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[Cancer Research 64, 472-481, January 15, 2004]
© 2004 American Association for Cancer Research

Regular Articles

Involvement of Rel/Nuclear Factor-{kappa}B Transcription Factors in Keratinocyte Senescence

David Bernard1, Karo Gosselin1, Didier Monte1, Chantal Vercamer1, Fatima Bouali1, Albin Pourtier2, Bernard Vandenbunder1 and Corinne Abbadie1

1 UMR 8117 CNRS-Institut Pasteur de Lille-Université Lille 1, Institut de Biologie de Lille, Lille Cedex, France, and
2 Laboratoire de Biologie du Développement, Université Lille 1, Villeneuve d’Ascq Cedex, France

After a finite doubling number, normal cells become senescent, i.e., nonproliferating and apoptosis resistant. Because Rel/nuclear factor (NF)-{kappa}B transcription factors regulate both proliferation and apoptosis, we have investigated their involvement in senescence. cRel overexpression in young normal keratinocytes results in premature senescence, as defined by proliferation blockage, apoptosis resistance, enlargement, and appearance of senescence-associated ß-galactosidase (SA-ß-Gal) activity. Normal senescent keratinocytes display a greater endogenous Rel/NF-{kappa}B DNA binding activity than young cells; inhibiting this activity in presenescent cells decreases the number of cells expressing the SA-ß-Gal marker. Normal senescent keratinocytes and cRel-induced premature senescent keratinocytes overexpressed manganese superoxide dismutase (MnSOD), a redox enzyme encoded by a Rel/NF-{kappa}B target gene. MnSOD transforms the toxic O

2 into H2O2, whereas catalase and glutathione peroxidase convert H2O2 into H2O. Neither catalase nor glutathione peroxidase is up-regulated during cRel-induced premature senescence or during normal senescence, suggesting that H2O2 accumulates. Quenching H2O2 by catalase delays the occurrence of both normal and premature cRel-induced senescence. Conversely, adding a nontoxic dose of H2O2 to the culture medium of young normal keratinocytes induces a premature senescence-like state. All these results indicate that Rel/NF-{kappa}B factors could take part in the occurrence of senescence by generating an oxidative stress via the induction of MnSOD.




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Copyright © 2004 by the American Association for Cancer Research.