Oxidative, multistep activation of the noncanonical NF-kappaB pathway via disulfide Bcl-3/p50 complex.
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-kappaB- and p65-independent NF-kappaB 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
Silvia
S
Laboratoire de Biologie Moléculaire et Cellulaire du Cancer, Fondation Recherche sur le Cancer et les Maladies du Sang, Hôpital Kirchberg, Luxembourg.
Morceau
Franck
F
Scovassi
A Ivana
AI
Dicato
Mario
M
Ghibelli
Lina
L
Diederich
Marc
M
D000081242:B-Cell Lymphoma 3 Protein; D019328:Buthionine Sulfoximine; D005786:Gene Expression Regulation / Q000502:physiology; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D052002:NF-kappa B p50 Subunit / Q000378:metabolism*; D010084:Oxidation-Reduction; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D017382:Reactive Oxygen Species; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D020298:U937 Cells; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D000081242:B-Cell Lymphoma 3 Protein; C000631344:BCL3 protein, human; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D051996:Transcription Factor RelA; D014157:Transcription Factors; D019328:Buthionine Sulfoximine; D051550:I-kappa B Kinase; D048051:p38 Mitogen-Activated Protein Kinases; D005978:Glutathione