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.