Oxidative stress induces premature senescence by stimulating caveolin-1 gene transcription through p38 mitogen-activated protein kinase/Sp1-mediated activation of two GC-rich promoter elements

Cancer Res. 2006 Nov 15;66(22):10805-14. doi: 10.1158/0008-5472.CAN-06-1236.


Cellular senescence is believed to represent a natural tumor suppressor mechanism. We have previously shown that up-regulation of caveolin-1 was required for oxidative stress-induced premature senescence in fibroblasts. However, the molecular mechanisms underlying caveolin-1 up-regulation in senescent cells remain unknown. Here, we show that subcytotoxic oxidative stress generated by hydrogen peroxide application promotes premature senescence and stimulates the activity of a (-1,296) caveolin-1 promoter reporter gene construct in fibroblasts. Functional deletion analysis mapped the oxidative stress response elements of the mouse caveolin-1 promoter to the sequences -244/-222 and -124/-101. The hydrogen peroxide-mediated activation of both Cav-1 (-244/-222) and Cav-1 (-124/-101) was prevented by the antioxidant quercetin. Combination of electrophoretic mobility shift studies, chromatin immunoprecipitation analysis, Sp1 overexpression experiments, as well as promoter mutagenesis identifies enhanced Sp1 binding to two GC-boxes at -238/-231 and -118/-106 as the core mechanism of oxidative stress-triggered caveolin-1 transactivation. In addition, signaling studies show p38 mitogen-activated protein kinase (MAPK) as the upstream regulator of Sp1-mediated activation of the caveolin-1 promoter following oxidative stress. Inhibition of p38 MAPK prevents the oxidant-induced Sp1-mediated up-regulation of caveolin-1 protein expression and development of premature senescence. Finally, we show that oxidative stress induces p38-mediated up-regulation of caveolin-1 and premature senescence in normal human mammary epithelial cells but not in MCF-7 breast cancer cells, which do not express caveolin-1 and undergo apoptosis. This study delineates for the first time the molecular mechanisms that modulate caveolin-1 gene transcription upon oxidative stress and brings new insights into the redox control of cellular senescence in both normal and cancer cells.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antioxidants / pharmacology
  • Caveolin 1 / biosynthesis*
  • Caveolin 1 / genetics
  • Caveolin 1 / metabolism
  • Cell Line, Tumor
  • Cellular Senescence / drug effects
  • Cellular Senescence / physiology
  • Enzyme Activation
  • Humans
  • Hydrogen Peroxide / pharmacology
  • Mice
  • NIH 3T3 Cells
  • Oxidants / pharmacology
  • Oxidative Stress / genetics
  • Oxidative Stress / physiology
  • Promoter Regions, Genetic
  • Quercetin / pharmacology
  • Response Elements
  • Sp1 Transcription Factor / biosynthesis
  • Sp1 Transcription Factor / genetics
  • Sp1 Transcription Factor / metabolism*
  • Transcription, Genetic
  • Up-Regulation
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • p38 Mitogen-Activated Protein Kinases / metabolism*


  • Antioxidants
  • Caveolin 1
  • Oxidants
  • Sp1 Transcription Factor
  • Quercetin
  • Hydrogen Peroxide
  • p38 Mitogen-Activated Protein Kinases