Inhibition of thioredoxin reductase 1 by caveolin 1 promotes stress-induced premature senescence.
Thioredoxin reductase 1 (TrxR1) is an important antioxidant enzyme that controls cellular redox homeostasis. By using a proteomic-based approach, here we identify TrxR1 as a caveolar membrane-resident protein. We show that caveolin 1, the structural protein component of caveolae, is a TrxR1-binding protein by demonstrating that the scaffolding domain of caveolin 1 (amino acids 82-101) binds directly to the caveolin-binding motif (CBM) of TrxR1 (amino acids 454-463). We also show that overexpression of caveolin 1 inhibits TrxR activity, whereas a lack of caveolin 1 activates TrxR, both in vitro and in vivo. Expression of a peptide corresponding to the caveolin 1 scaffolding domain is sufficient to inhibit TrxR activity. A TrxR1 mutant lacking the CBM, which fails to localize to caveolae and bind to caveolin 1, is constitutively active and inhibits oxidative-stress-mediated activation of the p53/p21(Waf1/Cip1) pathway and induction of premature senescence. Finally, we show that caveolin 1 expression inhibits TrxR1-mediated cell transformation. Thus, caveolin 1 links free radicals to activation of the p53/p21(Waf1/Cip1) pathway and induction of cellular senescence by acting as an endogenous inhibitor of TrxR1.
Volonte
Daniela
D
Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA.
Galbiati
Ferruccio
F
D000818:Animals; D051242:Caveolin 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics; D016922:Cellular Senescence / Q000187:drug effects / Q000235:genetics; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D008954:Models, Biological; D041681:NIH 3T3 Cells; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D034741:RNA, Small Interfering / Q000494:pharmacology / Q000627:therapeutic use; D054481:Thioredoxin Reductase 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D023041:Xenograft Model Antitumor Assays
D051242:Caveolin 1; D034741:RNA, Small Interfering; D006861:Hydrogen Peroxide; C516124:TXNRD1 protein, human; D054481:Thioredoxin Reductase 1