To senesce or not to senesce: How primary human fibroblasts decide their cell fate after DNA damage

Aging

Volumn 8, Issue 1, 2016, Pages 158-177

  Kollarovic, Gabriel ^a,b   Studencka, Maja ^a   Ivanova, Lyubomira ^a   Lauenstein, Claudia ^a   Heinze, Kristina ^a   Lapytsko, Anastasiya ^a   Talemi, Soheil Rastgou ^a   Figueiredo, Ana Sofia ^a   Schaber, Jörg ^a  

^a OTTO VON GUERICKE UNIVERSITY   (Germany)

^b INSTITUTE OF CHEMISTRY   (Slovakia)

Author keywords

Bistable hysteresis switch; Cdk2 p21 ratio; Cumulative DNA damage; Dynamic model; G1 S transition

Indexed keywords

CDK2 PROTEIN, HUMAN; CDKN1A PROTEIN, HUMAN; CYCLIN DEPENDENT KINASE 2; CYCLIN DEPENDENT KINASE INHIBITOR 1A;

BIOLOGICAL MODEL; CELL AGING; CELL CULTURE; CELL PROLIFERATION; DNA DAMAGE; FIBROBLAST; G1 PHASE CELL CYCLE CHECKPOINT; GENETIC TRANSFECTION; GENETICS; HUMAN; METABOLISM; PATHOLOGY; PRIMARY CELL CULTURE; RADIATION RESPONSE; RNA INTERFERENCE; SIGNAL TRANSDUCTION; TIME FACTOR;

CELL AGING; CELL PROLIFERATION; CELLS, CULTURED; CYCLIN-DEPENDENT KINASE 2; CYCLIN-DEPENDENT KINASE INHIBITOR P21; DNA DAMAGE; DOSE-RESPONSE RELATIONSHIP, RADIATION; FIBROBLASTS; G1 PHASE CELL CYCLE CHECKPOINTS; HUMANS; MODELS, BIOLOGICAL; PRIMARY CELL CULTURE; RNA INTERFERENCE; SIGNAL TRANSDUCTION; TIME FACTORS; TRANSFECTION;

EID: 84986573170     PISSN: 19454589     EISSN: None     Source Type: Journal    
DOI: 10.18632/aging.100883     Document Type: Article

References (71)

1. Campisi J. Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors. Cell. 2005; 120:513-522.
2. Collado M, Blasco MA and Serrano M. Cellular senescence in cancer and aging. Cell. 2007; 130:223-233.
3. Kuilman T, Michaloglou C, Mooi WJ and Peeper DS. The essence of senescence. Genes Dev. 2010; 24:2463-2479.
4. Campisi J. Aging, cellular senescence, and cancer. Annu Rev Physiol. 2013; 75:685-705.
5. Lawless C, Wang C, Jurk D, Merz A, Zglinicki T and Passos JF. Quantitative assessment of markers for cell senescence. Exp Gerontol. 2010; 45:772-778.
6. Beausejour CM, Krtolica A, Galimi F, Narita M, Lowe SW, Yaswen P and Campisi J. Reversal of human cellular senescence: roles of the p53 and p16 pathways. Embo J. 2003; 22:4212-4222.
7. Stein GH, Drullinger LF, Soulard A and Dulic V. Differential roles for cyclin-dependent kinase inhibitors p21 and p16 in the mechanisms of senescence and differentiation in human fibroblasts. Mol Cell Biol. 1999; 19:2109-2117.
8. Deckbar D, Jeggo PA and Lobrich M. Understanding the limitations of radiation-induced cell cycle checkpoints. Crit Rev Biochem Mol Biol. 2011; 46:271-283.
9. Fumagalli M, Rossiello F, Clerici M, Barozzi S, Cittaro D, Kaplunov JM, Bucci G, Dobreva M, Matti V, Beausejour CM, Herbig U, Longhese MP and d'Adda di Fagagna F. Telomeric DNA damage is irreparable and causes persistent DNA-damageresponse activation. Nat Cell Biol. 2012; 14:355-365.
10. Hewitt G, Jurk D, Marques FD, Correia-Melo C, Hardy T, Gackowska A, Anderson R, Taschuk M, Mann J and Passos JF. Telomeres are favoured targets of a persistent DNA damage response in ageing and stress-induced senescence. Nat Commun. 2012; 3:708.
11. Kaul Z, Cesare AJ, Huschtscha LI, Neumann AA and Reddel RR. Five dysfunctional telomeres predict onset of senescence in human cells. EMBO Rep. 2012; 13:52-59.
12. d'Adda di Fagagna F, Reaper PM, Clay-Farrace L, Fiegler H, Carr P, Von Zglinicki T, Saretzki G, Carter NP and Jackson SP. A DNA damage checkpoint response in telomere-initiated senescence. Nature. 2003; 426:194-198.
13. Noda A, Hirai Y, Hamasaki K, Mitani H, Nakamura N and Kodama Y. Unrepairable DNA double-strand breaks that are generated by ionising radiation determine the fate of normal human cells. J Cell Sci. 2012; 125:5280-5287.
14. Verdun RE and Karlseder J. Replication and protection of telomeres. Nature. 2007; 447:924-931.
15. Ben-Porath I and Weinberg RA. The signals and pathways activating cellular senescence. Int J Biochem Cell Biol. 2005; 37:961-976.
16. Gil J and Peters G. Regulation of the INK4b-ARF-INK4a tumour suppressor locus: all for one or one for all. Nat Rev Mol Cell Biol. 2006; 7:667-677.
17. Sherr CJ and McCormick F. The RB and p53 pathways in cancer. Cancer Cell. 2002; 2:103-112.
18. Polager S and Ginsberg D. p53 and E2f: partners in life and death. Nat Rev Cancer. 2009; 9:738-748.
19. Obaya AJ and Sedivy JM. Regulation of cyclin-Cdk activity in mammalian cells. Cell Mol Life Sci. 2002; 59:126-142.
20. Ekholm SV and Reed SI. Regulation of G(1) cyclin-dependent kinases in the mammalian cell cycle. Curr Opin Cell Biol. 2000; 12:676-684.
21. 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, et al. Feedback between p21 and reactive oxygen production is necessary for cell senescence. Mol Syst Biol. 2010; 6:347.
22. Bluwstein A, Kumar N, Leger K, Traenkle J, Oostrum J, Rehrauer H, Baudis M and Hottiger MO. PKC signaling prevents irradiation-induced apoptosis of primary human fibroblasts. Cell Death Dis. 2013; 4:e498.
23. Goldstein JC, Rodier F, Garbe JC, Stampfer MR and Campisi J. Caspase-independent cytochrome c release is a sensitive measure of low-level apoptosis in cell culture models. Aging Cell. 2005; 4:217-222.
24. Baus F, Gire V, Fisher D, Piette J and Dulic V. Permanent cell cycle exit in G2 phase after DNA damage in normal human fibroblasts. Embo J. 2003; 22:3992-4002.
25. Ye C, Zhang X, Wan J, Chang L, Hu W, Bing Z, Zhang S, Li J, He J, Wang J and Zhou G. Radiation-induced cellular senescence results from a slippage of long-term G2 arrested cells into G1 phase. Cell Cycle. 2013; 12:1424-1432.
26. Johmura Y, Shimada M, Misaki T, Naiki-Ito A, Miyoshi H, Motoyama N, Ohtani N, Hara E, Nakamura M, Morita A, Takahashi S and Nakanishi M. Necessary and sufficient role for a mitosis skip in senescence induction. Mol Cell. 2014; 55:73-84.
27. Kitagawa M, Higashi H, Jung HK, Suzuki-Takahashi I, Ikeda M, Tamai K, Kato J, Segawa K, Yoshida E, Nishimura S and Taya Y. The consensus motif for phosphorylation by cyclin D1-Cdk4 is different from that for phosphorylation by cyclin A/E-Cdk2. Embo J. 1996; 15:7060-7069.
28. Serrano M. The tumor suppressor protein p16INK4a. Exp Cell Res. 1997; 237:7-13.
29. Kastan MB and Bartek J. Cell-cycle checkpoints and cancer. Nature. 2004; 432:316-323.
30. Busino L, Chiesa M, Draetta GF and Donzelli M. Cdc25A phosphatase: combinatorial phosphorylation, ubiquitylation and proteolysis. Oncogene. 2004; 23:2050-2056.
31. Zhou BB and Elledge SJ. The DNA damage response: putting checkpoints in perspective. Nature. 2000; 408:433-439.
32. Ling H, Kulasiri D and Samarasinghe S. Robustness of G1/S checkpoint pathways in cell cycle regulation based on probability of DNA-damaged cells passing as healthy cells. Biosystems. 2010; 101:213-221.
33. Iwamoto K, Hamada H, Eguchi Y and Okamoto M. Mathematical modeling of cell cycle regulation in response to DNA damage: exploring mechanisms of cell-fate determination. Biosystems. 2011; 103:384-391.
34. Iwamoto K, Tashima Y, Hamada H, Eguchi Y and Okamoto M. Mathematical modeling and sensitivity analysis of G1/S phase in the cell cycle including the DNA-damage signal transduction pathway. Biosystems. 2008; 94:109-117.
35. Tyson JJ. Modeling the cell division cycle: cdc2 and cyclin interactions. Proc Natl Acad Sci U S A. 1991; 88:7328-7332.
36. Toettcher JE, Loewer A, Ostheimer GJ, Yaffe MB, Tidor B and Lahav G. Distinct mechanisms act in concert to mediate cell cycle arrest. Proc Natl Acad Sci U S A. 2009; 106:785-790.
37. Csikasz-Nagy A, Battogtokh D, Chen KC, Novak B and Tyson JJ. Analysis of a generic model of eukaryotic cell-cycle regulation. Biophys J. 2006; 90:4361-4379.
38. Chen KC, Calzone L, Csikasz-Nagy A, Cross FR, Novak B and Tyson JJ. Integrative analysis of cell cycle control in budding yeast. Mol Biol Cell. 2004; 15:3841-3862.
39. Gerard C, Tyson JJ and Novak B. Minimal models for cellcycle control based on competitive inhibition and multisite phosphorylations of Cdk substrates. Biophys J. 2013; 104:1367-1379.
40. Novak B, Kapuy O, Domingo-Sananes MR and Tyson JJ. Regulated protein kinases and phosphatases in cell cycle decisions. Curr Opin Cell Biol. 2010; 22:801-808.
41. Novak B and Tyson JJ. A model for restriction point control of the mammalian cell cycle. J Theor Biol. 2004; 230:563-579.
42. Gerard C and Goldbeter A. Temporal self-organization of the cyclin/Cdk network driving the mammalian cell cycle. Proc Natl Acad Sci U S A. 2009; 106:21643-21648.
43. Gerard C and Goldbeter A. The balance between cell cycle arrest and cell proliferation: control by the extracellular matrix and by contact inhibition. Interface Focus. 2014; 4:20130075.
44. Gerard C, Tyson JJ, Coudreuse D and Novak B. Cell cycle control by a minimal Cdk network. PLoS Comput Biol. 2015; 11:e1004056.
45. Ling H, Samarasinghe S and Kulasiri D. Computational experiments reveal the efficacy of targeting CDK2 and CKIs for significantly lowering cellular senescence bar for potential cancer treatment. Biosystems. 2013; 111:71-82.
46. Rastgou Talemi S, Kollarovic G, Lapytsko A and Schaber J. Development of a robust DNA damage model including persistent telomere-associated damage with application to secondary cancer risk assessment. Scientific Reports. 2015; 5.
47. Ma L, Wagner J, Rice JJ, Hu W, Levine AJ and Stolovitzky GA. A plausible model for the digital response of p53 to DNA damage. Proc Natl Acad Sci U S A. 2005; 102:14266-14271.
48. Boutros R, Lobjois V and Ducommun B. CDC25 phosphatases in cancer cells: key players? Good targets? Nat Rev Cancer. 2007; 7:495-507.
49. Goldbeter A and Koshland DE, Jr. An amplified sensitivity arising from covalent modification in biological systems. Proc Natl Acad Sci U S A. 1981; 78:6840-6844.
50. Tyson JJ, Chen KC and Novak B. Sniffers, buzzers, toggles and blinkers: dynamics of regulatory and signaling pathways in the cell. Curr Opin Cell Biol. 2003; 15:221-231.
51. Ferrell JE and Xiong W. Bistability in cell signaling: How to make continuous processes discontinuous, and reversible processes irreversible. Chaos. 2001; 11:227-236.
52. Novak B and Tyson JJ. Design principles of biochemical oscillators. Nat Rev Mol Cell Biol. 2008; 9:981-991.
53. Aleem E, Kiyokawa H and Kaldis P. Cdc2-cyclin E complexes regulate the G1/S phase transition. Nat Cell Biol. 2005; 7:831-836.
54. Satyanarayana A, Hilton MB and Kaldis P. p21 Inhibits Cdk1 in the absence of Cdk2 to maintain the G1/S phase DNA damage checkpoint. Mol Biol Cell. 2008; 19:65-77.
55. Rodier F, Coppe JP, Patil CK, Hoeijmakers WA, Munoz DP, Raza SR, Freund A, Campeau E, Davalos AR and Campisi J. Persistent DNA damage signalling triggers senescenceassociated inflammatory cytokine secretion. Nat Cell Biol. 2009; 11:973-979.
56. Baker DJ, Wijshake T, Tchkonia T, LeBrasseur NK, Childs BG, van de Sluis B, Kirkland JL and van Deursen JM. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature. 2011; 479:232-236.
57. Novak B, Tyson JJ, Gyorffy B and Csikasz-Nagy A. Irreversible cell-cycle transitions are due to systems-level feedback. Nat Cell Biol. 2007; 9:724-728.
58. Pomerening JR. Uncovering mechanisms of bistability in biological systems. Curr Opin Biotechnol. 2008; 19(4):381-388.
59. Morisaki H, Ando A, Nagata Y, Pereira-Smith O, Smith JR, Ikeda K and Nakanishi M. Complex mechanisms underlying impaired activation of Cdk4 and Cdk2 in replicative senescence: roles of p16, p21, and cyclin D1. Exp Cell Res. 1999; 253:503-510.
60. Lucibello FC, Sewing A, Brusselbach S, Burger C and Muller R. Deregulation of cyclins D1 and E and suppression of cdk2 and cdk4 in senescent human fibroblasts. J Cell Sci. 1993; 105:123-133.
61. Wyllie F, Haughton M, Bartek J, Rowson J and Wynford-Thomas D. Mutant p53 can delay growth arrest and loss of CDK2 activity in senescing human fibroblasts without reducing p21(WAF1) expression. Exp Cell Res. 2003; 285:236-242.
62. Freedman DA and Folkman J. CDK2 translational downregulation during endothelial senescence. Exp Cell Res. 2005; 307:118-130.
63. Campaner S, Doni M, Hydbring P, Verrecchia A, Bianchi L, Sardella D, Schleker T, Perna D, Tronnersjo S, Murga M, Fernandez-Capetillo O, Barbacid M, Larsson LG, et al. Cdk2 suppresses cellular senescence induced by the c-myc oncogene. Nat Cell Biol. 2010; 12:54-59.
64. Helmbold H, Komm N, Deppert W and Bohn W. Rb2/p130 is the dominating pocket protein in the p53-p21 DNA damage response pathway leading to senescence. Oncogene. 2009; 28:3456-3467.
65. Leontieva OV and Blagosklonny MV. 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 (Albany NY). 2010; 2:924-935.
66. Korotchkina LG, Leontieva OV, Bukreeva EI, Demidenko ZN, Gudkov AV and Blagosklonny MV. The choice between p53-induced senescence and quiescence is determined in part by the mTOR pathway. Aging (Albany NY). 2010; 2:344-352.
67. Spencer SL, Cappell SD, Tsai FC, Overton KW, Wang CL and Meyer T. The proliferation-quiescence decision is controlled by a bifurcation in CDK2 activity at mitotic exit. Cell. 2013; 155:369-383.
68. Debacq-Chainiaux F, Erusalimsky JD, Campisi J and Toussaint O. Protocols to detect senescence-associated beta-galactosidase (SA-betagal) activity, a biomarker of senescent cells in culture and in vivo. Nat Protoc. 2009; 4:1798-1806.
69. Noppe G, Dekker P, de Koning-Treurniet C, Blom J, van Heemst D, Dirks RW, Tanke HJ, Westendorp RG and Maier AB. Rapid flow cytometric method for measuring senescence associated beta-galactosidase activity in human fibroblasts. Cytometry A. 2009; 75:910-916.
70. Hoops S, Sahle S, Gauges R, Lee C, Pahle J, Simus N, Singhal M, Xu L, Mendes P and Kummer U. COPASI-a COmplex PAthway SImulator. Bioinformatics. 2006; 22:3067-3074.
71. Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novere N, et al. BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol. 2010; 4:92.