Skip to main content
SpringerLink
Log in

p38MAPK in the Senescence of Human and Murine Fibroblasts

  • Chapter
Protein Metabolism and Homeostasis in Aging

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 694))

Abstract

Oncogenic and environmental stresses, such as reactive oxygen species, UV radiation etc, can induce premature cellular senescence without critical telomere shortening. The role of the Ras/Raf/ERK signal transduction cascade in this process has been previously established, but recent evidence also indicates a critical role of the p38 MAP kinases pathway. Oncogenic and environmental stresses impinge upon the p38MAPK pathway, suggesting a major role of this pathway in senescence induced by stresses. Prematurely senescent cells are most likely to appear in several age-related pathologies associated with a stressful environment and/or the release of pro-inflammatory cytokines.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Campisi J, d’Adda di Fagagna F. Cellular senescence: when bad things happen to good cells. Nat Rev Mol Cell Biol 2007; 8:729–740.

    Article  CAS  PubMed  Google Scholar 

  2. Shay JW, Wright WE. Hayflick, his limit and cellular ageing. Nat Rev Mol Cell Biol 2000; 1:72–76.

    Article  CAS  PubMed  Google Scholar 

  3. Wright WE, Shay JW. Cellular senescence as a tumor-protection mechanism: the essential role of counting. Curr Opin Genet Dev 2001; 11:98–103.

    Article  CAS  PubMed  Google Scholar 

  4. von Zglinicki T. Oxidative stress shortens telomeres. Trends Biochem Sci 2002; 27:339–344.

    Article  Google Scholar 

  5. Serrano M, Blasco MA. Putting the stress on senescence. Curr Opin Cell Biol 2001; 13:748–753.

    Article  CAS  PubMed  Google Scholar 

  6. Toussaint O, Remacle J, Dierick JF et al. From the Hayflick mosaic to the mosaics of ageing. Role of stress-induced premature senescence in human ageing. Int J Biochem Cell Biol 2002; 34:1415–1429.

    Article  CAS  PubMed  Google Scholar 

  7. Toussaint O, Salmon M, Royer V et al. In: Nyström T, Osiewacz H, eds. Topics in Current Genetics. Heidelberg: Springer-Verlag Berlin, 2003:3.

    Google Scholar 

  8. Toussaint O, Medrano EE, von Zglinicki. T-Cellular and molecular mechanisms of stress-induced premature senescence (SIPS) of human diploid fibroblasts and melanocytes. Experimental Gerontology 2000; 35:927–945.

    Article  CAS  PubMed  Google Scholar 

  9. Schmitt CA. Senescence, apoptosis and therapy—cutting the lifelines of cancer. Nat Rev Cancer 2003; 3:286–295.

    Article  CAS  PubMed  Google Scholar 

  10. de Magalhaes JP, Chainiaux F, de Longueville F et al. Gene expression and regulation in H2O2-induced premature senescence of human foreskin fibroblasts expressing or not telomerase. Experimental Gerontology 2004; 39:1379–1389.

    Article  PubMed  Google Scholar 

  11. Shiloh, Y. Ataxia-telangiectasia and the Nijmegen breakage syndrome: related disorders but genes apart. Annu Rev Genet 1997; 31:635–662.

    Article  CAS  PubMed  Google Scholar 

  12. d’Adda di Fagagna F, Reaper PM, Clay-Farrace L et al. A DNA damage checkpoint response in telomere-initiated senescence. Nature 2003; 426:194–198.

    Article  PubMed  Google Scholar 

  13. Wong KK, Maser RS, Bachoo RM et al. Telomere dysfunction and Atm deficiency compromises organ homeostasis and accelerates ageing. Nature 2003; 421:643–648.

    Article  CAS  PubMed  Google Scholar 

  14. de Magalhaes JP, Chainiaux F, Remacle J et al. Stress-induced premature senescence in BJ and hTERT-BJ1 human foreskin fibroblasts. FEBS letters 2002; 523:157–162.

    Article  PubMed  Google Scholar 

  15. Gorbunova V, Seluanov A, Pereira-Smith OM. Expression of human telomerase (hTERT) does not prevent stress-induced senescence in normal human fibroblasts but protects the cells from stress-induced apoptosis and necrosis. The Journal of Biological Chemistry 2002; 277:38540–38549.

    Article  CAS  PubMed  Google Scholar 

  16. Naka K, Tachibana A, Ikeda K et al. Stress-induced premature senescence in hTERT-expressing ataxia telangiectasia fibroblasts. The Journal of Biological Chemistry 2004; 279:2030–2037.

    Article  CAS  PubMed  Google Scholar 

  17. Iwasa H, Han J, Ishikawa F. Mitogen-activated protein kinase p38 defines the common senescence-signalling pathway. Genes Cells 2003; 8:131–144.

    Article  CAS  PubMed  Google Scholar 

  18. Wang W, Chen JX, Liao R et al. Sequential activation of the MEK-extracellular signal-regulated kinase and MKK3/6-p38 mitogen-activated protein kinase pathways mediates oncogenic ras-induced premature senescence. Mol Cell Biol 2002; 22:3389–3403.

    Article  PubMed  Google Scholar 

  19. Parrinello S, Samper E, Krtolica A et al. Oxygen sensitivity severely limits the replicative lifespan of murine fibroblasts. Nat Cell Biol 2003; 5:741–747.

    Article  CAS  PubMed  Google Scholar 

  20. Sherr CJ, DePinho RA. Cellular senescence: mitotic clock or culture shock? Cell 2000; 102:407–410.

    Article  CAS  PubMed  Google Scholar 

  21. Shaulian E, Schreiber M, Piu F et al. The mammalian UV response: c-Jun induction is required for exit from p53-imposed growth arrest. Cell 2000; 103:897–907.

    Article  CAS  PubMed  Google Scholar 

  22. Haq R, Brenton JD, Takahashi M et al. Constitutive p38HOG mitogen-activated protein kinase activation induces permanent cell cycle arrest and senescence. Cancer Res 2002; 62:5076–5082.

    CAS  PubMed  Google Scholar 

  23. Deng Q, Liao R, Wu BL et al. High intensity ras signaling induces premature senescence by activating p38 pathway in primary human fibroblasts. The Journal of Biological Chemistry 2004; 279:1050–1059.

    Article  CAS  PubMed  Google Scholar 

  24. Borlon C, Debacq-Chainiaux F, Hinrichs C et al. The gene expression profile of psoralen plus UVA-induced premature senescence in skin fibroblasts resembles a combined DNA-damage and stress-induced cellular senescence response phenotype. Experimental Gerontology 2007; 42:911–923.

    Article  CAS  PubMed  Google Scholar 

  25. Borlon C, Weemaels G, Godard P et al. Expression profiling of senescent-associated genes in human dermis from young and old donors. Proof-of-concept study. Biogerontology 2008; 9:197–208.

    CAS  Google Scholar 

  26. Chretien A, Dierick JF, Delaive E et al. Role of TGF-beta1-independent changes in protein neosynthesis, p38alphaMAPK and cdc42 in hydrogen peroxide-induced senescence-like morphogenesis. Free Radical Biology & Medicine 2008; 44:1732–1751.

    Article  CAS  Google Scholar 

  27. Debacq-Chainiaux F, Borlon C, Pascal T et al. Repeated exposure of human skin fibroblasts to UVB at subcytotoxic level triggers premature senescence through the TGF-beta1 signaling pathway. J Cell Sci 2005; 118:743–758.

    Article  CAS  PubMed  Google Scholar 

  28. Frippiat C, Chen QM, Zdanov S et al. Subcytotoxic H2O2 stress triggers a release of transforming growth factor-beta 1, which induces biomarkers of cellular senescence of human diploid fibroblasts. The Journal of Biological Chemistry 2001; 276:2531–2537.

    Article  CAS  PubMed  Google Scholar 

  29. Glotin AL, Debacq-Chainiaux F, Brossas JY et al. Prematurely senescent ARPE-19 cells display features of age-related macular degeneration. Free Radical Biology and Medicine 2008; 44:1348–1361.

    Article  CAS  PubMed  Google Scholar 

  30. Pascal T, Debacq-Chainiaux F, Chretien A et al. Comparison of replicative senescence and stress-induced premature senescence combining differential display and low-density DNA arrays. FEBS Letters 2005; 579:3651–3659.

    Article  CAS  PubMed  Google Scholar 

  31. Debacq-Chainiaux F, Pascal T, Boilan E et al. Screening of senescence-associated genes with specific DNA array reveals the role of IGFBP-3 in premature senescence of human diploid fibroblasts. Free Radical Biology and Medicine 2008; 44:1817–1832.

    Article  CAS  PubMed  Google Scholar 

  32. Hanafusa H, Ninomiya-Tsuji J, Masuyama N et al. Involvement of the p38 mitogen-activated protein kinase pathway in transforming growth factor-beta-induced gene expression. The Journal of Biological Chemistry 1999; 274:27161–27167.

    Article  CAS  PubMed  Google Scholar 

  33. Frippiat C, Dewelle J, Remacle J et al. Signal transduction in H2O2-induced senescence-like phenotype in human diploid fibroblasts. Free Radical Biology and Medicine 2002; 33:1334–1346.

    Article  CAS  PubMed  Google Scholar 

  34. Thannickal VJ, Fanburg BL. Activation of an H2O2-generating NADH oxidase in human lung fibroblasts by transforming growth factor beta 1. The Journal of Biological Chemistry 1995; 270:30334–30338.

    Article  CAS  PubMed  Google Scholar 

  35. Zdanov S, Bernard D, Debacq-Chainiaux F et al. Normal or stress-induced fibroblast senescence involves COX-2 activity. Experimental Cell Research 2007; 313:3046–3056.

    Article  CAS  PubMed  Google Scholar 

  36. Zdanov S, Toussaint O, Debacq-Chainiaux F. p53 and ATF-2 partly mediate the overexpression of COX-2 in H(2)O (2)-induced premature senescence of human fibroblasts. Biogerontology 2009; 10:291–298.

    Article  CAS  PubMed  Google Scholar 

  37. Bulavin DV, Saito S, Hollander MC et al. Phosphorylation of human p53 by p38 kinase coordinates N-terminal phosphorylation and apoptosis in response to UV radiation. EMBO J 1999; 18:6845–6854.

    Article  CAS  PubMed  Google Scholar 

  38. Chen QM, Bartholomew JC, Campisi J et al. Molecular analysis of H2O2-induced senescent-like growth arrest in normal human fibroblasts: p53 and Rb control G1 arrest but not cell replication. Biochem J 1998; 332(Pt 1):43–50.

    CAS  PubMed  Google Scholar 

  39. Huang C, Ma WY, Maxiner A et al. p38 kinase mediates UV-induced phosphorylation of p53 protein at serine 389. The Journal of Biological Chemistry 1999; 274:12229–12235.

    Article  CAS  PubMed  Google Scholar 

  40. Sayed M, Kim SO, Salh BS et al. Stress-induced activation of protein kinase CK2 by direct interaction with p38 mitogen-activated protein kinase. The Journal of Biological Chemistry 2000; 275:16569–16573.

    Article  CAS  PubMed  Google Scholar 

  41. Shi Y, Gaestel M. In the cellular garden of forking paths: how p38 MAPKs signal for downstream assistance. Biol Chem 2002; 383:1519–1536.

    Article  CAS  PubMed  Google Scholar 

  42. Bulavin DV, Demidov ON, Saito S et al. Amplification of PPM1D in human tumors abrogates p53 tumor-suppressor activity. Nat Genet 2002; 31:210–215.

    Article  CAS  PubMed  Google Scholar 

  43. Park JS, Kim HY, Kim HW et al. Increased caveolin-1, a cause for the declined adipogenic potential of senescent human mesenchymal stem cells. Mechanisms of Ageing and Development 2005; 126:551–559.

    Article  CAS  PubMed  Google Scholar 

  44. Cho KA, Ryu SJ, Oh YS et al. Morphological adjustment of senescent cells by modulating caveolin-1 status. The Journal of Biological Chemistry 2004; 279:42270–42278.

    Article  CAS  PubMed  Google Scholar 

  45. Volonte D, Zhang K, Lisanti MP et al. Expression of caveolin-1 induces premature cellular senescence in primary cultures of murine fibroblasts. Mol Biol Cell 2002; 13:2502–2517.

    Article  CAS  PubMed  Google Scholar 

  46. Volonte D, Galbiati F, Pestell RG et al. Cellular stress induces the tyrosine phosphorylation of caveolin-1 (Tyr(14)) via activation of p38 mitogen-activated protein kinase and c-Src kinase. Evidence for caveolae, the actin cytoskeleton and focal adhesions as mechanical sensors of osmotic stress. The Journal of Biological Chemistry 2001; 276:8094–8103.

    Article  CAS  PubMed  Google Scholar 

  47. Norata GD, Callegari E, Inoue H et al. HDL3 induces cyclooxygenase-2 expression and prostacyclin release in human endothelial cells via a p38 MAPK/CRE-dependent pathway: effects on COX-2/PGI-synthase coupling. Arterioscler Thromb Vasc Biol 2004; 24:871–877.

    Article  CAS  PubMed  Google Scholar 

  48. Seo M, Cho CH, Lee YI et al. Cdc42-dependent mediation of UV-induced p38 activation by G protein betagamma subunits. The Journal of Biological Chemistry 2004; 279:17366–17375.

    Article  CAS  PubMed  Google Scholar 

  49. Chretien A, Piront N, Delaive E et al. Increased abundance of cytoplasmic and nuclear caveolin 1 in human diploid fibroblasts in H(2)O(2)-induced premature senescence and interplay with p38alpha(MAPK). FEBS Letters 2008; 582:1685–1692.

    Article  CAS  PubMed  Google Scholar 

  50. Serrano M, Lin AW, McCurrach ME et al. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 1997; 88:593–602.

    Article  CAS  PubMed  Google Scholar 

  51. Spyridopoulos I, Isner JM, Losordo DW. Oncogenic ras induces premature senescence in endothelial cells: role of p21(Cip1/Waf1). Basic Res Cardiol 2002; 97:117–124.

    Article  CAS  PubMed  Google Scholar 

  52. Tremain R, Marko M, Kinnimulki V et al. Defects in TGF-beta signaling overcome senescence of mouse keratinocytes expressing v-Ha-ras. Oncogene 2000; 19:1698–1709.

    Article  CAS  PubMed  Google Scholar 

  53. Barbacid M. ras genes. Annu Rev Biochem 1987; 56:779–827.

    Article  CAS  PubMed  Google Scholar 

  54. Cahill MA, Janknecht R, Nordheim A. Signalling pathways: jack of all cascades. Curr Biol 1996; 6:16–19.

    Article  CAS  PubMed  Google Scholar 

  55. Medema RH, Bos JL. The role of p21ras in receptor tyrosine kinase signaling. Crit Rev Oncog 1993; 4:615–661.

    CAS  PubMed  Google Scholar 

  56. Frippiat C, Remacle J, Toussaint O. Down-regulation and decreased activity of cyclin-dependent kinase 2 in H2O2-induced premature senescence. Int J Biochem Cell Biol 2003; 35:246–254.

    Article  CAS  PubMed  Google Scholar 

  57. Peeper DS, Dannenberg JH, Douma S et al. Escape from premature senescence is not sufficient for oncogenic transformation by Ras. Nat Cell Biol 2001; 3:198–203.

    Article  CAS  PubMed  Google Scholar 

  58. Shvarts A, Brummelkamp TR, Scheeren F et al. A senescence rescue screen identifies BCL6 as an inhibitor of anti-proliferative p19(ARF)-p53 signaling. Genes Dev 2002; 16:681–686.

    Article  CAS  PubMed  Google Scholar 

  59. Morales CP, Holt SE, Ouellette M et al. Absence of cancer-associated changes in human fibroblasts immortalized with telomerase. Nat Genet 1999; 21:115–118.

    Article  CAS  PubMed  Google Scholar 

  60. Hahn WC, Dessain SK, Brooks MW et al. Enumeration of the simian virus 40 early region elements necessary for human cell transformation. Mol Cell Biol 2002; 22:2111–2123.

    Article  CAS  PubMed  Google Scholar 

  61. Franza BR Jr, Maruyama K, Garrels JI et al. In vitro establishment is not a sufficient prerequisite for transformation by activated ras oncogenes. Cell 1986; 44:409–418.

    Article  CAS  PubMed  Google Scholar 

  62. Hirakawa T, Ruley HE. Rescue of cells from ras oncogene-induced growth arrest by a second, complementing, oncogene. Proc Natl Acad Sci USA 1988; 85:1519–1523.

    Article  CAS  PubMed  Google Scholar 

  63. Hunter T. Cooperation between oncogenes. Cell 1991; 64:249–270.

    Article  CAS  PubMed  Google Scholar 

  64. Ruley HE. Transforming collaborations between ras and nuclear oncogenes. Cancer Cells 1990; 2:258–268.

    CAS  PubMed  Google Scholar 

  65. Weinberg RA. Oncogenes, antioncogenes and the molecular bases of multistep carcinogenesis. Cancer Res 1989; 49:3713–3721.

    CAS  PubMed  Google Scholar 

  66. Lee AC, Fenster BE, Ito H et al. Ras proteins induce senescence by altering the intracellular levels of reactive oxygen species. The Journal of Biological Chemistry 1999; 274:7936–7940.

    Article  CAS  PubMed  Google Scholar 

  67. Chen Q, Ames BN. Senescence-like growth arrest induced by hydrogen peroxide in human diploid fibroblast F65 cells. Proc Natl Acad Sci USA 1994; 91:4130–4134.

    Article  CAS  PubMed  Google Scholar 

  68. Dumont P, Burton M, Chen QM et al. Induction of replicative senescence biomarkers by sublethal oxidative stresses in normal human fibroblast. Free Radical Biology & Medicine 2000; 28:361–373.

    Article  CAS  Google Scholar 

  69. Lin AW, Barradas M, Stone JC et al. Premature senescence involving p53 and p16 is activated in response to constitutive MEK/MAPK mitogenic signaling. Genes Dev 1998; 12:3008–3019.

    Article  CAS  PubMed  Google Scholar 

  70. Zhu J, Woods D, McMahon M et al. Senescence of human fibroblasts induced by oncogenic Raf. Genes Dev 1998; 12:2997–3007.

    Article  CAS  PubMed  Google Scholar 

  71. Bulavin DV, Kovalsky O, Hollander MC et al. Loss of oncogenic H-ras-induced cell cycle arrest and p38 mitogen-activated protein kinase activation by disruption of Gadd45a. Mol Cell Biol 2003; 23:3859–3871.

    Article  CAS  PubMed  Google Scholar 

  72. Hollander MC, Sheikh MS, Bulavin DV et al. Genomic instability in Gadd45a-deficient mice. Nat Genet 1999; 23:176–184.

    Article  CAS  PubMed  Google Scholar 

  73. Prowse KR, Greider CW. Developmental and tissue-specific regulation of mouse telomerase and telomere length. Proc Natl Acad Sci USA 1995; 92:4818–4822.

    Article  CAS  PubMed  Google Scholar 

  74. Brancho D, Tanaka N, Jaeschke A et al. Mechanism of p38 MAP kinase activation in vivo. Genes Dev 2003; 17:1969–1978.

    Article  CAS  PubMed  Google Scholar 

  75. Ge B, Gram H, Di Padova F et al. MAPKK-independent activation of p38alpha mediated by TAB1-dependent autophosphorylation of p38alpha. Science 2002; 295:1291–1294.

    Article  CAS  PubMed  Google Scholar 

  76. Tanno M, Bassi R, Gorog DA et al. Diverse mechanisms of myocardial p38 mitogen-activated protein kinase activation: evidence for MKK-independent activation by a TAB1-associated mechanism contributing to injury during myocardial ischemia. Circ Res 2003; 93:254–261.

    Article  CAS  PubMed  Google Scholar 

  77. Chen QM, Tu VC, Catania J et al. Involvement of Rb family proteins, focal adhesion proteins and protein synthesis in senescent morphogenesis induced by hydrogen peroxide. J Cell Sci 2000; 113(Pt 22):4087–4097.

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Research Unit on Cellular Biology, University of Namur, Rue de Bruxelles, 61, Namur, B-5000, Belgium

    Florence Debacq-Chainiaux, Emmanuelle Boilan, Jérémie Dedessus Le Moutier, Geoffroy Weemaels & Olivier Toussaint

Authors
  1. Florence Debacq-Chainiaux
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Emmanuelle Boilan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jérémie Dedessus Le Moutier
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Geoffroy Weemaels
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Olivier Toussaint
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Florence Debacq-Chainiaux .

Editor information

Editors and Affiliations

  1. Institute of Molecular Biology and Biotechnology (IMBB), Foundation for Research and Technology Hellas (FORTH), Heraklion, Crete, Greece

    Nektarios Tavernarakis PhD

Rights and permissions

Reprints and permissions

Copyright information

© 2010 Landes Bioscience and Springer Science+Business Media

About this chapter

Cite this chapter

Debacq-Chainiaux, F., Boilan, E., Le Moutier, J.D., Weemaels, G., Toussaint, O. (2010). p38MAPK in the Senescence of Human and Murine Fibroblasts. In: Tavernarakis, N. (eds) Protein Metabolism and Homeostasis in Aging. Advances in Experimental Medicine and Biology, vol 694. Springer, Boston, MA. https://doi.org/10.1007/978-1-4419-7002-2_10

Download citation

Publish with us

Policies and ethics

Search

Navigation