title: Involvement of Rel/nuclear factor-kappaB transcription factors in keratinocyte senescence.
abstract: After a finite doubling number, normal cells become senescent, i.e., nonproliferating and apoptosis resistant. Because Rel/nuclear factor (NF)-kappaB 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 beta-galactosidase (SA-beta-Gal) activity. Normal senescent keratinocytes display a greater endogenous Rel/NF-kappaB DNA binding activity than young cells; inhibiting this activity in presenescent cells decreases the number of cells expressing the SA-beta-Gal marker. Normal senescent keratinocytes and cRel-induced premature senescent keratinocytes overexpressed manganese superoxide dismutase (MnSOD), a redox enzyme encoded by a Rel/NF-kappaB target gene. MnSOD transforms the toxic O()(2) into H(2)O(2), whereas catalase and glutathione peroxidase convert H(2)O(2) into H(2)O. Neither catalase nor glutathione peroxidase is up-regulated during cRel-induced premature senescence or during normal senescence, suggesting that H(2)O(2) accumulates. Quenching H(2)O(2) by catalase delays the occurrence of both normal and premature cRel-induced senescence. Conversely, adding a nontoxic dose of H(2)O(2) to the culture medium of young normal keratinocytes induces a premature senescence-like state. All these results indicate that Rel/NF-kappaB factors could take part in the occurrence of senescence by generating an oxidative stress via the induction of MnSOD.
authors.affiliation: UMR 8117 CNRS-Institut Pasteur de Lille-Université Lille 1, Institut de Biologie de Lille, Lille Cedex, France.
authors.forename: David
authors.initials: D
authors.lastname: Bernard
authors.forename: Karo
authors.initials: K
authors.lastname: Gosselin
authors.forename: Didier
authors.initials: D
authors.lastname: Monte
authors.forename: Chantal
authors.initials: C
authors.lastname: Vercamer
authors.forename: Fatima
authors.initials: F
authors.lastname: Bouali
authors.forename: Albin
authors.initials: A
authors.lastname: Pourtier
authors.forename: Bernard
authors.initials: B
authors.lastname: Vandenbunder
authors.forename: Corinne
authors.initials: C
authors.lastname: Abbadie
mesh_terms: D000260:Adenoviruses, Human / Q000235:genetics; D000328:Adult; D000368:Aged; D017209:Apoptosis; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000502:physiology*; D017931:DNA Primers; D004847:Epithelial Cells / Q000166:cytology / Q000502:physiology; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D005822:Genetic Vectors; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000502:physiology*; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D020569:Proto-Oncogene Proteins c-rel / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D017931:DNA Primers; D016328:NF-kappa B; D020569:Proto-Oncogene Proteins c-rel