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Four Faces of Cellular Senescence

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Four Faces of Cellular Senescence Published February 14, 2011 JCB: Review Four faces of cellular senescence Francis Rodier1,2 and Judith Campisi3,4 1The Research Centre of the University of Montreal Hospital Centre/Institut du Cancer de Montréal, Montreal, Quebec, H2L 4M1 Canada 2Department of Radiology, Radio-Oncology and Nuclear Medicine, Université de Montréal, Montreal, Quebec, H3C 3J7 Canada 3Buck Institute for Age Research, Novato, CA 94945 4Lawrence Berkeley National Laboratory, Berkeley, CA 94720 Cellular senescence is an important mechanism for pre- also offer insights into why, beyond the simple growth arrest, venting the proliferation of potential cancer cells. Recently, the complex senescent phenotypes may have evolved. however, it has become apparent that this process entails Cellular senescence: a primer more than a simple cessation of cell growth. In addition Cellular senescence refers to the essentially irreversible growth to suppressing tumorigenesis, cellular senescence might arrest that occurs when cells that can divide encounter onco- also promote tissue repair and fuel inflammation associ- genic stress. With the possible exception of embryonic stem Downloaded from ated with aging and cancer progression. Thus, cellular cells (Miura et al., 2004), most division-competent cells, in- senescence might participate in four complex biological cluding some tumor cells, can undergo senescence when appro- priately stimulated (Shay and Roninson, 2004; Campisi and processes (tumor suppression, tumor promotion, aging, d’Adda di Fagagna, 2007). and tissue repair), some of which have apparently op- What causes cellular senescence? Senescence- posing effects. The challenge now is to understand the inducing stimuli are myriad. We now know that the limited senescence response well enough to harness its benefits growth of human cells in culture is due in part to telomere ero- jcb.rupress.org while suppressing its drawbacks. sion, the gradual loss of DNA at the ends of chromosomes (telo- meres). Telomeric DNA is lost with each S phase because DNA polymerases are unidirectional and cannot prime a new DNA strand, resulting in loss of DNA near the end of a chromosome; additionally, most cells do not express telomerase, the special- on February 21, 2011 Introduction ized enzyme that can restore telomeric DNA sequences de novo Cellular senescence was formally described more than 40 years (Harley et al., 1990; Bodnar et al., 1998). We also know that ago as a process that limited the proliferation (growth) of nor- eroded telomeres generate a persistent DNA damage response mal human cells in culture (Hayflick, 1965). This landmark (DDR), which initiates and maintains the senescence growth paper contained two prescient statements. The first statement arrest (d’Adda di Fagagna et al., 2003; Takai et al., 2003; Herbig was “unlimited cellular division or . escape from senescent- et al., 2004; Rodier et al., 2009, 2011). In fact, many senescent like changes . can only be achieved by [somatic] cells which cells harbor genomic damage at nontelomeric sites, which also have . assumed properties of cancer cells.” The second was generate the persistent DDR signaling needed for the senes- “the [cessation of cell growth in culture] may be related to se- cence growth arrest (Nakamura et al., 2008). DNA double strand THE JOURNAL OF CELL BIOLOGY nescence [aging] in vivo.” Thus, nearly half a century ago, the breaks are especially potent senescence inducers (DiLeonardo process now known as cellular senescence was linked to both et al., 1994). In addition, compounds such as histone deacetylase tumor suppression and aging. inhibitors, which relax chromatin without physically damaging In the ensuing decades, we learned much about what causes DNA, activate the DDR proteins ataxia telangiectasia mutated cellular senescence and the nature of the senescent phenotype. (ATM) and the p53 tumor suppressor (Bakkenist and Kastan, Importantly, we are beginning to understand its physiological 2003), and induce a senescence response (Ogryzko et al., 1996; relevance. Recent data validate the early idea that cellular se- Munro et al., 2004). Finally, many cells senesce when they ex- nescence is important for tumor suppression. The data now also perience strong mitogenic signals, such as those delivered by strongly suggest that cellular senescence contributes to aging, certain oncogenes or highly expressed pro-proliferative genes and, further, that senescence-associated phenotypes can con- (Serrano et al., 1997; Lin et al., 1998; Zhu et al., 1998; Dimri et al., tribute to both tumor progression and normal tissue repair. They 2000). Notably, these mitogenic signals can create DNA damage Correspondence to Judith Campisi: [email protected] or [email protected] and a persistent DDR due to misfired replication origins and Abbreviations used in this paper: ATM, ataxia telangiectasia mutated; DDR, DNA © 2011 Rodier and Campisi This article is distributed under the terms of an Attribution– damage response; DNA-SCARS, DNA segments with chromatin alterations rein- Noncommercial–Share Alike–No Mirror Sites license for the first six months after the pub- forcing senescence; IL, interleukin; MMP, matrix metalloproteinase; NF-B, nuclear lication date (see http://www.rupress.org/terms). After six months it is available under a factor B; SA-Bgal, senescence-associated -galactosidase; SASP, senescence- Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, associated secretory phenotype. as described at http://creativecommons.org/licenses/by-nc-sa/3.0/). The Rockefeller University Press J. Cell Biol. Vol. 192 No. 4 547–556 www.jcb.org/cgi/doi/10.1083/jcb.201009094 JCB 547 Published February 14, 2011 Figure 1. Hallmarks of senescent cells. Senescent cells differ from other nondividing (quiescent, terminally differentiated) cells in several ways, although no single feature of the senescent phenotype is exclusively specific. Hallmarks of senescent cells include an essentially irreversible growth arrest; expression Downloaded from of SA-Bgal and p16INK4a; robust secretion of numerous growth factors, cytokines, proteases, and other proteins (SASP); and nuclear foci containing DDR proteins (DNA-SCARS/TIF) or heterochromatin (SAHF). The pink circles in the nonsenescent cell (left) and senescent cell (right) represent the nucleus. replication fork collapse (Bartkova et al., 2006; Di Micco et al., (b) Senescent cells increase in size, sometimes enlarging 2006; Mallette et al., 2007). Thus, many senescence-inducing more than twofold relative to the size of nonsenescent counter- stimuli cause epigenomic disruption or genomic damage. parts (Hayflick, 1965). Senescence can also occur, however, without detect- (c) Senescent cells express a senescence-associated jcb.rupress.org able DDR signaling. “Culture stress,” the natural and in vivo -galactosidase (SA-Bgal; Dimri et al., 1995), which partly equivalent of which are unknown, causes a senescence ar- reflects the increase in lysosomal mass (Lee et al., 2006). rest without significant telomere erosion (Ramirez et al., (d) Most senescent cells express p16INK4a, which is 2001). These stresses could include inappropriate substrata not commonly expressed by quiescent or terminally differ- (e.g., tissue culture plastic), serum (most cells experience entiated cells (Alcorta et al., 1996; Hara et al., 1996; Serrano plasma, not serum, in vivo), and oxidative stress (e.g., cul- et al., 1997; Brenner et al., 1998; Stein et al., 1999). In some on February 21, 2011 ture in atmospheric O2, which is hyperphysiological; Fusenig cells, p16INK4a, by activating the pRB tumor suppressor, and Boukamp, 1998; Yaswen and Stampfer, 2002; Parrinello causes formation of senescence-associated heterochromatin et al., 2003). Cells also senesce without a DDR upon loss foci (SAHF), which silence critical pro-proliferative genes of the Pten tumor suppressor, a phosphatase that counteracts (Narita et al., 2003). p16INK4a, a tumor suppressor, is in- pro-proliferative/pro-survival kinases (Alimonti et al., 2010). duced by culture stress and as a late response to telomeric Additionally, ectopic expression of the cyclin-dependent ki- or intrachromosomal DNA damage (Brenner et al., 1998; nase inhibitors (CDKis) that normally enforce the senescence Robles and Adami, 1998; Ramirez et al., 2001; te Poele et al., growth arrest, notably p21WAF1 and p16INK4a, cause se- 2002; Jacobs and de Lange, 2004; Le et al., 2010). Moreover, nescence without an obvious DDR (McConnell et al., 1998; p16INK4a expression increases with age in mice and humans Rodier et al., 2009). (Zindy et al., 1997; Nielsen et al., 1999; Krishnamurthy What defines a senescent cell? Senescent cells are et al., 2004; Ressler et al., 2006; Liu et al., 2009), and its ac- not quiescent or terminally differentiated cells, although the tivity has been functionally linked to the reduction in progeni- distinction is not always straightforward. No marker or hall- tor cell number that occurs in multiple tissues during aging mark of senescence identified thus far is entirely specific to the (Janzen et al., 2006; Krishnamurthy et al., 2006; Molofsky senescent state. Further, not all senescent cells express all pos- et al., 2006). sible senescence markers. Nonetheless, senescent cells display (e) Cells that senesce with persistent DDR signaling harbor several phenotypes, which, in aggregate, define the senescent persistent nuclear foci, termed DNA segments with chromatin state (Fig. 1). Salient features of senescent cells are:
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