Involvement of Rel/nuclear factor-kappaB transcription factors in keratinocyte senescence.
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.
Bernard
David
D
UMR 8117 CNRS-Institut Pasteur de Lille-Université Lille 1, Institut de Biologie de Lille, Lille Cedex, France.
Gosselin
Karo
K
Monte
Didier
D
Vercamer
Chantal
C
Bouali
Fatima
F
Pourtier
Albin
A
Vandenbunder
Bernard
B
Abbadie
Corinne
C
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
D017931:DNA Primers; D016328:NF-kappa B; D020569:Proto-Oncogene Proteins c-rel