Oxidative stress activates a specific p53 transcriptional response that regulates cellular senescence and aging

Abstract

Summary Oxidative stress is a determining factor of cellular senescence and aging and a potent inducer of the tumour‐suppressor p53. Resistance to oxidative stress correlates with delayed aging in mammals, in the absence of accelerated tumorigenesis, suggesting inactivation of selected p53‐downstream pathways. We investigated p53 regulation in mice carrying deletion of p66, a mutation that retards aging and confers cellular resistance and systemic resistance to oxidative stress. We identified a transcriptional network of ~200 genes that are repressed by p53 and encode for determinants of progression through mitosis or suppression of senescence. They are selectively down‐regulated in cultured fibroblasts after oxidative stress, and, in vivo , in proliferating tissues and during physiological aging. Selectivity is imposed by p66 expression and activation of p44/p53 (also named Delta40p53), a p53 isoform that accelerates aging and prevents mitosis after protein damage. p66 deletion retards aging and increases longevity of p44/p53 transgenic mice. Thus, oxidative stress activates a specific p53 transcriptional response, mediated by p44/p53 and p66, which regulates cellular senescence and aging.

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References 44

1. 1.

   Alderman JM, Flurkey K, Brooks NL, Naik SB, Gutierrez JM, Srinivas U, Ziara KB, Jing L, Boysen G, Bronson R, Klebanov S, Chen X, Swenberg JA, Stridsberg M, Parker CE, Harrison DE, Combs TP. Neuroendocrine inhibition of glucose production and resistance to cancer in dwarf mice. Exp. Gerontol. 2009;44:26-33.

   Not in our library10.1016/j.exger.2008.05.014

2. 2.

   Baker DJ, Jeganathan KB, Cameron JD, Thompson M, Juneja S, Kopecka A, Kumar R, Jenkins RB, de Groen PC, Roche P, van Deursen JM. BubR1 insufficiency causes early onset of aging-associated phenotypes and infertility in mice. Nat. Genet. 2004;36:744-749.

   Not in our library10.1038/ng1382

3. 3.

   Baker DJ, Jeganathan KB, Malureanu L, Perez-Terzic C, Terzic A, van Deursen JM. Early aging-associated phenotypes in Bub3/Rae1 haploinsufficient mice. J. Cell Biol. 2006;172:529-540.

   Not in our library10.1083/jcb.200507081

4. 4.

   Baker DJ, Wijshake T, Tchkonia T, LeBrasseur NK, Childs BG, van de Sluis B, Kirkland JL, van Deursen JM. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature. 2011;479:232-236.

   Not in our library10.1038/nature10600

5. 5.

   Bluher M, Kahn BB, Kahn CR. Extended longevity in mice lacking the insulin receptor in adipose tissue. Science. 2003;299:572-574.

   Not in our library10.1126/science.1078223

6. 6.

   Bluher M, Patti ME, Gesta S, Kahn BB, Kahn CR. Intrinsic heterogeneity in adipose tissue of fat-specific insulin receptor knock-out mice is associated with differences in patterns of gene expression. J. Biol. Chem. 2004;279:31891-31901.

   Not in our library10.1074/jbc.m404569200

7. 7.

   Bokov A, Chaudhuri A, Richardson A. The role of oxidative damage and stress in aging. Mech. Ageing Dev. 2004;125:811-826.

   Not in our library10.1016/j.mad.2004.07.009

8. 8.

   Bourougaa K, Naski N, Boularan C, Mlynarczyk C, Candeias MM, Marullo S, Fahraeus R. Endoplasmic reticulum stress induces G2 cell-cycle arrest via mRNA translation of the p53 isoform p53/47. Mol. Cell. 2010;38:78-88.

   Not in our library10.1016/j.molcel.2010.01.041

9. 9.

   Brown-Borg HM. Longevity in mice: is stress resistance a common factor? Age (Dordr). 2006;28:145-162.

   Not in our library10.1007/s11357-006-9003-y

10. 10.

    Candeias MM, Powell DJ, Roubalova E, Apcher S, Bourougaa K, Vojtesek B, Bruzzoni-Giovanelli H, Fahraeus R. Expression of p53 and p53/47 are controlled by alternative mechanisms of messenger RNA translation initiation. Oncogene. 2006;25:6936-6947.

    Not in our library10.1038/sj.onc.1209996

11. 11.

    Desaint S, Luriau S, Aude JC, Rousselet G, Toledano MB. Mammalian antioxidant defences are not inducible by H2O2. J. Biol. Chem. 2004;279:31157-31163.

    Not in our library10.1074/jbc.m401888200

12. 12.

    Feng Z, Lin M, Wu R. The regulation of aging and longevity: a new and complex role of p53. Genes Cancer. 2011;2:443-452.

    Not in our library10.1177/1947601911410223

13. 13.

    Giorgio M, Migliaccio E, Orsini F, Paolucci D, Moroni M, Contursi C, Pelliccia G, Luzi L, Minucci S, Marcaccio M, Pinton P, Rizzuto R, Bernardi P, Paolucci F, Pelicci PG. Electron transfer between cytochrome c and p66Shc generates reactive oxygen species that trigger mitochondrial apoptosis. Cell. 2005;122:221-233.

    Not in our library10.1016/j.cell.2005.05.011

14. 14.

    Giorgio M, Trinei M, Migliaccio E, Pelicci PG. Hydrogen peroxide: a metabolic by-product or a common mediator of ageing signals? Nat. Rev. Mol. Cell Biol. 2007;8:722-728.

    Not in our library10.1038/nrm2240

15. 15.

    Gutierrez-Uzquiza A, Arechederra M, Molina I, Banos R, Maia V, Benito M, Guerrero C, Porras A. C3G down-regulates p38 MAPK activity in response to stress by Rap-1 independent mechanisms: involvement in cell death. Cell. Signal. 2010;22:533-542.

    Not in our library10.1016/j.cellsig.2009.11.008

16. 16.

    Hauck SJ, Aaron JM, Wright C, Kopchick JJ, Bartke A. Antioxidant enzymes, free-radical damage, and response to paraquat in liver and kidney of long-living growth hormone receptor/binding protein gene-disrupted mice. Horm. Metab. Res. 2002;34:481-486.

    Not in our library10.1055/s-2002-34787

17. 17.

    Huang TT, Carlson EJ, Gillespie AM, Shi Y, Epstein CJ. Ubiquitous overexpression of CuZn superoxide dismutase does not extend life span in mice. J. Gerontol. A Biol. Sci. Med. Sci. 2000;55:B5-B9.

    Not in our library10.1093/gerona/55.1.b5

18. 18.

    Hursting SD, Perkins SN, Phang JM. Calorie restriction delays spontaneous tumorigenesis in p53-knockout transgenic mice. Proc. Natl Acad. Sci. U.S.A. 1994;91:7036-7040.

    Not in our library10.1073/pnas.91.15.7036

19. 19.

    Ikeno Y, Bronson RT, Hubbard GB, Lee S, Bartke A. Delayed occurrence of fatal neoplastic diseases in ames dwarf mice: correlation to extended longevity. J. Gerontol. A Biol. Sci. Med. Sci. 2003;58:291-296.

    Not in our library10.1093/gerona/58.4.b291

20. 20.

    Ikeno Y, Hubbard GB, Lee S, Cortez LA, Lew CM, Webb CR, Berryman DE, List EO, Kopchick JJ, Bartke A. Reduced incidence and delayed occurrence of fatal neoplastic diseases in growth hormone receptor/binding protein knockout mice. J. Gerontol. A Biol. Sci. Med. Sci. 2009;64:522-529.

    Not in our library10.1093/gerona/glp017

21. 21.

    Imbriano C, Gurtner A, Cocchiarella F, Di Agostino S, Basile V, Gostissa M, Dobbelstein M, Del Sal G, Piaggio G, Mantovani R. Direct p53 transcriptional repression: in vivo analysis of CCAAT-containing G2/M promoters. Mol. Cell. Biol. 2005;25:3737-3751.

    Not in our library10.1128/mcb.25.9.3737-3751.2005

22. 22.

    Jagus R, Safer B. Activity of eukaryotic initiation factor 2 is modified by processes distinct from phosphorylation. II. Activity of eukaryotic initiation factor 2 in lysate is modified by oxidation-reduction state of its sulfhydryl groups. J. Biol. Chem. 1981;256:1324-1329.

    Not in our library

23. 23.

    Jang YC, Perez VI, Song W, Lustgarten MS, Salmon AB, Mele J, Qi W, Liu Y, Liang H, Chaudhuri A, Ikeno Y, Epstein CJ, Van Remmen H, Richardson A. Overexpression of Mn superoxide dismutase does not increase life span in mice. J. Gerontol. A Biol. Sci. Med. Sci. 2009;64:1114-1125.

    Not in our library10.1093/gerona/glp100

24. 24.

    Johnson TM, Yu ZX, Ferrans VJ, Lowenstein RA, Finkel T. Reactive oxygen species are downstream mediators of p53-dependent apoptosis. Proc. Natl Acad. Sci. U.S.A. 1996;93:11848-11852.

    Not in our library10.1073/pnas.93.21.11848

25. 25.

    Kim I, Xu W, Reed JC. Cell death and endoplasmic reticulum stress: disease relevance and therapeutic opportunities. Nat. Rev. Drug Discov. 2008;7:1013-1030.

    Not in our library10.1038/nrd2755

26. 26.

    Lim DS, Vogel H, Willerford DM, Sands AT, Platt KA, Hasty P. Analysis of ku80-mutant mice and cells with deficient levels of p53. Mol. Cell. Biol. 2000;20:3772-3780.

    Not in our library10.1128/mcb.20.11.3772-3780.2000

27. 27.

    Lim Y, Lee E, Lee J, Oh S, Kim S. Down-regulation of asymmetric arginine methylation during replicative and H2O2-induced premature senescence in WI-38 human diploid fibroblasts. J. Biochem. 2008;144:523-529.

    Not in our library10.1093/jb/mvn097

28. 28.

    Maier B, Gluba W, Bernier B, Turner T, Mohammad K, Guise T, Sutherland A, Thorner M, Scrable H. Modulation of mammalian life span by the short isoform of p53. Genes Dev. 2004;18:306-319.

    Not in our library10.1101/gad.1162404

29. 29.

    Migliaccio E, Giorgio M, Mele S, Pelicci G, Reboldi P, Pandolfi PP, Lanfrancone L, Pelicci PG. The p66shc adaptor protein controls oxidative stress response and life span in mammals. Nature. 1999;402:309-313.

    Not in our library10.1038/46311

30. 30.

    Migliaccio E, Giorgio M, Pelicci PG. Apoptosis and aging: role of p66Shc redox protein. Antioxid. Redox Signal. 2006;8:600-608.

    Not in our library10.1089/ars.2006.8.600

31. 31.

    Muller GA, Engeland K. The central role of CDE/CHR promoter elements in the regulation of cell cycle-dependent gene transcription. FEBS J. 2010;277:877-893.

    Not in our library10.1111/j.1742-4658.2009.07508.x

32. 32.

    Muller FL, Lustgarten MS, Jang Y, Richardson A, Van Remmen H. Trends in oxidative aging theories. Free Radic. Biol. Med. 2007;43:477-503.

    Not in our library10.1016/j.freeradbiomed.2007.03.034

33. 33.

    Olivares-Illana V, Fahraeus R. p53 isoforms gain functions. Oncogene. 2010;29:5113-5119.

    Not in our library10.1038/onc.2010.266

34. 34.
    The overexpression of major antioxidant enzymes does not extend the lifespan of mice · 2009

    No notice
35. 35.

    Perez VI, Cortez LA, Lew CM, Rodriguez M, Webb CR, Van RemmenH, Chaudhuri A, Qi W, Lee S, Bokov A, Fok W, Jones D, Richardson A, Yodoi J, Zhang Y, Tominaga K, Hubbard GB, Ikeno Y. Thioredoxin 1 overexpression extends mainly the earlier part of life span in mice. J. Gerontol. A Biol. Sci. Med. Sci. 2011;66:1286-1299.

    Not in our library10.1093/gerona/glr125

36. 36.

    Ristow M, Schmeisser S. Extending life span by increasing oxidative stress. Free Radic. Biol. Med. 2011;51:327-336.

    Not in our library10.1016/j.freeradbiomed.2011.05.010

37. 37.

    Salmon AB, Murakami S, Bartke A, Kopchick J, Yasumura K, Miller RA. Fibroblast cell lines from young adult mice of long-lived mutant strains are resistant to multiple forms of stress. Am. J. Physiol. Endocrinol. Metab. 2005;289:E23-E29.

    Not in our library10.1152/ajpendo.00575.2004

38. 38.

    Salmon AB, Richardson A, Perez VI. Update on the oxidative stress theory of aging: does oxidative stress play a role in aging or healthy aging? Free Radic. Biol. Med. 2010;48:642-655.

    Not in our library10.1016/j.freeradbiomed.2009.12.015

39. 39.

    Schriner SE, Linford NJ, Martin GM, Treuting P, Ogburn CE, Emond M, Coskun PE, Ladiges W, Wolf N, Van Remmen H, Wallace DC, Rabinovitch PS. Extension of murine life span by overexpression of catalase targeted to mitochondria. Science. 2005;308:1909-1911.

    Not in our library10.1126/science.1106653

40. 40.

    Soussi T, Beroud C. Assessing TP53 status in human tumours to evaluate clinical outcome. Nat. Rev. Cancer. 2001;1:233-240.

    Not in our library10.1038/35106009

41. 41.

    Trinei M, Giorgio M, Cicalese A, Barozzi S, Ventura A, Migliaccio E, Milia E, Padura IM, Raker VA, Maccarana M, Petronilli V, Minucci S, Bernardi P, Lanfrancone L, Pelicci PG. A p53–p66Shc signalling pathway controls intracellular redox status, levels of oxidation-damaged DNA and oxidative stress-induced apoptosis. Oncogene. 2002;21:3872-3878.

    Not in our library10.1038/sj.onc.1205513

42. 42.

    Tyner SD, Venkatachalam S, Choi J, Jones S, Ghebranious N, Igelmann H, Lu X, Soron G, Cooper B, Brayton C, Park SH, Thompson T, Karsenty G, Bradley A, Donehower LA. p53 mutant mice that display early ageing-associated phenotypes. Nature. 2002;415:45-53.

    Not in our library10.1038/415045a

43. 43.
    Deletion of Ku86 causes early onset of senescence in mice · 1999

    Not checked
44. 44.

    Zhang Y, Ikeno Y, Qi W, Chaudhuri A, Li Y, Bokov A, Thorpe SR, Baynes JW, Epstein C, Richardson A, Van Remmen H. Mice deficient in both Mn superoxide dismutase and glutathione peroxidase-1 have increased oxidative damage and a greater incidence of pathology but no reduction in longevity. J. Gerontol. A Biol. Sci. Med. Sci. 2009;64:1212-1220.

    Not in our library10.1093/gerona/glp132

Cited by papers we hold 1

• A Comprehensive Overview of the Complex Role of Oxidative Stress in Aging, The Contributing Environmental Stressors and Emerging Antioxidant Therapeutic Interventions · 2022
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