Subcytotoxic H2O2 stress triggers a release of transforming growth factor-beta 1, which induces biomarkers of cellular senescence of human diploid fibroblasts

J Biol Chem. 2001 Jan 26;276(4):2531-7. doi: 10.1074/jbc.M006809200. Epub 2000 Nov 1.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cells, Cultured
  • Cellular Senescence / physiology*
  • Fibroblasts / cytology
  • Gene Expression Regulation
  • Humans
  • Hydrogen Peroxide / pharmacology*
  • Oncogene Proteins, Viral
  • Oxidative Stress / physiology*
  • Papillomavirus E7 Proteins
  • Protein-Serine-Threonine Kinases
  • RNA, Messenger / biosynthesis
  • Receptor, Transforming Growth Factor-beta Type II
  • Receptors, Transforming Growth Factor beta
  • Repressor Proteins*
  • Transforming Growth Factor beta / metabolism*
  • Transforming Growth Factor beta1
  • beta-Galactosidase / biosynthesis
  • beta-Galactosidase / genetics


  • E6 protein, Human papillomavirus type 16
  • Oncogene Proteins, Viral
  • Papillomavirus E7 Proteins
  • RNA, Messenger
  • Receptors, Transforming Growth Factor beta
  • Repressor Proteins
  • TGFB1 protein, human
  • Transforming Growth Factor beta
  • Transforming Growth Factor beta1
  • oncogene protein E7, Human papillomavirus type 16
  • Hydrogen Peroxide
  • Protein-Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type II
  • beta-Galactosidase