title: Polymerase I and transcript release factor (PTRF)/cavin-1 is a novel regulator of stress-induced premature senescence.
abstract: According to the "free radical theory" of aging, premature senescence induced by oxidative stress contributes to organismal aging. Polymerase I and transcript release factor (PTRF)/cavin-1 is a structural protein component of caveolae, invaginations of the plasma membrane involved in signal transduction. We show that oxidative stress up-regulates PTRF/cavin-1 protein expression and promotes the interaction between PTRF/cavin-1 and caveolin-1, another structural protein component of caveolae. Consistent with these data, the number of caveolae is dramatically increased in cells subjected to oxidative stress. We demonstrate that down-regulation of PTRF/cavin-1 by shRNA significantly inhibits oxidative stress-induced premature senescence. Mechanistically, we found that PTRF/cavin-1 expression is necessary for the oxidant-induced sequestration of Mdm2, a negative regulator of p53, into caveolar membranes, away from p53, and activation of the p53/p21(Waf1/Cip1) pathway. Expression of a mutant form of PTRF/cavin-1, which fails to localize to caveolar membranes after oxidative stress, inhibits oxidative stress-induced activation of p53 and induction of premature senescence. Thus, PTRF/cavin-1 is a novel regulator of oxidative stress-induced premature senescence by acting as a link between free radicals and activation of the p53/p21(Waf1/Cip1) pathway.
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261.
authors.forename: Daniela
authors.initials: D
authors.lastname: Volonte
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261. Electronic address: feg5@pitt.edu.
authors.forename: Ferruccio
authors.initials: F
authors.lastname: Galbiati
mesh_terms: D021941:Caveolae / Q000378:metabolism*; D051242:Caveolin 1 / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D016922:Cellular Senescence / Q000502:physiology*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009154:Mutation; D018384:Oxidative Stress / Q000502:physiology*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000502:physiology*
chemical_list: C497835:CAVIN1 protein, human; C493956:CDKN1A protein, human; D051242:Caveolin 1; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016601:RNA-Binding Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2