of the complex and trans-activation of Bcl-2.—Cristofanon, S., Morceau, F., Scovassi, A. I., Dicato, M., Ghibelli, L., Diederich, M. Oxidative, multistep activation of the noncanonical NF-B pathway via disulfide Bcl-3/p50 complex.

Key Words: glutathione • Bcl-2 • ROS • p38

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