Nuclear Erythroid Factor 2-mediated Proteasome Activation Delays Senescence in Human Fibroblasts

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2010 Jan 14

PMID 20068043

Citations 110

Authors

Suzanne Kapeta

Niki Chondrogianni

Efstathios S Gonos

Affiliations

Soon will be listed here.

Abstract

Replicative senescence in human fibroblasts is accompanied with alterations of various biological processes, including the impaired function of the proteasome. The proteasome is responsible for the removal of both normal and damaged proteins. Due to its latter function, proteasome is also considered a representative secondary antioxidant cellular mechanism. Nrf2 is a basic transcription factor responsible for the regulation of the cellular antioxidant response that has also been shown to regulate several proteasome subunits in mice. We have established in this study the proteasome-related function of Nrf2 in human fibroblasts undergoing replicative senescence. We demonstrate that Nrf2 has a declined function in senescence, whereas its silencing leads to premature senescence. However, upon its activation by a novel Nrf2 inducer, elevated levels of proteasome activity and content are recorded only in cell lines possessing a functional Nrf2. Moreover, treatment by the Nrf2 inducer results in the enhanced survival of cells following oxidative stress, whereas continuous treatment leads to lifespan extension of human fibroblasts. Importantly the Nrf2-proteasome axis is functional in terminally senescent cultures as these cells retain their responsiveness to the Nrf2 stimuli. In conclusion, these findings open up new directions for future manipulation of the senescence phenotype.

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References

Kensler T, Wakabayashi N, Biswal S . Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway. Annu Rev Pharmacol Toxicol. 2006; 47:89-116. DOI: 10.1146/annurev.pharmtox.46.120604.141046. View

Kwak M, Wakabayashi N, Greenlaw J, Yamamoto M, Kensler T . Antioxidants enhance mammalian proteasome expression through the Keap1-Nrf2 signaling pathway. Mol Cell Biol. 2003; 23(23):8786-94. PMC: 262680. DOI: 10.1128/MCB.23.23.8786-8794.2003. View

Wei P, Ahn Y, Housley P, Alam J, Vedeckis W . Modulation of hormone-dependent glucocorticoid receptor function using a tetracycline-regulated expression system. J Steroid Biochem Mol Biol. 1998; 64(1-2):1-12. DOI: 10.1016/s0022-1759(97)89907-3. View

Ciechanover A . Intracellular protein degradation: from a vague idea, through the lysosome and the ubiquitin-proteasome system, and onto human diseases and drug targeting (Nobel lecture). Angew Chem Int Ed Engl. 2005; 44(37):5944-67. DOI: 10.1002/anie.200501428. View

Dinkova-Kostova A, Holtzclaw W, Cole R, Itoh K, Wakabayashi N, Katoh Y . Direct evidence that sulfhydryl groups of Keap1 are the sensors regulating induction of phase 2 enzymes that protect against carcinogens and oxidants. Proc Natl Acad Sci U S A. 2002; 99(18):11908-13. PMC: 129367. DOI: 10.1073/pnas.172398899. View

Thimmulappa R, Fuchs R, Malhotra D, Scollick C, Traore K, Bream J . Preclinical evaluation of targeting the Nrf2 pathway by triterpenoids (CDDO-Im and CDDO-Me) for protection from LPS-induced inflammatory response and reactive oxygen species in human peripheral blood mononuclear cells and neutrophils. Antioxid Redox Signal. 2007; 9(11):1963-70. PMC: 2396226. DOI: 10.1089/ars.2007.1745. View

Przybysz A, Choe K, Roberts L, Strange K . Increased age reduces DAF-16 and SKN-1 signaling and the hormetic response of Caenorhabditis elegans to the xenobiotic juglone. Mech Ageing Dev. 2009; 130(6):357-69. PMC: 2680786. DOI: 10.1016/j.mad.2009.02.004. View

Petropoulou C, Chondrogianni N, Simoes D, Agiostratidou G, Drosopoulos N, Kotsota V . Aging and longevity. A paradigm of complementation between homeostatic mechanisms and genetic control?. Ann N Y Acad Sci. 2000; 908:133-42. DOI: 10.1111/j.1749-6632.2000.tb06642.x. View

Wasserman W, Fahl W . Functional antioxidant responsive elements. Proc Natl Acad Sci U S A. 1997; 94(10):5361-6. PMC: 24683. DOI: 10.1073/pnas.94.10.5361. View

10.

Alam J, Stewart D, Touchard C, Boinapally S, Choi A, Cook J . Nrf2, a Cap'n'Collar transcription factor, regulates induction of the heme oxygenase-1 gene. J Biol Chem. 1999; 274(37):26071-8. DOI: 10.1074/jbc.274.37.26071. View

11.

Chondrogianni N, Stratford F, Trougakos I, Friguet B, Rivett A, Gonos E . Central role of the proteasome in senescence and survival of human fibroblasts: induction of a senescence-like phenotype upon its inhibition and resistance to stress upon its activation. J Biol Chem. 2003; 278(30):28026-37. DOI: 10.1074/jbc.M301048200. View

12.

Tanaka K . Proteasomes: structure and biology. J Biochem. 1998; 123(2):195-204. DOI: 10.1093/oxfordjournals.jbchem.a021922. View

13.

Pearson K, Lewis K, Price N, Chang J, Perez E, Victoria Cascajo M . Nrf2 mediates cancer protection but not prolongevity induced by caloric restriction. Proc Natl Acad Sci U S A. 2008; 105(7):2325-30. PMC: 2268135. DOI: 10.1073/pnas.0712162105. View

14.

Hong F, Freeman M, Liebler D . Identification of sensor cysteines in human Keap1 modified by the cancer chemopreventive agent sulforaphane. Chem Res Toxicol. 2005; 18(12):1917-26. DOI: 10.1021/tx0502138. View

15.

Nguyen T, Yang C, Pickett C . The pathways and molecular mechanisms regulating Nrf2 activation in response to chemical stress. Free Radic Biol Med. 2004; 37(4):433-41. DOI: 10.1016/j.freeradbiomed.2004.04.033. View

16.

Surh Y, Kundu J, Na H . Nrf2 as a master redox switch in turning on the cellular signaling involved in the induction of cytoprotective genes by some chemopreventive phytochemicals. Planta Med. 2008; 74(13):1526-39. DOI: 10.1055/s-0028-1088302. View

17.

Kobayashi M, Li L, Iwamoto N, Nakajima-Takagi Y, Kaneko H, Nakayama Y . The antioxidant defense system Keap1-Nrf2 comprises a multiple sensing mechanism for responding to a wide range of chemical compounds. Mol Cell Biol. 2008; 29(2):493-502. PMC: 2612520. DOI: 10.1128/MCB.01080-08. View

18.

Kwak M, Kensler T . Induction of 26S proteasome subunit PSMB5 by the bifunctional inducer 3-methylcholanthrene through the Nrf2-ARE, but not the AhR/Arnt-XRE, pathway. Biochem Biophys Res Commun. 2006; 345(4):1350-7. DOI: 10.1016/j.bbrc.2006.05.043. View

19.

Kobayashi A, Kang M, Okawa H, Ohtsuji M, Zenke Y, Chiba T . Oxidative stress sensor Keap1 functions as an adaptor for Cul3-based E3 ligase to regulate proteasomal degradation of Nrf2. Mol Cell Biol. 2004; 24(16):7130-9. PMC: 479737. DOI: 10.1128/MCB.24.16.7130-7139.2004. View

20.

Chondrogianni N, Petropoulos I, Franceschi C, Friguet B, Gonos E . Fibroblast cultures from healthy centenarians have an active proteasome. Exp Gerontol. 2000; 35(6-7):721-8. DOI: 10.1016/s0531-5565(00)00137-6. View