Caveolin-1 expression is required for the development of pulmonary emphysema through activation of the ATM-p53-p21 pathway.
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.
Volonte
Daniela
D
Department of Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA.
Kahkonen
Beth
B
Shapiro
Steven
S
Di
Yuanpu
Y
Galbiati
Ferruccio
F
D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D021941:Caveolae; D051242:Caveolin 1 / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002462:Cell Membrane; D016922:Cellular Senescence / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D015151:Immunoblotting; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D054648:Protein Phosphatase 2; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011656:Pulmonary Emphysema / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D012907:Smoking / Q000009:adverse effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
D051242:Caveolin 1; C493957:Cdkn1a protein, mouse; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases; D054648:Protein Phosphatase 2