Gene expression and regulation in H₂O₂-induced premature senescence of human foreskin fibroblasts expressing or not telomerase

We compared the DNA-binding activity of transcription factors and gene expression patterns in BJ human diploid fibroblasts (HDFs) expressing or not telomerase (hTERT) in stress-induced premature senescence (SIPS). Senescent BJ cells were also studied. Hydrogen peroxide (H₂O₂)-induced SIPS modulated gene expression in both BJ and hTERT-BJ1 cells. Increased p21^WAF-1 mRNA level was amongst the common gene expression changes in BJ and hTERT-BJ1 cells induced by SIPS. Telomerase expression markedly changed gene expression in non-stressful conditions. Expression patterns of senescent BJ cells partially overlapped those of BJ and hTERT-BJ1 cells in SIPS. The basal levels of DNA-binding activity of NF-κB and phosphorylated ATF-2 were different in BJ and hTERT-BJ1 cells. Both cell lines displayed a higher DNA-binding activity of p53 and HIF-1 72 h after H₂O₂ exposure. Our results indicate that similar mechanisms involving p21 ^WAF-1 and probably p53 are at work in BJ and hTERT-BJ1 HDFs under H₂O₂-induced SIPS, suggesting that generalized DNA damage rather than telomere length/telomerase plays a crucial role in H ₂O₂-induced SIPS. We propose that H₂O ₂-induced SIPS involves a rearrangement of proliferative and apoptotic pathways. The marked changes in gene expression induced by telomerase suggest that apart from immortalization of HDFs, telomerase also alters the normal cellular functions but does not protect against SIPS. © 2004 Elsevier Inc. All rights reserved.