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Antiproliferative and Antiapoptotic Effects of cRel May Occur within the Same Cells via the Up-Regulation of Manganese Superoxide Dismutase¹

EP 560 [D. B., B. V., C. A.] and UMR 8526 [B. Q., A. B.], Centre National de la Recherche Scientifique/Institut Pasteur de Lille/Université Lille 2, Institut de Biologie de Lille, 59021 Lille Cedex, France

Rel/nuclear factor B transcription factors were shown to have either pro- or antiapoptotic as well as pro- or antiproliferative functions, and it is often assumed that the outcome of their activation depends on the cell type or cellular context. Inconsistent with this assumption, we show here that cRel is able in one cell type to inhibit proliferation, protect against apoptosis induced by tumor necrosis factor (TNF-) + cycloheximide (CHX), and increase the basal rate of apoptosis. Both the effects of proliferation inhibition and protection against TNF- + CHX-induced apoptosis are massive and occur in the same cells. Using reverse transcription-PCR, Western blot and immunofluorescence, and transactivation assays, we found that the manganese superoxide dismutase (MnSOD), an enzyme that converts O₂ in H₂O₂, is up-regulated by cRel through a B site in intron 2. Inhibition of MnSOD induction by antisense oligonucleotides and overexpression of MnSOD respectively reverts and mimics both the antiproliferative and antiapoptotic effects of cRel, suggesting that they both occur via the induction of this gene. On one hand, MnSOD could improve the efficiency of cRel-overexpressing cells in eliminating toxic O₂ produced on TNF- treatment, explaining why they escape TNF--induced apoptosis. On the other hand, cRel-overexpressing cells should accumulate H₂O₂. We present evidence linking this H₂O₂ accumulation to the proliferation arrest induced by cRel. Therefore, different effects on proliferation and apoptosis could arise from the induction of MnSOD and thus coexist in cRel-overexpressing cells.

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