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The cell fate: senescence or quiescence

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Abstract

Senescence and quiescence are frequently used as interchangeable terms in the literature unwittingly. Despite the fact that common molecules play role in decision of cell cycle arrest, senescent and quiescent cells have some distinctive phenotypes at both molecular and morphological levels. Thus, in this review we summarized the features of senescence and quiescence with respect to visual characteristics and prominent key molecules. A PubMed research was conducted for the key words; “senescence”, “quiescence” and “cell cycle arrest”. The results which are related to cell cycle control were selected. The selection criteria of the target articles used for this review included also key cell cycle molecules such as p53, pRB, p21, p16, mTOR, p27, etc. The results were not evaluated statistically. The mechanistic target of rapamycin (mTOR) has been claimed to be key molecule in switching on/off senescence/quiescence. Specifically, although maximal p53 activation blocks mTOR and causes quiescence, partial p53 activation sustains mTOR activity and causes senescence subsequently. In broader perspective, quiescence occurs due to lack of nutrition and growth factors whereas senescence takes place due to aging and serious DNA damages. Contrary to quiescence, senescence is a degenerative process ensuing a certain cell death. We highlighted several differences between senescence and quiescence and their key molecules in this review. Whereas quiescence (cell cycle arrest) is only one half of the senescence, the other half is growth stimulation which causes actual senescence phenotype.

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References

  1. Kuilman T, Michaloglou C, Mooi WJ, Peeper DS (2010) The essence of senescence. Genes Dev 24(22):2463–2479. doi:10.1101/gad.1971610

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Hayflick L, Moorhead PS (1961) The serial cultivation of human diploid cell strains. Exp Cell Res 25:585–621

    Article  CAS  PubMed  Google Scholar 

  3. Fridlyanskaya I, Alekseenko L, Nikolsky N (2015) Senescence as a general cellular response to stress: a mini-review. Exp Gerontol 72:124–128. doi:10.1016/j.exger.2015.09.021

    Article  PubMed  Google Scholar 

  4. Masutomi K, Yu EY, Khurts S, Ben-Porath I, Currier JL, Metz GB, Brooks MW, Kaneko S, Murakami S, DeCaprio JA, Weinberg RA, Stewart SA, Hahn WC (2003) Telomerase maintains telomere structure in normal human cells. Cell 114(2):241–253

    Article  CAS  PubMed  Google Scholar 

  5. Blagosklonny MV (2013) Hypoxia, MTOR and autophagy: converging on senescence or quiescence. Autophagy 9(2):260–262. doi:10.4161/auto.22783

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Yao G (2014) Modelling mammalian cellular quiescence. Interface Focus 4(3):20130074. doi:10.1098/rsfs.2013.0074

    Article  PubMed  PubMed Central  Google Scholar 

  7. 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(20):9363–9367

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Dulic V (2011) Be quiet and you’ll keep young: does mTOR underlie p53 action in protecting against senescence by favoring quiescence? Aging 3(1):3–4

    Article  PubMed  PubMed Central  Google Scholar 

  9. Vogelstein B, Lane D, Levine AJ (2000) Surfing the p53 network. Nature 408(6810):307–310. doi:10.1038/35042675

    Article  CAS  PubMed  Google Scholar 

  10. Serrano M (2010) Shifting senescence into quiescence by turning up p53. Cell Cycle 9(21):4256–4257

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Blagosklonny MV (2011) Cell cycle arrest is not senescence. Aging 3(2):94–101

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Chandeck C, Mooi WJ (2010) Oncogene-induced cellular senescence. Adv Anat Pathol 17(1):42–48. doi:10.1097/PAP.0b013e3181c66f4e

    CAS  PubMed  Google Scholar 

  13. Bernadotte A, Mikhelson VM, Spivak IM (2016) Markers of cellular senescence. Telomere shortening as a marker of cellular senescence. Aging 8(1):3–11

    Article  PubMed  PubMed Central  Google Scholar 

  14. Narita M, Narita M, Krizhanovsky V, Nunez S, Chicas A, Hearn SA, Myers MP, Lowe SW (2006) A novel role for high-mobility group a proteins in cellular senescence and heterochromatin formation. Cell 126(3):503–514. doi:10.1016/j.cell.2006.05.052

    Article  CAS  PubMed  Google Scholar 

  15. Funayama R, Saito M, Tanobe H, Ishikawa F (2006) Loss of linker histone H1 in cellular senescence. J Cell Biol 175(6):869–880. doi:10.1083/jcb.200604005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Baker DJ, Sedivy JM (2013) Probing the depths of cellular senescence. J Cell Biol 202(1):11–13. doi:10.1083/jcb.201305155

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Chandler H, Peters G (2013) Stressing the cell cycle in senescence and aging. Curr Opin Cell Biol 25(6):765–771. doi:10.1016/j.ceb.2013.07.005

    Article  CAS  PubMed  Google Scholar 

  18. Young AR, Narita M, Ferreira M, Kirschner K, Sadaie M, Darot JF, Tavare S, Arakawa S, Shimizu S, Watt FM, Narita M (2009) Autophagy mediates the mitotic senescence transition. Genes Dev 23(7):798–803. doi:10.1101/gad.519709

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Kuilman T, Michaloglou C, Vredeveld LC, Douma S, van Doorn R, Desmet CJ, Aarden LA, Mooi WJ, Peeper DS (2008) Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network. Cell 133(6):1019–1031. doi:10.1016/j.cell.2008.03.039

    Article  CAS  PubMed  Google Scholar 

  20. Cho S, Hwang ES (2012) Status of mTOR activity may phenotypically differentiate senescence and quiescence. Mol Cells 33(6):597–604. doi:10.1007/s10059-012-0042-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Jeyapalan JC, Sedivy JM (2008) Cellular senescence and organismal aging. Mech Ageing Dev 129(7–8):467–474. doi:10.1016/j.mad.2008.04.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Siddiqi S, Sussman MA (2014) The heart: mostly postmitotic or mostly premitotic? Myocyte cell cycle, senescence, and quiescence. Can J Cardiol 30(11):1270–1278. doi:10.1016/j.cjca.2014.08.014

    Article  PubMed  PubMed Central  Google Scholar 

  23. Vousden KH, Prives C (2009) Blinded by the light: the growing complexity of p53. Cell 137(3):413–431. doi:10.1016/j.cell.2009.04.037

    Article  CAS  PubMed  Google Scholar 

  24. Ventura A, Kirsch DG, McLaughlin ME, Tuveson DA, Grimm J, Lintault L, Newman J, Reczek EE, Weissleder R, Jacks T (2007) Restoration of p53 function leads to tumour regression in vivo. Nature 445(7128):661–665. doi:10.1038/nature05541

    Article  CAS  PubMed  Google Scholar 

  25. Kovatcheva M, Liu DD, Dickson MA, Klein ME, O’Connor R, Wilder FO, Socci ND, Tap WD, Schwartz GK, Singer S, Crago AM, Koff A (2015) MDM2 turnover and expression of ATRX determine the choice between quiescence and senescence in response to CDK4 inhibition. Oncotarget 6(10):8226–8243. doi:10.18632/oncotarget.3364

    Article  PubMed  PubMed Central  Google Scholar 

  26. Yoshida A, Diehl JA (2015) CDK4/6 inhibitor: from quiescence to senescence. Oncoscience 2(11):896–897

    PubMed  PubMed Central  Google Scholar 

  27. Leontieva OV, Gudkov AV, Blagosklonny MV (2010) Weak p53 permits senescence during cell cycle arrest. Cell Cycle 9(21):4323–4327

    Article  CAS  PubMed  Google Scholar 

  28. Leontieva OV, Demidenko ZN, Gudkov AV, Blagosklonny MV (2011) Elimination of proliferating cells unmasks the shift from senescence to quiescence caused by rapamycin. PLoS One 6(10):e26126. doi:10.1371/journal.pone.0026126

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Vassilev LT (2004) Small-molecule antagonists of p53-MDM2 binding: research tools and potential therapeutics. Cell Cycle 3(4):419–421

    Article  CAS  PubMed  Google Scholar 

  30. Korotchkina LG, Leontieva OV, Bukreeva EI, Demidenko ZN, Gudkov AV, Blagosklonny MV (2010) The choice between p53-induced senescence and quiescence is determined in part by the mTOR pathway. Aging 2(6):344–352

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Xue W, Zender L, Miething C, Dickins RA, Hernando E, Krizhanovsky V, Cordon-Cardo C, Lowe SW (2007) Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature 445(7128):656–660. doi:10.1038/nature05529

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Gil J, Peters G (2006) Regulation of the INK4b-ARF-INK4a tumour suppressor locus: all for one or one for all. Nat Rev Mol Cell Biol 7(9):667–677. doi:10.1038/nrm1987

    Article  CAS  PubMed  Google Scholar 

  33. Sage J, Mulligan GJ, Attardi LD, Miller A, Chen S, Williams B, Theodorou E, Jacks T (2000) Targeted disruption of the three Rb-related genes leads to loss of G(1) control and immortalization. Genes Dev 14(23):3037–3050

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Imai Y, Takahashi A, Hanyu A, Hori S, Sato S, Naka K, Hirao A, Ohtani N, Hara E (2014) Crosstalk between the Rb pathway and AKT signaling forms a quiescence-senescence switch. Cell Rep 7(1):194–207. doi:10.1016/j.celrep.2014.03.006

    Article  CAS  PubMed  Google Scholar 

  35. Kapic A, Helmbold H, Reimer R, Klotzsche O, Deppert W, Bohn W (2006) Cooperation between p53 and p130(Rb2) in induction of cellular senescence. Cell Death Differ 13(2):324–334. doi:10.1038/sj.cdd.4401756

    Article  CAS  PubMed  Google Scholar 

  36. Leontieva OV, Blagosklonny MV (2010) DNA damaging agents and p53 do not cause senescence in quiescent cells, while consecutive re-activation of mTOR is associated with conversion to senescence. Aging 2(12):924–935

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Chen C, Liu Y, Liu R, Ikenoue T, Guan KL, Liu Y, Zheng P (2008) TSC-mTOR maintains quiescence and function of hematopoietic stem cells by repressing mitochondrial biogenesis and reactive oxygen species. J Exp Med 205(10):2397–2408. doi:10.1084/jem.20081297

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Lehmann BD, Brooks AM, Paine MS, Chappell WH, McCubrey JA, Terrian DM (2008) Distinct roles for p107 and p130 in Rb-independent cellular senescence. Cell Cycle 7(9):1262–1268

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Flores JM, Martin-Caballero J, Garcia-Fernandez RA (2014) p21 and p27 a shared senescence history. Cell Cycle 13(11):1655–1656. doi:10.4161/cc.29147

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Perucca P, Cazzalini O, Madine M, Savio M, Laskey RA, Vannini V, Prosperi E, Stivala LA (2009) Loss of p21 CDKN1A impairs entry to quiescence and activates a DNA damage response in normal fibroblasts induced to quiescence. Cell Cycle 8(1):105–114

    Article  CAS  PubMed  Google Scholar 

  41. Kippin TE, Martens DJ, van der Kooy D (2005) p21 loss compromises the relative quiescence of forebrain stem cell proliferation leading to exhaustion of their proliferation capacity. Genes Dev 19(6):756–767. doi:10.1101/gad.1272305

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Sousa-Victor P, Gutarra S, Garcia-Prat L, Rodriguez-Ubreva J, Ortet L, Ruiz-Bonilla V, Jardi M, Ballestar E, Gonzalez S, Serrano AL, Perdiguero E, Munoz-Canoves P (2014) Geriatric muscle stem cells switch reversible quiescence into senescence. Nature 506(7488):316–321. doi:10.1038/nature13013

    Article  CAS  PubMed  Google Scholar 

  43. Sherr CJ, Roberts JM (1999) CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev 13(12):1501–1512

    Article  CAS  PubMed  Google Scholar 

  44. Helmbold H, Komm N, Deppert W, Bohn W (2009) Rb2/p130 is the dominating pocket protein in the p53-p21 DNA damage response pathway leading to senescence. Oncogene 28(39):3456–3467. doi:10.1038/onc.2009.222

    Article  CAS  PubMed  Google Scholar 

  45. Aird KM, Zhang R (2015) ATM in senescence. Oncotarget 6(17):14729–14730. doi:10.18632/oncotarget.4411

    Article  PubMed  PubMed Central  Google Scholar 

  46. Aird KM, Worth AJ, Snyder NW, Lee JV, Sivanand S, Liu Q, Blair IA, Wellen KE, Zhang R (2015) ATM couples replication stress and metabolic reprogramming during cellular senescence. Cell Rep 11(6):893–901. doi:10.1016/j.celrep.2015.04.014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Nair RR, Bagheri M, Saini DK (2015) Temporally distinct roles of ATM and ROS in genotoxic-stress-dependent induction and maintenance of cellular senescence. J Cell Sci 128(2):342–353. doi:10.1242/jcs.159517

    Article  CAS  PubMed  Google Scholar 

  48. Sangfelt O, Erickson S, Grander D (2000) Mechanisms of interferon-induced cell cycle arrest. Front Biosci 5:D479–D487

    Article  CAS  PubMed  Google Scholar 

  49. Yu Q, Katlinskaya YV, Carbone CJ, Zhao B, Katlinski KV, Zheng H, Guha M, Li N, Chen Q, Yang T, Lengner CJ, Greenberg RA, Johnson FB, Fuchs SY (2015) DNA-damage-induced type I interferon promotes senescence and inhibits stem cell function. Cell Rep 11(5):785–797. doi:10.1016/j.celrep.2015.03.069

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Kim KS, Kang KW, Seu YB, Baek SH, Kim JR (2009) Interferon-gamma induces cellular senescence through p53-dependent DNA damage signaling in human endothelial cells. Mech Ageing Dev 130(3):179–188. doi:10.1016/j.mad.2008.11.004

    Article  CAS  PubMed  Google Scholar 

  51. Duan X, Ponomareva L, Veeranki S, Panchanathan R, Dickerson E, Choubey D (2011) Differential roles for the interferon-inducible IFI16 and AIM2 innate immune sensors for cytosolic DNA in cellular senescence of human fibroblasts. Mol Cancer Res 9(5):589–602. doi:10.1158/1541-7786.MCR-10-0565

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Hasegawa H, Yamada Y, Iha H, Tsukasaki K, Nagai K, Atogami S, Sugahara K, Tsuruda K, Ishizaki A, Kamihira S (2009) Activation of p53 by Nutlin-3a, an antagonist of MDM2, induces apoptosis and cellular senescence in adult T-cell leukemia cells. Leukemia 23(11):2090–2101. doi:10.1038/leu.2009.171

    Article  CAS  PubMed  Google Scholar 

  53. Madan E, Gogna R, Kuppusamy P, Bhatt M, Pati U, Mahdi AA (2012) TIGAR induces p53-mediated cell-cycle arrest by regulation of RB-E2F1 complex. Br J Cancer 107(3):516–526. doi:10.1038/bjc.2012.260

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Roy A, Banerjee S (2015) p27 and leukemia: cell cycle and beyond. J Cell Physiol 230(3):504–509. doi:10.1002/jcp.24819

    Article  CAS  PubMed  Google Scholar 

  55. Schug TT (2010) mTOR favors senescence over quiescence in p53-arrested cells. Aging 2(6):327–328

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Maryanovich M, Oberkovitz G, Niv H, Vorobiyov L, Zaltsman Y, Brenner O, Lapidot T, Jung S, Gross A (2012) The ATM-BID pathway regulates quiescence and survival of haematopoietic stem cells. Nat Cell Biol 14(5):535–541. doi:10.1038/ncb2468

    Article  CAS  PubMed  Google Scholar 

  57. Lin SP, Chiu FY, Wang Y, Yen ML, Kao SY, Hung SC (2014) RB maintains quiescence and prevents premature senescence through upregulation of DNMT1 in mesenchymal stromal cells. Stem Cell Rep 3(6):975–986. doi:10.1016/j.stemcr.2014.10.002

    Article  CAS  Google Scholar 

  58. Courtois-Cox S, Jones SL, Cichowski K (2008) Many roads lead to oncogene-induced senescence. Oncogene 27(20):2801–2809. doi:10.1038/sj.onc.1210950

    Article  CAS  PubMed  Google Scholar 

  59. Tamaki S, Nye C, Slorach E, Scharp D, Blau HM, Whiteley PE, Pomerantz JH (2014) Simultaneous silencing of multiple RB and p53 pathway members induces cell cycle reentry in intact human pancreatic islets. BMC Biotechnol 14:86. doi:10.1186/1472-6750-14-86

    Article  PubMed  PubMed Central  Google Scholar 

  60. Hanna J, Saha K, Pando B, van Zon J, Lengner CJ, Creyghton MP, van Oudenaarden A, Jaenisch R (2009) Direct cell reprogramming is a stochastic process amenable to acceleration. Nature 462(7273):595–601. doi:10.1038/nature08592

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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  1. Department of Medical Biology, Faculty of Medicine, Mustafa Kemal University, Serinyol Campus, 31034, Antakya, Hatay, Turkey

    Menderes Yusuf Terzi, Muzeyyen Izmirli & Bulent Gogebakan

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  1. Menderes Yusuf Terzi
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Terzi, M.Y., Izmirli, M. & Gogebakan, B. The cell fate: senescence or quiescence. Mol Biol Rep 43, 1213–1220 (2016). https://doi.org/10.1007/s11033-016-4065-0

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