Escape from Cellular Quiescence

Part of the Current Cancer Research book series (CUCR)


Quiescent: From Latin quies, referring to a state of being at rest, dormant, inactive, quiet, still (Merriam-Webster, 2009, Online Dictionary: This term refers to a state of dormancy as opposed to a proliferative state. However, quiescent cells are in any other regard metabolically active. In many tissues with relative fast cell renewal rates the primary function of a small group of undifferentiated cells is limited to self-renewal (stem cells). These cells remain quiescent most of the time dividing only occasionally. In other tissues, key cell types perform fundamental tissue functions while remaining quiescent. Both stem cells and cells from tissues that renew via simple duplication can remain quiescent for long periods of time while retaining the capacity to re-enter the cell cycle. This chapter will discuss the mechanisms emerging as responsible for the maintenance of quiescence as well as those pathways that mediate quiescence entry and exit. We will also review signaling pathways deregulated during infection by Simian Virus 40 (SV40) and oncogenic transformation, which result in unscheduled exit from quiescence into the cell cycle, with focus on SV40 small t antigen.


Quiescent Cell Mitogenic Stimulation Normal Human Fibroblast Cell Cycle Exit Pocket Protein 
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.



We thank Manuel Serrano, David G. Johnson, Alison Kurimchak, and Judit Garriga for critically reading this manuscript and helpful suggestions. Work in this lab has been supported by a grant project under CA095569 and a Career Development Award (K02 AI01823) to XG of the National Institutes of Health.


  1. Albanese C, Johnson J, Watanabe G, Eklund N, Vu D, Arnold A, Pestell RG (1995) Transforming p21ras mutants and c-Ets-2 activate the cyclin D1 promoter through distinguishable regions. J Biol Chem 270: 23589–23597.CrossRefPubMedGoogle Scholar
  2. Ali SH, DeCaprio JA (2001) Cellular transformation by SV40 large T antigen: interaction with host proteins. Semin Cancer Biol 11: 15–23.CrossRefPubMedGoogle Scholar
  3. Arnold HK, Sears RC (2006) Protein phosphatase 2A regulatory subunit B56alpha associates with c-myc and negatively regulates c-myc accumulation. Mol Cell Biol 26: 2832–2844.CrossRefPubMedGoogle Scholar
  4. Berthet C, Kaldis P (2007) Cell-specific responses to loss of cyclin-dependent kinases. Oncogene 26: 4469–4477.CrossRefPubMedGoogle Scholar
  5. Blais A, Dynlacht BD (2004) Hitting their targets: an emerging picture of E2F and cell cycle control. Curr Opin Genet Dev 14: 527–532.CrossRefPubMedGoogle Scholar
  6. Blais A, Dynlacht BD (2007) E2F-associated chromatin modifiers and cell cycle control. Curr Opin Cell Biol 19: 658–662.CrossRefPubMedGoogle Scholar
  7. Blasco MA, Hahn WC (2003) Evolving views of telomerase and cancer. Trends Cell Biol 13: 289–294.CrossRefPubMedGoogle Scholar
  8. Blow JJ, Hodgson B (2002) Replication licensing – defining the proliferative state? Trends Cell Biol 12: 72–78.CrossRefPubMedGoogle Scholar
  9. Boehm JS, Hession MT, Bulmer SE, Hahn WC (2005) Transformation of human and murine fibroblasts without viral oncoproteins. Mol Cell Biol 25: 6464–6474.CrossRefPubMedGoogle Scholar
  10. Bouchard C, Marquardt J, Bras A, Medema RH, Eilers M (2004) Myc-induced proliferation and transformation require Akt-mediated phosphorylation of FoxO proteins. EMBO J 23: 2830–2840.CrossRefPubMedGoogle Scholar
  11. Burgering BM, Medema RH (2003) Decisions on life and death: FOXO Forkhead transcription factors are in command when PKB/Akt is off duty. J Leukoc Biol 73: 689–701.CrossRefPubMedGoogle Scholar
  12. Calbó J, Parreño M, Sotillo E, Yong T, Mazo A, Garriga J, Graña X (2002) G1 cyclin/CDK coordinated phosphorylation of endogenous pocket proteins differentially regulates their interactions with E2F4 and E2F1 and gene expression. J Biol Chem 277: 50263–50274.CrossRefPubMedGoogle Scholar
  13. Chen W, Hahn WC (2003) SV40 early region oncoproteins and human cell transformation. Histol Histopathol 18: 541–550.PubMedGoogle Scholar
  14. Chen W, Possemato R, Campbell KT, Plattner CA, Pallas DC, Hahn WC (2004) Identification of specific PP2A complexes involved in human cell transformation. Cancer Cell 5: 127–136.CrossRefPubMedGoogle Scholar
  15. Coller HA, Sang L, Roberts JM (2006) A new description of cellular quiescence. PLoS Biol 4: e83.CrossRefPubMedGoogle Scholar
  16. Connell-Crowley L, Elledge SJ, Harper JW (1998) G1 cyclin-dependent kinases are sufficient to initiate DNA synthesis in quiescent human fibroblasts. Curr Biol 8: 65–68.CrossRefPubMedGoogle Scholar
  17. Dannenberg JH, van Rossum A, Schuijff L, te Riele H (2000) Ablation of the retinoblastoma gene family deregulates G(1) control causing immortalization and increased cell turnover under growth-restricting conditions. Genes Dev 14: 3051–3064.CrossRefPubMedGoogle Scholar
  18. Diehl JA, Cheng M, Roussel MF, Sherr CJ (1998) Glycogen synthase kinase-3beta regulates cyclin D1 proteolysis and subcellular localization. Genes Dev 12: 3499–3511.CrossRefPubMedGoogle Scholar
  19. Diffley JF (2004) Regulation of early events in chromosome replication. Curr Biol 14: R778–R786.CrossRefPubMedGoogle Scholar
  20. Eddy BE, Borman GS, Grubbs GE, Young RD (1962) Identification of the oncogenic substance in rhesus monkey kidney cell culture as simian virus 40. Virology 17: 65–75.CrossRefPubMedGoogle Scholar
  21. Elenbaas B, Spirio L, Koerner F, Fleming MD, Zimonjic DB, Donaher JL, Popescu NC, Hahn WC, Weinberg RA (2001) Human breast cancer cells generated by oncogenic transformation of primary mammary epithelial cells. Genes Dev 15: 50–65.CrossRefPubMedGoogle Scholar
  22. Fernandez PC, Frank SR, Wang L, Schroeder M, Liu S, Greene J, Cocito A, Amati B (2003) Genomic targets of the human c-Myc protein. Genes Dev 17: 1115–1129.CrossRefPubMedGoogle Scholar
  23. Ferrari R, Berk AJ, Kurdistani SK (2009) Viral manipulation of the host epigenome for oncogenic transformation. Nat Rev Genet 10: 290–294.CrossRefPubMedGoogle Scholar
  24. Ferrari R, Pellegrini M, Horwitz GA, Xie W, Berk AJ, Kurdistani SK (2008) Epigenetic reprogramming by adenovirus e1a. Science 321: 1086–1088.CrossRefPubMedGoogle Scholar
  25. Geng Y, Yu Q, Sicinska E, Das M, Schneider JE, Bhattacharya S, Rideout WM, Bronson RT, Gardner H, Sicinski P (2003) Cyclin E ablation in the mouse. Cell 114: 431–443.CrossRefPubMedGoogle Scholar
  26. Gerber P (1963) Tumors induced in hamsters by simian virus 40: persistent subviral infection. Science 140: 889–890.CrossRefPubMedGoogle Scholar
  27. Girardi AJ, Sweet BH, Slotnick VB, Hilleman MR (1962) Development of tumors in hamsters inoculated in the neonatal period with vacuolating virus, SV-40. Proc Soc Exp Biol Med 109: 649–660.PubMedGoogle Scholar
  28. Graña X, Garriga J, Mayol X (1998) Role of the retinoblastoma protein family, pRB, p107 and p130 in the negative control of cell growth. Oncogene 17: 3365–3383.CrossRefPubMedGoogle Scholar
  29. Hahn WC (2002) Immortalization and transformation of human cells. Mol Cell 13: 351–361.Google Scholar
  30. Hahn WC, Counter CM, Lundberg AS, Beijersbergen RL, Brooks MW, Weinberg RA (1999) Creation of human tumour cells with defined genetic elements. Nature 400: 464–468.CrossRefPubMedGoogle Scholar
  31. Hahn WC, Dessain SK, Brooks MW, King JE, Elenbaas B, Sabatini DM, DeCaprio JA, Weinberg RA (2002) Enumeration of the simian virus 40 early region elements necessary for human cell transformation. Mol Cell Biol 22: 2111–2123.CrossRefPubMedGoogle Scholar
  32. Hahn WC, Weinberg RA (2002) Rules for making human tumor cells. N Engl J Med 347: 1593–1603.CrossRefPubMedGoogle Scholar
  33. Hallstrom TC, Mori S, Nevins JR (2008) An E2F1-dependent gene expression program that determines the balance between proliferation and cell death. Cancer Cell 13: 11–22.CrossRefPubMedGoogle Scholar
  34. Hallstrom TC, Nevins JR (2009) Balancing the decision of cell proliferation and cell fate. Cell Cycle 8: 532–535.CrossRefPubMedGoogle Scholar
  35. Henry DO, Moskalenko SA, Kaur KJ, Fu M, Pestell RG, Camonis JH, White MA (2000) Ral GTPases contribute to regulation of cyclin D1 through activation of NF-kappaB. Mol Cell Biol 20: 8084–8092.CrossRefPubMedGoogle Scholar
  36. Horwitz GA, Zhang K, McBrian MA, Grunstein M, Kurdistani SK, Berk AJ (2008) Adenovirus small e1a alters global patterns of histone modification. Science 321: 1084–1085.CrossRefPubMedGoogle Scholar
  37. Itahana K, Dimri GP, Hara E, Itahana Y, Zou Y, Desprez PY, Campisi J (2002) A role for p53 in maintaining and establishing the quiescence growth arrest in human cells. J Biol Chem 277: 18206–18214.CrossRefPubMedGoogle Scholar
  38. Jinno S, Yageta M, Nagata A, Okayama H (2002) Cdc6 requires anchorage for its expression. Oncogene 21: 1777–1784.CrossRefPubMedGoogle Scholar
  39. Johnson JE, Broccoli D (2007) Telomere maintenance in sarcomas. Curr Opin Oncol 19: 377–382.CrossRefPubMedGoogle Scholar
  40. Johnson DG, Schwarz JK, Cress WD, Nevins JR (1993) Expression of transcription factor E2F1 induces quiescent cells to enter S phase. Nature 365: 349–352.CrossRefPubMedGoogle Scholar
  41. Kaldis P, Russo AA, Chou HS, Pavletich NP, Solomon MJ (1998) Human and yeast cdk-activating kinases (CAKs) display distinct substrate specificities. Mol Biol Cell 9: 2545–2560.PubMedGoogle Scholar
  42. Kato J, Matsuoka M, Polyak K, Massague J, Sherr CJ (1994) Cyclic AMP-induced G1 phase arrest mediated by an inhibitor (p27Kip1) of cyclin-dependent kinase 4 activation. Cell 79: 487–496.CrossRefPubMedGoogle Scholar
  43. Keniry M, Parsons R (2008) The role of PTEN signaling perturbations in cancer and in targeted therapy. Oncogene 27: 5477–5485.CrossRefPubMedGoogle Scholar
  44. Lee YM, Sicinski P (2006) Targeting cyclins and cyclin-dependent kinases in cancer: lessons from mice, hopes for therapeutic applications in human. Cell Cycle 5: 2110–2114.CrossRefPubMedGoogle Scholar
  45. Leone G, DeGregori J, Sears R, Jakoi L, Nevins JR (1997) Myc and Ras collaborate in inducing accumulation of active cyclin E/Cdk2 and E2F [published erratum appears in Nature 1997 Jun 26;387(6636):932]. Nature 387: 422–426.CrossRefPubMedGoogle Scholar
  46. Leone G, Sears R, Huang E, Rempel R, Nuckolls F, Park CH, Giangrande P, Wu L, Saavedra HI, Field SJ, Thompson MA, Yang H, Fujiwara Y, Greenberg ME, Orkin S, Smith C, Nevins JR (2001) Myc requires distinct E2F activities to induce S phase and apoptosis. Mol Cell 8: 105–113.CrossRefPubMedGoogle Scholar
  47. Leung JY, Ehmann GL, Giangrande PH, Nevins JR (2008) A role for Myc in facilitating transcription activation by E2F1. Oncogene 27: 4172–4179.CrossRefPubMedGoogle Scholar
  48. Lin AW, Barradas M, Stone JC, van Aelst L, Sarrano M, Lowe SW (1998) Premature senescence involving p53 and p16 is activated in response to constitutive MEK/MAPK mitogenic signalling. Genes Dev 12: 3008–3019.Google Scholar
  49. Litovchick L, Sadasivam S, Florens L, Zhu X, Swanson SK, Velmurugan S, Chen R, Washburn MP, Liu XS, DeCaprio JA (2007) Evolutionarily conserved multisubunit RBL2/p130 and E2F4 protein complex represses human cell cycle-dependent genes in quiescence. Mol Cell 26: 539–551.CrossRefPubMedGoogle Scholar
  50. Liu F, Matsuura I (2005) Inhibition of Smad antiproliferative function by CDK phosphorylation. Cell Cycle 4: 63–66.PubMedGoogle Scholar
  51. Mailand N, Diffley JF (2005) CDKs promote DNA replication origin licensing in human cells by protecting Cdc6 from APC/C-dependent proteolysis. Cell 122: 915–926.CrossRefPubMedGoogle Scholar
  52. Malumbres M, Barbacid M (2001) To cycle or not to cycle: a critical decision in cancer. Nat Rev Cancer 1: 222–231.CrossRefPubMedGoogle Scholar
  53. Malumbres M, Barbacid M (2009) Cell cycle, CDKs and cancer: a changing paradigm. Nat Rev Cancer 9: 153–166.CrossRefPubMedGoogle Scholar
  54. Medema RH, Kops GJ, Bos JL, Burgering BM (2000) AFX-like Forkhead transcription factors mediate cell-cycle regulation by Ras and PKB through p27kip1. Nature 404: 782–787.CrossRefPubMedGoogle Scholar
  55. Mirza AM, Gysin S, Malek N, Nakayama K, Roberts JM, McMahon M (2004) Cooperative regulation of the cell division cycle by the protein kinases RAF and AKT. Mol Cell Biol 24: 10868–10881.CrossRefPubMedGoogle Scholar
  56. Moreno CS, Ramachandran S, Ashby DG, Laycock N, Plattner CA, Chen W, Hahn WC, Pallas DC (2004) Signaling and transcriptional changes critical for transformation of human cells by simian virus 40 small tumor antigen or protein phosphatase 2A B56gamma knockdown. Cancer Res 64: 6978–6988.CrossRefPubMedGoogle Scholar
  57. Moroy T, Geisen C (2004) Cyclin E. Int J Biochem Cell Biol 36: 1424–1439.CrossRefPubMedGoogle Scholar
  58. Mulligan G, Jacks T (1998) The retinoblastoma gene family: cousins with overlapping interests. Trends Genet 14: 223–229.CrossRefPubMedGoogle Scholar
  59. Nevis KR, Cordeiro-Stone M, Cook JG (2009) Origin licensing and p53 status regulate Cdk2 activity during G(1). Cell Cycle 8: 1952–1963.PubMedCrossRefGoogle Scholar
  60. Ohtsubo M, Roberts JM (1993) Cyclin-dependent regulation of G1 in mammalian fibroblasts. Science 259: 1908–1912.CrossRefPubMedGoogle Scholar
  61. Owen TA, Soprano DR, Soprano KJ (1989) Analysis of the growth factor requirements for stimulation of WI-38 cells after extended periods of density-dependent growth arrest. J Cell Physiol 139: 424–431.CrossRefPubMedGoogle Scholar
  62. Pallas DC, Shahrik LK, Martin BL, Jaspers S, Miller TB, Brautigan DL, Roberts TM (1990) Polyoma small and middle T antigens and SV40 small t antigen form stable complexes with protein phosphatase 2A. Cell 60: 167–176.CrossRefPubMedGoogle Scholar
  63. Pallas DC, Weller W, Jaspers S, Miller TB, Lane WS, Roberts TM (1992) The third subunit of protein phosphatase 2A (PP2A), a 55-kilodalton protein which is apparently substituted for by T antigens in complexes with the 36- and 63-kilodalton PP2A subunits, bears little resemblance to T antigens. J Virol 66: 886–893.PubMedGoogle Scholar
  64. Pardee AB (1974) A restriction point for control of normal animal cell proliferation. Proc Natl Acad Sci U S A 71: 1286–1290.CrossRefPubMedGoogle Scholar
  65. Pipas JM (2009) SV40: cell transformation and tumorigenesis. Virology 384: 294–303.CrossRefPubMedGoogle Scholar
  66. Porras A, Bennett J, Howe A, Tokos K, Bouck N, Henglein B, Sathyamangalam S, Thimmapaya B, Rundell K (1996) A novel simian virus 40 early-region domain mediates transactivation of the cyclin A promoter by small-t antigen and is required for transformation in small-t antigen-dependent assays. J Virol 70: 6902–6908.PubMedGoogle Scholar
  67. Porras A, Gaillard S, Rundell K (1999) The simian virus 40 small-t and large-T antigens jointly regulate cell cycle reentry in human fibroblasts. J Virol 73: 3102–3107.PubMedGoogle Scholar
  68. Quelle DE, Ashmun RA, Shurtleff SA, Kato JY, Bar SD, Roussel MF, Sherr CJ (1993) Overexpression of mouse D-type cyclins accelerates G1 phase in rodent fibroblasts. Genes Dev 7: 1559–1571.CrossRefPubMedGoogle Scholar
  69. Resnitzky D, Gossen M, Bujard H, Reed SI (1994) Acceleration of the G1/S phase transition by expression of cyclins D1 and E with an inducible system. Mol Cell Biol 14: 1669–1679.PubMedGoogle Scholar
  70. Rowland BD, Bernards R (2006) Re-evaluating cell-cycle regulation by E2Fs. Cell 127: 871–874.CrossRefPubMedGoogle Scholar
  71. 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: 3037–3050.CrossRefPubMedGoogle Scholar
  72. Sang L, Coller HA, Roberts JM (2008) Control of the reversibility of cellular quiescence by the transcriptional repressor HES1. Science 321: 1095–1100.CrossRefPubMedGoogle Scholar
  73. Santamaria D, Barriere C, Cerqueira A, Hunt S, Tardy C, Newton K, Caceres JF, Dubus P, Malumbres M, Barbacid M (2007) Cdk1 is sufficient to drive the mammalian cell cycle. Nature 448: 811–815.CrossRefPubMedGoogle Scholar
  74. Schmidt M, Fernandez de Mattos S, van der Horst A, Klompmaker R, Kops GJ, Lam EW, Burgering BM, Medema RH (2002) Cell cycle inhibition by FoxO forkhead transcription factors involves downregulation of cyclin D. Mol Cell Biol 22: 7842–7852.CrossRefPubMedGoogle Scholar
  75. Serrano M, Blasco MA (2007) Cancer and ageing: convergent and divergent mechanisms. Nat Rev Mol Cell Biol 8: 715–722.CrossRefPubMedGoogle Scholar
  76. Serrano M, Lin AW, McCurrach ME, Beach D, Lowe SW (1997) Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 88: 593–602.Google Scholar
  77. Sherr CJ, DePinho RA (2000) Cellular senescence: mitotic clock or culture shock? Cell 102: 407–410.CrossRefPubMedGoogle Scholar
  78. Sherr CJ, Roberts JM (1999) CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev 13: 1501–1512.CrossRefPubMedGoogle Scholar
  79. Sherr CJ, Roberts JM (2004) Living with or without cyclins and cyclin-dependent kinases. Genes Dev 18: 2699–2711.CrossRefPubMedGoogle Scholar
  80. Skoczylas C, Fahrbach KM, Rundell K (2004) Cellular targets of the SV40 small-t antigen in human cell transformation. Cell Cycle 3: 606–610.CrossRefPubMedGoogle Scholar
  81. Skoczylas C, Henglein B, Rundell K (2005) PP2A-dependent transactivation of the cyclin A promoter by SV40 ST is mediated by a cell cycle-regulated E2F site. Virology 332: 596–601.CrossRefPubMedGoogle Scholar
  82. Sontag E, Fedorov S, Kamibayashi C, Robbins D, Cobb M, Mumby M (1993) The interaction of SV40 small tumor antigen with protein phosphatase 2A stimulates the map kinase pathway and induces cell proliferation. Cell 75: 887–897.CrossRefPubMedGoogle Scholar
  83. Sontag E, Sontag JM, Garcia A (1997) Protein phosphatase 2A is a critical regulator of protein kinase C zeta signaling targeted by SV40 small t to promote cell growth and NF-kappaB activation. EMBO J 16: 5662–5671.CrossRefPubMedGoogle Scholar
  84. Sotillo E, Garriga J, Kurimchak A, Cook J, Grana X (2008) Cyclin E and SV40 small T antigen cooperate to bypass quiescence and contribute to transformation by activating CDK2 in human fibroblasts. J Biol Chem 283: 11280–11292.CrossRefPubMedGoogle Scholar
  85. Sotillo E, Garriga J, Padgaonkar A, Kurimchak A, Cook J, Grana X (2009) Coordinated activation of the origin licensing factor CDC6 and CDK2 in resting human fibroblasts expressing SV40 small T antigen and cyclin E. J Biol Chem 284: 14126–14135.CrossRefPubMedGoogle Scholar
  86. Stewart SA, Weinberg RA (2006) Telomeres: cancer to human aging. Annu Rev Cell Dev Biol 22: 531–557.CrossRefPubMedGoogle Scholar
  87. Virshup DM, Shenolikar S (2009) From promiscuity to precision: protein phosphatases get a makeover. Mol Cell 33: 537–545.CrossRefPubMedGoogle Scholar
  88. Watanabe G, Howe A, Lee RJ, Albanese C, Shu IW, Karnezis AN, Zon L, Kyriakis J, Rundell K, Pestell RG (1996) Induction of cyclin D1 by simian virus 40 small tumor antigen. Proc Natl Acad Sci U S A 93: 12861–12866.CrossRefPubMedGoogle Scholar
  89. Yang SI, Lickteig RL, Estes R, Rundell K, Walter G, Mumby MC (1991) Control of protein phosphatase 2A by simian virus 40 small-t antigen. Mol Cell Biol 11: 1988–1995.PubMedGoogle Scholar
  90. Yeh E, Cunningham M, Arnold H, Chasse D, Monteith T, Ivaldi G, Hahn WC, Stukenberg PT, Shenolikar S, Uchida T, Counter CM, Nevins JR, Means AR, Sears R (2004) A signalling pathway controlling c-Myc degradation that impacts oncogenic transformation of human cells. Nat Cell Biol 6: 308–318.CrossRefPubMedGoogle Scholar
  91. Yuan TL, Cantley LC (2008) PI3K pathway alterations in cancer: variations on a theme. Oncogene 27: 5497–5510.CrossRefPubMedGoogle Scholar
  92. Zetterberg A, Larsson O (1985) Kinetic analysis of regulatory events in G1 leading to proliferation or quiescence of Swiss 3T3 cells. Proc Natl Acad Sci U S A 82: 5365–5369.CrossRefPubMedGoogle Scholar
  93. Zhao JJ, Gjoerup OV, Subramanian RR, Cheng Y, Chen W, Roberts TM, Hahn WC (2003) Human mammary epithelial cell transformation through the activation of phosphatidylinositol 3-kinase. Cancer Cell 3: 483–495.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Department of PathologyChildren’s Hospital of PhiladelphiaPhiladelphiaUSA
  2. 2.Fels Institute for Cancer Research and Molecular BiologyTemple University School of MedicinePhiladelphiaUSA
  3. 3.Department of BiochemistryTemple University School of MedicinePhiladelphiaUSA

Personalised recommendations