Caveolin-1 expression is required for the development of pulmonary emphysema through activation of the ATM-p53-p21 pathway

J Biol Chem. 2009 Feb 27;284(9):5462-6. doi: 10.1074/jbc.C800225200. Epub 2008 Dec 22.

Abstract

Free radicals play a role in aging and age-related human diseases, including pulmonary emphysema. Cigarette smoke represents a source of oxidants and is considered an environmental hazard that causes pulmonary emphysema. Here, we show that caveolin-1 activates ataxia telangiectasia-mutated (ATM) after oxidative stress by sequestering the ATM inhibitor, the catalytic subunit of protein phosphatase 2A, into caveolar membranes. We demonstrate that cigarette smoke extracts promote stress-induced premature senescence in wild type but not caveolin-1 null lung fibroblasts and that caveolin-1 expression is required for activation of the ATM-p53-p21(Waf1)(/)(Cip1) pathway following stimulation with cigarette smoke extracts in vitro. In vivo studies show that caveolin-1 expression is necessary for cigarette smoking-induced senescence of lung fibroblasts and pulmonary emphysema. These findings bring new insights into the molecular mechanism underlying free radical activation of the ATM-p53 pathway and indicate that caveolin-1 is a novel therapeutic target for the treatment and/or prevention of pulmonary emphysema.

Publication types

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

MeSH terms

  • Animals
  • Ataxia Telangiectasia Mutated Proteins
  • Caveolae
  • Caveolin 1 / physiology*
  • Cell Cycle Proteins / metabolism*
  • Cell Membrane
  • Cellular Senescence / drug effects
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism*
  • DNA-Binding Proteins / metabolism*
  • Fibroblasts / metabolism
  • Fibroblasts / pathology
  • Immunoblotting
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Protein Phosphatase 2
  • Protein Serine-Threonine Kinases / metabolism*
  • Pulmonary Emphysema / etiology
  • Pulmonary Emphysema / metabolism*
  • Pulmonary Emphysema / pathology
  • Signal Transduction*
  • Smoking / adverse effects
  • Tumor Suppressor Protein p53 / metabolism*
  • Tumor Suppressor Proteins / metabolism*

Substances

  • Caveolin 1
  • Cdkn1a protein, mouse
  • Cell Cycle Proteins
  • Cyclin-Dependent Kinase Inhibitor p21
  • DNA-Binding Proteins
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Atm protein, mouse
  • Protein Serine-Threonine Kinases
  • Protein Phosphatase 2