An altered repertoire of [formula omitted] (AP-1) at the onset of replicative senescence

Abstract

With multiple divisions in culture, normal diploid cells suffer a loss of growth potential that leads to replicative senescence and a finite replicative capacity. Using quantitative RT-PCR, we have monitored mRNA expression levels of c-fos, c-jun, Jun B, c-myc, p53, H-ras, and histone H4 during the replicative senescence of human fibroblasts. The earliest and the largest changes in gene expression occurred in c-fosand jun B at mid-senescence prior to the first slowing in cell growth rates. The basal level of c- fos mRNA decreased to one-ninth that of the early-passage levels, while junB declined to one-third and c- jun expression remained constant. The decline in the basal c- fos mRNA level in mid-senescence should lead to an increase in Jun/Jun AP-1 homodimers at the expense of Fos/Jun heterodimers and may trigger a cascade of further changes in c- myc, p53, and H- ras expression in late-passage senescent fibroblasts.