Nuclear Barrier Hypothesis of Aging as Mechanism for Trade-Off Growth to Survival

  • Sang Chul ParkEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 720)


When the aging-dependent cellular behaviors toward growth factors and toxic stress have been analyzed, the perinuclear accumulation of the activated signals, either mitogenic or apoptotic, has been observed, suggesting the aging-dependent inefficiency of the nucleocytoplasmic trafficking of the signals. Thereby, it would be natural to assume the operation of the functional nuclear barrier in aging-dependent manner, which would be designated as “Park and Lim’s Barrier.” And for the ultimate transcriptional factor for these aging-dependent changes of the functional nuclear barrier, Sp1 transcriptional factor has been suggested to be the most probable candidate. This novel mechanism of aging-dependent operation of the functional nuclear barrier is proposed as the ultimate checking mechanism for cellular protection against toxic environment and the general mechanism for the trade-off growth to survival in aging.


Senescent Cell Major Vault Protein Epidermal Growth Factor Stimulation Cargo Molecule Growth Factor Response 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MEST) (2010-0029150) and also by the Korea Research Foundation for Health Science.


  1. 1.
    Ahn JS, Jang IS, Kim DI, Cho KA, Park YH, Kim KT, Kwak CS, Park SC (2003) Aging-associated increase of gelsolin for apoptosis resistance. Biochem Biophys Res Comun 312:1335–1341CrossRefGoogle Scholar
  2. 2.
    Anderson RG (1998) The caveolae membrane system. Annu Rev Biochem 67:1996–2003CrossRefGoogle Scholar
  3. 3.
    Beck M, Forster F, Ecke M, Plitzko JM, Melchior F, Gerisch G, Baumeister W, Medalia O (2004) Nuclear pore complex structure and dynamics revealed by cryoelectron tomography. Science 306:1387–1390PubMedCrossRefGoogle Scholar
  4. 4.
    Bretscher MS, Whytock S (1977) Membrane-associated vesicles in fibroblasts. J Ultrastruct Res 6:215–217CrossRefGoogle Scholar
  5. 5.
    Carlin CR, Phillips PD, Knowles BB, Cristofalo VJ (1983) Diminished in vitro tyrosine kinase activity of the EGF receptor of senescent human fibroblasts. Nature 306(5943):617–620PubMedCrossRefGoogle Scholar
  6. 6.
    Carman CV, Lisanti MP, Benovic JL (1999) Regulation of G protein-coupled receptor kinases by caveolin. J Biol Chem 274:8858–8864PubMedCrossRefGoogle Scholar
  7. 7.
    Chang L, Karin M (2001) Mammalian MAP kinase signalling cascades. Nature 410:37–40PubMedCrossRefGoogle Scholar
  8. 8.
    Chapman HA, Wei Y, Simon DI, Waltz DA (1999) Role of urokinase receptor and caveolin in regulation of integrin signaling. Thromb Haemost 82:291–297PubMedGoogle Scholar
  9. 9.
    Chen QM, Tu VC, Catania J, Burton M, Toussaint O, Dilley T (2000) Involvement of Rb family proteins, focal adhesion proteins and protein synthesis in senescent morphogenesis induced by hydrogen peroxide. J Cell Sci 113:4087–4097PubMedGoogle Scholar
  10. 10.
    Cho KA, Park SC (2005) Caveolin-1 as a prime modulator of aging: A new modality for phenotypic restoration? Mech Ageing Dev 126(1):105–110PubMedCrossRefGoogle Scholar
  11. 11.
    Cho KA, Ryu SJ, Oh YS, Park JH, Lee JW, Kim HP, Kim KT, Jang IS, Park SC (2004) Morphological adjustment of senescent cells by modulating caveolin-1 status. J Biol Chem 279:42270–42278PubMedCrossRefGoogle Scholar
  12. 12.
    Cho KA, Ryu SJ, Park JS, Is J, Ahn JS, Kim KT, Park SC (2003) Senescent pheonotype can be reversed by reduction of caveolin status. J Biol Chem 278(30):27789–27795PubMedCrossRefGoogle Scholar
  13. 13.
    Couet J, Sargiacomo M, Lisanti MP (1997) Interaction of a receptor tyrosine kinase, EGF-R, with caveolins: caveolin-binding negatively regulates tyrosine and serine/threonine kinase activities. J Biol Chem 272:30429–30438PubMedCrossRefGoogle Scholar
  14. 14.
    Couet J, Li S, Okamoto T, Ikezu T, Lisanti MP (1997) Identification of peptide and protein ligands for the caveolin-scaffolding domain. Implications for the interaction of caveolin with caveolae-associated proteins. J Biol Chem 272:6525–6533PubMedCrossRefGoogle Scholar
  15. 15.
    D’Angelo MA, Hetzer MW (2008) Structure, dynamics and function of nuclear pore complexes. Trends Cell Biol 18:456–466PubMedCrossRefGoogle Scholar
  16. 16.
    Dent P, Yacoub A, Fisher PB, Hagan MP, Grant S (2003) MAPK pathways in radiation responses. Oncogene 22:5885–5896PubMedCrossRefGoogle Scholar
  17. 17.
    Diaz-Horta O, Van Eylen F, Herchuelz A (2003) Na/Ca exchanger overexpression induces endoplasmic reticulum stress, caspase-12 release, and apoptosis. Ann N Y Acad Sci 1010:430–432PubMedCrossRefGoogle Scholar
  18. 18.
    Dimri GP, Lee X, Basile G, Acosta M, Scott G, Roskelley C, Medrano EE, Linskens M, Rubelj I, Pereira-Smith O et al (1995) A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci USA 92:9363–9367PubMedCrossRefGoogle Scholar
  19. 19.
    Engelman JA, Chu C, Lin A, Jo H, Ikezu T, Okamoto T, Kohtz DS, Lisanti MP (1998) Caveolin-mediated regulation of signaling along the p42/44 MAP kinase cascade in vivo. A role for the caveolin-scaffolding domain. FEBS Lett 428:205–211PubMedCrossRefGoogle Scholar
  20. 20.
    Galbiati F, Volonte D, Liu J, Capozza F, Frank PG, Zhu L, Pestell RG, Lisanti MP (2001) Caveolin-1 expression negatively regulates cell cycle progression by inducing G(0)/G(1) arrest via a p53/p21(WAF1/Cip1)-dependent mechanism. Mol Biol Cell 12(8):2229–2244PubMedGoogle Scholar
  21. 21.
    Hardman RA, Afshari CA, Barrett JC (2001) Involvement of mammalian MLH1 in the apoptotic response to peroxide-induced oxidative stress. Cancer Res 61(4):1392–1397PubMedGoogle Scholar
  22. 22.
    Hoelz A, Blobel G (2004) Cell biology: popping out of the nucleus. Nature 432:815–816PubMedCrossRefGoogle Scholar
  23. 23.
    Izaurralde E, Kutay U, von Kobbe C, Mattaj IW, Gorlich D (1997) The asymmetric distribution of the constituents of the Ran system is essential for transport into and out of the nucleus. EMBO J 16:6535–6547PubMedCrossRefGoogle Scholar
  24. 24.
    Jang IS, Yeo EJ, Park JA, Ahn JS, Cho KA, Juhnn YS, Park SC (2003) Altered cAMP signaling induced by lysophosphatidic acid in senescent human diploid fibroblasts. Biochem Biophys Res Comm 302(4):778–784PubMedCrossRefGoogle Scholar
  25. 25.
    Jang IS, Rhim JH, Park SC, Yeo EJ (2006) Downstream molecular events in the altered profiles of lysophosphatidic acid-induced cAMP in senescent human diploid fibroblasts. Exp Mol Med 38(2):134–143PubMedCrossRefGoogle Scholar
  26. 26.
    Jang IS, Rhim JH, Kim KT, Cho KA, Yeo EJ, Park SC (2006) Lysophosphatidic acid-induced changes in cAMP profiles in young and senescent human fibroblasts as a clue to the ageing process. Mech Ageing Dev 127(5):481–92006PubMedCrossRefGoogle Scholar
  27. 27.
    Johnson GL, Lapadat R (2002) Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science 298(5600):1911–1912PubMedCrossRefGoogle Scholar
  28. 28.
    Kang HT, Ju JW, Cho JW, Hwang ES (2003) Down-regulation of Sp1 activity through modulation of O-glycosylation by treatment with a low glucose mimetic, 2-deoxyglucose. J Biol Chem 278:51223–51231PubMedCrossRefGoogle Scholar
  29. 29.
    Kuwana T, Newmeyer DD (2003) Bcl-2-family proteins and the role of mitochondria in apoptosis. Curr Opin Cell Biol 15(6):691–699PubMedCrossRefGoogle Scholar
  30. 30.
    Kim K, Nose K, Shibanuma M (2000) Significance of nuclear relocalization of ERK1/2 in reactivation of c-fos transcription and DNA synthesis in senescent fibroblasts. J Biol Chem 275:20685–20692CrossRefGoogle Scholar
  31. 31.
    Kim SY, Ryu SJ, Ahn HJ, Choi HR, Kang HT, Park SC (2010) Senescence-related functional nuclear barrier by down-regulation of nucleo-cytoplasmic trafficking gene expression. Biochem Biophys Res Commun 391:28–32PubMedCrossRefGoogle Scholar
  32. 32.
    Kim SY, Kang HT, Choi HR, Park SC (2010) Reduction of Nup107 attenuates the growth factor signaling in the senescent cells. Biochem Biophys Res Commun 401:131–136PubMedCrossRefGoogle Scholar
  33. 33.
    Kirkwood TB, Holliday R (1979) The evolution of ageing and longevity. Proc R Soc Lond B Biol Sci 205(1161):531–546PubMedCrossRefGoogle Scholar
  34. 34.
    Kwon HJ, Rhim JH, Jang IS, Jun G, Park SC, Yeo EJ (2010) Activation of AMP-activated protein kinase stimulates the nuclear localization of glyceraldehyde 3-phosphate dehydrogenase in human diploid fibroblasts. Exp Mol Med 42(4):254–269PubMedCrossRefGoogle Scholar
  35. 35.
    Li L, Ren CH, Tahir SA, Ren C, Thompson TC (2003) Caveolin-1 maintains activated Akt in prostate cancer cells through scaffolding domain binding site interaction with and inhibition of serine/threonine protein phosphatases PP1 and PP2A. Mol Cell Biol 23:9389–9404PubMedCrossRefGoogle Scholar
  36. 36.
    Li L, Yang G, Ebara S, Satoh T, Nasu Y, Timme TL, Ren C, Wang J, Tahir SA, Thonpson TC (2001) Caveloin-1 mediates testosterone-stimulated survival/clonal growth and promotes metastatic activities in prostate cancer cells. Cancer Res 61:4386–4392PubMedGoogle Scholar
  37. 37.
    Li S, Couet J, Lisanti MP (1996) Src tyrosine kinases, G alpha subunits and H-Ras share a common membrane-anchored scaffolding protein, caveolin. Caveolin binding negatively regulates the auto-activation of Src tyrosine kinases. J Biol Chem 271:29182–29190PubMedCrossRefGoogle Scholar
  38. 38.
    Li S, Okamoto T, Chun M, Sargiacomo M, Casanova JE, Hansen SH, Nishimoto I, Lisanti MP (1995) Evidence for a regulated interaction between hetero-trimeric G proteins and caveolin. J Biol Chem 270:15693–15701PubMedCrossRefGoogle Scholar
  39. 39.
    Lim IK, Hong K, Kwak IH, Yoon G, Park SC (2000) Cytoplasmic retention of p-Erk1/2 and nuclear accumulation of actin proteins during cellular senescence in human diploid fibroblasts. Mech Ageing Dev 119:113–130PubMedCrossRefGoogle Scholar
  40. 40.
    Martin D, Salinas M, Fujita N, Tsuruo T, Cuadrado A (2002) Ceramide and reactive oxygen species generated by H2O2 induce caspase-3-independent degradation of Akt/protein kinase B. J Biol Chem 277(45):42943–42952PubMedCrossRefGoogle Scholar
  41. 41.
    Okamoto T, Schlegel A, Schlegel PE, Schlegel MP (1998) Caveolins, a family of scaffolding proteins for organizing ‘preassembled signaling complexes’ at the plasma membrane. J Biol Chem 273:5419–5422PubMedCrossRefGoogle Scholar
  42. 42.
    Park JS, Park WY, Cho KA, Kim DI, Jhun BH, Kim SR, Park SC (2001) Down-regulation of amphiphysin-1 is responsible for reduced receptor-mediated endocytosis in senescent cells. FASEB J 15:1625–1627PubMedGoogle Scholar
  43. 43.
    Park SC (2002) Functional recovery of senescent cells through restoration of receptor-mediated endocytosis. Mech Ageing Dev 123:917–926PubMedCrossRefGoogle Scholar
  44. 44.
    Park SC (2006) New molecular target for modulation of aging process. Antioxid Redox Signal 8(3–4):620–627PubMedCrossRefGoogle Scholar
  45. 45.
    Park SC (2004) Phenotypic adjustment of senescent cells: replace or restore. Geriatr Gerontol Int 4:517–520Google Scholar
  46. 46.
    Park SC, Cho KA, Jang IS, Kim KT, Ryu SJ (2004) Functional efficiency of the senescent cells: replace or restore. Ann NY Acad Sci 1019:309–316PubMedCrossRefGoogle Scholar
  47. 47.
    Park WY, Park JS, Cho KA, Kim DI, Ko YG, Seo JS, Park SC (2000) Up-regulation of caveolin attenuates epidermal growth factor signaling in senescent cells. J Biol Chem 275(27):20847–20852PubMedCrossRefGoogle Scholar
  48. 48.
    Parton RG, Way M, Zorzi N, Stang E (1997) Caveolin-3 associates with developing T-tubules during muscle differentiation. J Cell Biol 136:137–154PubMedCrossRefGoogle Scholar
  49. 49.
    Pepper C, Bentley P (2000) The role of the Bcl-2 family in the modulation of apoptosis. Symp Soc Exp Biol 52:43–53PubMedGoogle Scholar
  50. 50.
    Phillips PD, Kuhnle E, Cristofalo VJ (1983) EGF binding ability is stable throughout the replicative life-span of WI-38 cells. J Cell Physiol 114(3):311–316PubMedCrossRefGoogle Scholar
  51. 51.
    Razani B, Schlegel A, Liu J, Lisanti MP (2001) Caveolin-1, a putative tumour suppressor gene. Biochem Soc Trans 29:494–499PubMedCrossRefGoogle Scholar
  52. 52.
    Royuela M, Arenas MI, Bethencourt FR, Sanchez-Chapado M, Fraile B, Paniagua R (2002) Regulation of proliferation/apoptosis equilibrium by mitogen-activated protein kinases in normal, hyperplastic, and carcinomatous human prostate. Hum Pathol 33(3):299–306PubMedCrossRefGoogle Scholar
  53. 53.
    Ryu SJ, Oh YS, Park SC (2007) Failure of stress-­induced downregulation of Bcl-2 contributes to apoptosis resistance in senescent human diploid fibroblasts. Cell Death Differ 14(5):1020–1028PubMedGoogle Scholar
  54. 54.
    Ryu SJ, An HJ, Oh YS, Choi HR, Ha MK, Park SC (2008) On the role of major vault protein in the resistance of senescent human diploid fibroblast to apoptosis. Cell Death Differ 15(11): 1678–1680PubMedCrossRefGoogle Scholar
  55. 55.
    Sargiacomo M, Scherer PE, Tang Z, Kubler E, Song KS, Sanders MC, Lisanti MP (1995) Oligomeric structure of caveolin: implications for caveolae membrane organization. Proc Natl Acad Sci USA 92:9407–9411PubMedCrossRefGoogle Scholar
  56. 56.
    Scherer PE, Lewis RY, Volonte D, Engelman JA, Galbiati F, Couet J, Kohtz DS, Donselaar E, Peters P, Lisanti MP (1997) Cell-type and tissue-specific expression of caveolin-2. Caveolins-1 and -2 co-localize and form a stable hetero-oligomeric complex in vivo. J Biol Chem 272:29337–29346PubMedCrossRefGoogle Scholar
  57. 57.
    Scherer PE, Okamoto T, Chun M, Nishimoto I, Lodish HF, Lisanti MP (1996) Identification, sequence, and expression of caveolin-2 defines a caveolin gene family. Proc Natl Acad Sci USA 93:131–135PubMedCrossRefGoogle Scholar
  58. 58.
    Schlegel A, Schwab RB, Scherer PE, Lisanti MP (1999) A role for the caveolin-scaffolding domain in mediating the membrane attachment of caveolin-1. The caveolin-scaffolding domain is both necessary and sufficient for membrane binding in vitro. J Biol Chem 274:22660–22667PubMedCrossRefGoogle Scholar
  59. 59.
    Seger R, Krebs EG (1995) The MAPK signaling cascade. FASEB J 9(9):726–735PubMedGoogle Scholar
  60. 60.
    Seluanov A, Gorbunova V, Falcovitz A, Sigal A, Milyavsky M, Zurer I, Shohat G, Goldfinger N, Rotter V (2001) Change of the death pathway in senescent human fibroblasts in response to DNA damage is caused by an inability to stabilize p53. Mol Cell Biol 21:1552–1564PubMedCrossRefGoogle Scholar
  61. 61.
    Song KS, Li S, Okamoto T, Quilliam LA, Sargiacomo M, Lisanti MP (1996) Copurification and direct interaction of Ras with caveolin, an integral membrane protein of caveolae microdomains. Detergent free purification of caveolae membranes. J Biol Chem 271:9690–9697PubMedCrossRefGoogle Scholar
  62. 62.
    Stoffler D, Fahrenkrog B, Aebi U (1999) The nuclear pore complex: from molecular architecture to functional dynamics. Curr Opin Cell Biol 11:391–401PubMedCrossRefGoogle Scholar
  63. 63.
    Suh Y, Lee KA, Kim WH, Han BG, Vijg J, Park SC (2002) Aging alters the apoptotic response to genotoxic stress. Nat Med 8:3–4PubMedCrossRefGoogle Scholar
  64. 64.
    Tang Z, Scherer PE, Okamoto T, Song KC (1996) Molecular cloning of caveolin-3, a novel member of the caveolin gene family expressed predominantly in muscle. J Biol Chem 271:2255–2261PubMedCrossRefGoogle Scholar
  65. 65.
    Teixeira A, Chaverot N, Schroder C, Strosberg AD, Couraud PO, Cazaubon S (1999) Requirement of caveolae microdomains in extracellular signal-regulated kinase and focal adhesion kinase activation induced by endothelin-1 in primary astrocytes, J. Neurochemistry 72(1):120–128Google Scholar
  66. 66.
    Tesauro M, Thompson WC, Moss J (2006) Effect of staurosporine-induced apoptosis on endothelial nitric oxide synthase in transfected COS-7 cells and primary endothelial cells. Cell Death Differ 13(4):597–606PubMedCrossRefGoogle Scholar
  67. 67.
    Turpin P, Ossareh-Nazari B, Dargemont C (1999) Nuclear transport and transcriptional regulation. FEBS Lett 452:82–86PubMedCrossRefGoogle Scholar
  68. 68.
    Volonte D, Zhang K, Lisanti MP, Galbiati F (2002) Expression of caveolin-1 induces premature cellular senescence in primary cultures of murine fibroblasts. Mol Biol Cell 13(7):2502–2517PubMedCrossRefGoogle Scholar
  69. 69.
    Wei Y, Yang X, Liu Q, Wilkins JA, Chapman HA (1999) A role for caveolin and the urokinase receptor in integrin-mediated adhesion and signaling. J Cell Biol 144(6):1285–1294PubMedCrossRefGoogle Scholar
  70. 70.
    Yeo EJ, Hwang YC, Kang CM, Choy HE, Park SC (2000) Reduction of UV-induced cell death in the human senescent fibroblasts. Mol Cells 10:415–422PubMedGoogle Scholar
  71. 71.
    Yeo EJ, Jang IS, Lim HK, Ha KS, Park SC (2002) Agonist-specific differential changes of cellular signal transduction pathways in senescent human diploid fibroblasts. Exp Gerontol 37(7):871–883PubMedCrossRefGoogle Scholar
  72. 72.
    Yeo EJ, Park SC (2002) Age-dependent agonist-­specific dysregulation of membrane-mediated signal transduction: Emergence of the gate theory of aging. Mech Age Devel 123:1563–1578CrossRefGoogle Scholar

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© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Department of Biochemistry and Molecular BiologySeoul National University Medical SchoolSeoulSouth Korea
  2. 2.Lee Gil Ya Cancer and Diabetes InstituteGachon University of Medicine and ScienceIncheonSouth Korea

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