Subcytotoxic H2O2 stress triggers a release of transforming growth factor-beta 1, which induces biomarkers of cellular senescence of human diploid fibroblasts.
Stress-induced premature senescence (SIPS) is induced 3 days after exposure of human diploid fibroblasts to subcytotoxic oxidative stress with H(2)O(2), with appearance of several biomarkers of replicative senescence. In this work, we show that transforming growth factor-beta1 (TGF-beta1) regulates the induction of several of these biomarkers in SIPS: cellular morphology, senescence-associated beta-galactosidase activity, increase in the steady-state level of fibronectin, apolipoprotein J, osteonectin, and SM22 mRNA. Indeed, the neutralization of TGF-beta1 or its receptor (TGF-beta RII) using specific antibodies decreases sharply the percentage of cells positive for the senescent-associated beta-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-beta1 in stressful conditions, leading to SIPS and overexpression of these four genes.
Frippiat
C
C
University of Namur, Facultés Universitaires Notre-Dame de la Paix, Department of Biology, Unit of Cellular Biochemistry & Biology, 61 Rue de Bruxelles, B-5000 Namur, Belgium.
Chen
Q M
QM
Zdanov
S
S
Magalhaes
J P
JP
Remacle
J
J
Toussaint
O
O
D002478:Cells, Cultured; D016922:Cellular Senescence / Q000502:physiology*; D005347:Fibroblasts / Q000166:cytology; D005786:Gene Expression Regulation; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D009856:Oncogene Proteins, Viral; D018384:Oxidative Stress / Q000502:physiology*; D050725:Papillomavirus E7 Proteins; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger / Q000096:biosynthesis; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta; D012097:Repressor Proteins; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D053773:Transforming Growth Factor beta1; D001616:beta-Galactosidase / Q000096:biosynthesis / Q000235:genetics
C068651:E6 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; D012097:Repressor Proteins; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; C059731:oncogene protein E7, Human papillomavirus type 16; D006861:Hydrogen Peroxide; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D001616:beta-Galactosidase