Abstract
Senescence is an irreversible state of the cell, in which the cell becomes incapable of further cell division. The concept of stress-induced senescence indicates that the major causes of senescence are various types of stresses that act on cells. These stresses act via intracellular pathways, which may be multiple, to a final common state of irreversible cell division. In this state the cell is held in the nondividing state by the combination of cyclin-dependent kinase inhibitor (CDKI) activity, heterochromatin formation, gene expression changes, and other mechanisms. While the mediators of stress-induced senescence are multiple and complex, the p38 MAP kinase pathway has a prominent role in linking stresses to the permanently nondividing state. The means by which it may become activated by stresses and the means by which it acts to cause senescence are being unraveled. While most of the past studies on senescence have used cells in culture, the recent emergence of novel mouse models in which senescence can be studied has opened up exciting avenues toward mechanistic insights and possible therapeutic interventions.
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References
Acosta JC, Gil J (2012) Senescence: a new weapon for cancer therapy. Trends Cell Biol 22:211–219
Baker DJ, Wijshake T, Tchkonia T, LeBrasseur NK, Childs BG, van de Sluis B, Kirkland JL, van Deursen JM (2011) Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature 479:232–236
Barascu A, Le Chalony C, Pennarun G, Genet D, Imam N, Lopez B, Bertrand P (2012) Oxidative stress induces an ATM-independent senescence pathway through p38 MAPK-mediated lamin B1 accumulation. EMBO J 31:1080–1094
Beausejour CM, Krtolica A, Galimi F, Narita M, Lowe SW, Yaswen P, Campisi J (2003) Reversal of human cellular senescence: roles of the p53 and p16 pathways. EMBO J 22:4212–4222
Cao K, Blair CD, Faddah DA, Kieckhaefer JE, Olive M, Erdos MR, Nabel EG, Collins FS (2011) Progerin and telomere dysfunction collaborate to trigger cellular senescence in normal human fibroblasts. J Clin Invest 121:2833–2844
Choi J, Southworth LK, Sarin KY, Venteicher AS, Ma W, Chang W, Cheung P, Jun S, Artandi MK, Shah N, Kim SK, Artandi SE (2008) TERT promotes epithelial proliferation through transcriptional control of a Myc- and Wnt-related developmental program. PLoS Genet 4:e10
Chung HK, Cheong C, Song J, Lee HW (2005) Extratelomeric functions of telomerase. Curr Mol Med 5:233–241
de Jesus BB, Blasco MA (2012) Assessing cell and organ senescence biomarkers. Circ Res 111:97–109
de Lange T (2010) Telomere biology and DNA repair: enemies with benefits. FEBS Lett 584:3673–3674
Fumagalli M, d’Adda di Fagagna F (2009) SASPense and DDRama in cancer and ageing. Nat Cell Biol 11:921–923
Fumagalli M, Rossiello F, Clerici M, Barozzi S, Cittaro D, Kaplunov JM, Bucci G, Dobreva M, Matti V, Beausejour CM, Herbig U, Longhese MP, d’Adda di Fagagna F (2012) Telomeric DNA damage is irreparable and causes persistent DNA-damage-response activation. Nat Cell Biol 14:355–365
Gorgoulis VG, Halazonetis TD (2010) Oncogene-induced senescence: the bright and dark side of the response. Curr Opin Cell Biol 22:816–827
Herbig U, Ferreira M, Condel L, Carey D, Sedivy JM (2006) Cellular senescence in aging primates. Science 311:1257
Hewitt G, Jurk D, Marques FD, Correia-Melo C, Hardy T, Gackowska A, Anderson R, Taschuk M, Mann J, Passos JF (2012) Telomeres are favoured targets of a persistent DNA damage response in ageing and stress-induced senescence. Nat Commun 3:708
Hornsby PJ (2001) Cell proliferation in mammalian aging. In: Masoro EJ, Austad SN (eds) Handbook of the biology of aging, 5th edn. Academic, San Diego, pp 207–266
Hornsby PJ (2003) Mouse and human cells versus oxygen. Sci Aging Knowl Environ 85:285–290
Hornsby PJ (2010) Stress-induced senescence. In: Adams PD, Sedivy JM (eds) Cellular senescence and tumor suppression. Springer, New York, pp 85–106
Jeanblanc M, Ragu S, Gey C, Contrepois K, Courbeyrette R, Thuret J-Y, Mann C (2012) Parallel pathways in RAF-induced senescence and conditions for its reversion. Oncogene 31:3072–3085
Jung MS, Jin DH, Chae HD, Kang S, Kim SC, Bang YJ, Choi TS, Choi KS, Shin DY (2004) Bcl-xL and E1B-19K proteins inhibit p53-induced irreversible growth arrest and senescence by preventing reactive oxygen species-dependent p38 activation. J Biol Chem 279:17765–17771
Kim WY, Sharpless NE (2006) The regulation of INK4/ARF in cancer and aging. Cell 127:265–275
Kim J, Hwangbo J, Wong PK (2011) p38 MAPK-mediated Bmi-1 down-regulation and defective proliferation in ATM-deficient neural stem cells can be restored by Akt activation. PLoS One 6:e16615
Kosar M, Bartkova J, Hubackova S, Hodny Z, Lukas J, Bartek J (2011) Senescence-associated heterochromatin foci are dispensable for cellular senescence, occur in a cell type- and insult-dependent manner and follow expression of p16(ink4a). Cell Cycle 10:457–468
Kuilman T, Michaloglou C, Mooi WJ, Peeper DS (2010) The essence of senescence. Genes Dev 24:2463–2479
Liang S, Mele J, Wu Y, Buffenstein R, Hornsby PJ (2010) Resistance to experimental tumorigenesis in cells of a long-lived mammal, the naked mole-rat (Heterocephalus glaber). Aging Cell 9:626–635
Lichterfeld M, Cung T, Seiss K, Rosenberg ES, Pereyra F, Yu XG (2012) Shelterin dysfunction and p16(INK4a)-mediated growth inhibition in HIV-1-specific CD8 T cells. J Virol 86:5533–5540
Mirzayans R, Andrais B, Scott A, Murray D (2012) New insights into p53 signaling and cancer cell response to DNA damage: implications for cancer therapy. J Biomed Biotechnol 2012:170325
Ohtani N, Yamakoshi K, Takahashi A, Hara E (2010) Real-time in vivo imaging of p16gene expression: a new approach to study senescence stress signaling in living animals. Cell Div 5:1
Passos JF, Nelson G, Wang C, Richter T, Simillion C, Proctor CJ, Miwa S, Olijslagers S, Hallinan J, Wipat A, Saretzki G, Rudolph KL, Kirkwood TB, von Zglinicki T (2010) Feedback between p21 and reactive oxygen production is necessary for cell senescence. Mol Syst Biol 6:347
Polo SE, Jackson SP (2011) Dynamics of DNA damage response proteins at DNA breaks: a focus on protein modifications. Genes Dev 25:409–433
Rodier F, Munoz DP, Teachenor R, Chu V, Le O, Bhaumik D, Coppe JP, Campeau E, Beausejour CM, Kim SH, Davalos AR, Campisi J (2011) DNA-SCARS: distinct nuclear structures that sustain damage-induced senescence growth arrest and inflammatory cytokine secretion. J Cell Sci 124:68–81
Ruzankina Y, Asare A, Brown EJ (2008) Replicative stress, stem cells and aging. Mech Ageing Dev 129:460–466
Sahin E, DePinho RA (2012) Axis of ageing: telomeres, p53 and mitochondria. Nat Rev Mol Cell Biol 13:397–404
Sedelnikova OA, Horikawa I, Zimonjic DB, Popescu NC, Bonner WM, Barrett JC (2004) Senescing human cells and ageing mice accumulate DNA lesions with unrepairable double-strand breaks. Nat Cell Biol 6:168–170
Serrano M, Lin AW, Mccurrach ME, Beach D, Lowe SW (1997) Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16 INK4A. Cell 88:593–602
Shao L, Li H, Pazhanisamy SK, Meng A, Wang Y, Zhou D (2011) Reactive oxygen species and hematopoietic stem cell senescence. Int J Hematol 94:24–32
Shkreli M, Sarin KY, Pech MF, Papeta N, Chang W, Brockman SA, Cheung P, Lee E, Kuhnert F, Olson JL, Kuo CJ, Gharavi AG, D’Agati VD, Artandi SE (2012) Reversible cell-cycle entry in adult kidney podocytes through regulated control of telomerase and Wnt signaling. Nat Med 18:111–119
Takahashi A, Ohtani N, Yamakoshi K, Iida S, Tahara H, Nakayama K, Nakayama KI, Ide T, Saya H, Hara E (2006) Mitogenic signalling and the p16INK4a-Rb pathway cooperate to enforce irreversible cellular senescence. Nat Cell Biol 8:1291–1297
Tchkonia T, Morbeck DE, Von Zglinicki T, Van Deursen J, Lustgarten J, Scrable H, Khosla S, Jensen MD, Kirkland JL (2010) Fat tissue, aging, and cellular senescence. Aging Cell 9:667–684
Tilstra JS, Robinson AR, Wang J, Gregg SQ, Clauson CL, Reay DP, Nasto LA, St Croix CM, Usas A, Vo N, Huard J, Clemens PR, Stolz DB, Guttridge DC, Watkins SC, Garinis GA, Wang Y, Niedernhofer LJ, Robbins PD (2012) NF-kappaB inhibition delays DNA damage-induced senescence and aging in mice. J Clin Invest 122:2601–2612
Waterstrat A, Van Zant G (2009) Effects of aging on hematopoietic stem and progenitor cells. Curr Opin Immunol 21:408–413
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Hornsby, P.J. (2013). Stress-Induced Senescence: Molecular Pathways. In: Hayat, M. (eds) Tumor Dormancy, Quiescence, and Senescence, Volume 1. Tumor Dormancy and Cellular Quiescence and Senescence, vol 1. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-5958-9_11
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DOI: https://doi.org/10.1007/978-94-007-5958-9_11
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