Subcytotoxic H2O2 Stress Triggers a Release of Transforming Growth Factor-β1, Which Induces Biomarkers of Cellular Senescence of Human Diploid Fibroblasts

Abstract

Stress-induced premature senescence (SIPS) is induced 3 days after exposure of human diploid fibroblasts to subcytotoxic oxidative stress with H2O2, with appearance of several biomarkers of replicative senescence. In this work, we show that transforming growth factor-β1 (TGF-β1) regulates the induction of several of these biomarkers in SIPS: cellular morphology, senescence-associated β-galactosidase activity, increase in the steady-state level of fibronectin, apolipoprotein J, osteonectin, and SM22 mRNA. Indeed, the neutralization of TGF-β1 or its receptor (TGF-β RII) using specific antibodies decreases sharply the percentage of cells positive for the senescent-associated β-galactosidase activity and displaying a senescent morphology. In the presence of each of these antibodies, the steady-state level of fibronectin, osteonectin, apolipoprotein J, and SM22 mRNA is no more increased at 72 h after stress. Results obtained on fibroblasts retrovirally transfected with the human papillomavirus E7 cDNA suggest that retinoblastoma protein (Rb) regulates the expression of TGF-β1 in stressful conditions, leading to SIPS and overexpression of these four genes.