Feedback Between P21 and Reactive Oxygen Production is Necessary for Cell Senescence

Overview

Journal Mol Syst Biol

Specialty Molecular Biology

Date 2010 Feb 18

PMID 20160708

Citations 472

Authors

Joao F Passos

Glyn Nelson

Chunfang Wang

Torsten Richter

Cedric Simillion

Carole J Proctor

Satomi Miwa

Sharon Olijslagers

Jennifer Hallinan

Anil Wipat

Gabriele Saretzki

Karl Lenhard Rudolph

Tom B L Kirkwood

Thomas von Zglinicki

Affiliations

Soon will be listed here.

Abstract

Cellular senescence--the permanent arrest of cycling in normally proliferating cells such as fibroblasts--contributes both to age-related loss of mammalian tissue homeostasis and acts as a tumour suppressor mechanism. The pathways leading to establishment of senescence are proving to be more complex than was previously envisaged. Combining in-silico interactome analysis and functional target gene inhibition, stochastic modelling and live cell microscopy, we show here that there exists a dynamic feedback loop that is triggered by a DNA damage response (DDR) and, which after a delay of several days, locks the cell into an actively maintained state of 'deep' cellular senescence. The essential feature of the loop is that long-term activation of the checkpoint gene CDKN1A (p21) induces mitochondrial dysfunction and production of reactive oxygen species (ROS) through serial signalling through GADD45-MAPK14(p38MAPK)-GRB2-TGFBR2-TGFbeta. These ROS in turn replenish short-lived DNA damage foci and maintain an ongoing DDR. We show that this loop is both necessary and sufficient for the stability of growth arrest during the establishment of the senescent phenotype.

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References

Debacq-Chainiaux F, Borlon C, Pascal T, Royer V, Eliaers F, Ninane N . Repeated exposure of human skin fibroblasts to UVB at subcytotoxic level triggers premature senescence through the TGF-beta1 signaling pathway. J Cell Sci. 2005; 118(Pt 4):743-58. DOI: 10.1242/jcs.01651. View

Moiseeva O, Bourdeau V, Roux A, Deschenes-Simard X, Ferbeyre G . Mitochondrial dysfunction contributes to oncogene-induced senescence. Mol Cell Biol. 2009; 29(16):4495-507. PMC: 2725737. DOI: 10.1128/MCB.01868-08. View

Choudhury A, Ju Z, Djojosubroto M, Schienke A, Lechel A, Schaetzlein S . Cdkn1a deletion improves stem cell function and lifespan of mice with dysfunctional telomeres without accelerating cancer formation. Nat Genet. 2006; 39(1):99-105. DOI: 10.1038/ng1937. View

Panda S, Isbatan A, Adami G . Modification of the ATM/ATR directed DNA damage response state with aging and long after hepatocyte senescence induction in vivo. Mech Ageing Dev. 2008; 129(6):332-40. PMC: 2532062. DOI: 10.1016/j.mad.2008.02.014. View

Kuilman T, Michaloglou C, Vredeveld L, Douma S, van Doorn R, Desmet C . Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network. Cell. 2008; 133(6):1019-31. DOI: 10.1016/j.cell.2008.03.039. View

Wang C, Jurk D, Maddick M, Nelson G, Martin-Ruiz C, von Zglinicki T . DNA damage response and cellular senescence in tissues of aging mice. Aging Cell. 2009; 8(3):311-23. DOI: 10.1111/j.1474-9726.2009.00481.x. View

Muller F, Lustgarten M, Jang Y, Richardson A, Van Remmen H . Trends in oxidative aging theories. Free Radic Biol Med. 2007; 43(4):477-503. DOI: 10.1016/j.freeradbiomed.2007.03.034. View

Baker D, Perez-Terzic C, Jin F, Pitel K, Pitel K, Niederlander N . Opposing roles for p16Ink4a and p19Arf in senescence and ageing caused by BubR1 insufficiency. Nat Cell Biol. 2008; 10(7):825-36. PMC: 2594014. DOI: 10.1038/ncb1744. View

Parrinello S, Samper E, Krtolica A, Goldstein J, Melov S, Campisi J . Oxygen sensitivity severely limits the replicative lifespan of murine fibroblasts. Nat Cell Biol. 2003; 5(8):741-7. PMC: 4940195. DOI: 10.1038/ncb1024. View

10.

Chang B, Broude E, Fang J, Kalinichenko T, Abdryashitov R, Poole J . p21Waf1/Cip1/Sdi1-induced growth arrest is associated with depletion of mitosis-control proteins and leads to abnormal mitosis and endoreduplication in recovering cells. Oncogene. 2000; 19(17):2165-70. DOI: 10.1038/sj.onc.1203573. View

11.

dAdda di Fagagna F . Living on a break: cellular senescence as a DNA-damage response. Nat Rev Cancer. 2008; 8(7):512-22. DOI: 10.1038/nrc2440. View

12.

Macip S, Igarashi M, Berggren P, Yu J, Lee S, Aaronson S . Influence of induced reactive oxygen species in p53-mediated cell fate decisions. Mol Cell Biol. 2003; 23(23):8576-85. PMC: 262651. DOI: 10.1128/MCB.23.23.8576-8585.2003. View

13.

Rai P, Onder T, Young J, McFaline J, Pang B, Dedon P . Continuous elimination of oxidized nucleotides is necessary to prevent rapid onset of cellular senescence. Proc Natl Acad Sci U S A. 2009; 106(1):169-74. PMC: 2629241. DOI: 10.1073/pnas.0809834106. View

14.

Kirkwood T, Boys R, Gillespie C, Proctor C, Shanley D, Wilkinson D . Towards an e-biology of ageing: integrating theory and data. Nat Rev Mol Cell Biol. 2003; 4(3):243-9. DOI: 10.1038/nrm1051. View

15.

Ventura A, Kirsch D, McLaughlin M, Tuveson D, Grimm J, Lintault L . Restoration of p53 function leads to tumour regression in vivo. Nature. 2007; 445(7128):661-5. DOI: 10.1038/nature05541. View

16.

Kearsey J, Coates P, Prescott A, Warbrick E, Hall P . Gadd45 is a nuclear cell cycle regulated protein which interacts with p21Cip1. Oncogene. 1995; 11(9):1675-83. View

17.

Chen Q, Fischer A, Reagan J, Yan L, Ames B . Oxidative DNA damage and senescence of human diploid fibroblast cells. Proc Natl Acad Sci U S A. 1995; 92(10):4337-41. PMC: 41939. DOI: 10.1073/pnas.92.10.4337. View

18.

Sang L, Coller H, Roberts J . Control of the reversibility of cellular quiescence by the transcriptional repressor HES1. Science. 2008; 321(5892):1095-100. PMC: 2721335. DOI: 10.1126/science.1155998. View

19.

Stark C, Breitkreutz B, Reguly T, Boucher L, Breitkreutz A, Tyers M . BioGRID: a general repository for interaction datasets. Nucleic Acids Res. 2005; 34(Database issue):D535-9. PMC: 1347471. DOI: 10.1093/nar/gkj109. View

20.

Sone H, Kagawa Y . Pancreatic beta cell senescence contributes to the pathogenesis of type 2 diabetes in high-fat diet-induced diabetic mice. Diabetologia. 2004; 48(1):58-67. DOI: 10.1007/s00125-004-1605-2. View