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Journal ArticleDOI

Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence.

TL;DR: A distinct heterochromatic structure that accumulates in senescent human fibroblasts is described, which is designated senescence-associated heterochROMatic foci (SAHF) and is associated with the stable repression of E2F target genes.
About: This article is published in Cell.The article was published on 2003-06-13 and is currently open access. It has received 2055 citations till now. The article focuses on the topics: Senescence-associated heterochromatin focus & E2F.
Citations
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Journal ArticleDOI
TL;DR: Understanding the causes and consequences of cellular senescence has provided novel insights into how cells react to stress, especially genotoxic stress, and how this cellular response can affect complex organismal processes such as the development of cancer and ageing.
Abstract: Cells continually experience stress and damage from exogenous and endogenous sources, and their responses range from complete recovery to cell death. Proliferating cells can initiate an additional response by adopting a state of permanent cell-cycle arrest that is termed cellular senescence. Understanding the causes and consequences of cellular senescence has provided novel insights into how cells react to stress, especially genotoxic stress, and how this cellular response can affect complex organismal processes such as the development of cancer and ageing.

3,677 citations

Journal ArticleDOI
TL;DR: A senescence-associated secretory phenotype (SASP) is acquired that turns senescent fibroblasts into proinflammatory cells that have the ability to promote tumor progression.
Abstract: Cellular senescence is a tumor-suppressive mechanism that permanently arrests cells at risk for malignant transformation. However, accumulating evidence shows that senescent cells can have deleterious effects on the tissue microenvironment. The most significant of these effects is the acquisition of a senescence-associated secretory phenotype (SASP) that turns senescent fibroblasts into proinflammatory cells that have the ability to promote tumor progression.

3,332 citations


Cites background from "Rb-mediated heterochromatin formati..."

  • ...This may imply that, once senescence is established, unknown mechanisms—potentially related to chromatin alterations—permanently lock the SASP in an irreversible open chromatin confirmation, analogous to the way the p16INK4a/pRB pathway is proposed to lock growth-promoting genes into a heterochromatic state (103)....

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Journal ArticleDOI
25 Feb 2005-Cell
TL;DR: The senescence response may be antagonistically pleiotropic, promoting early-life survival by curtailing the development of cancer but eventually limiting longevity as dysfunctional senescent cells accumulate.

2,114 citations


Cites background from "Rb-mediated heterochromatin formati..."

  • ...Replicatively senescent cells develop dense foci of heterochromatin (Narita et al., 2003; Zhang et al., 2005) which coincide with pRBdependent heterochromatic repression of genes encoding cyclins and other positive cell cycle regulators (Bandyopadhyay et al., 2002; Narita et al., 2003)....

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  • ...Replicatively senescent cells develop dense foci of heterochromatin (Narita et al., 2003; Zhang et al., 2005) which coincide with pRBdependent heterochromatic repression of genes encoding cyclins and other positive cell cycle regulators (Bandyopadhyay et al....

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  • ...Many of these repressed genes are activation targets of E2F transcription factors (Narita et al., 2003), some of which are converted to transcriptional repressors when complexed with pRB (Trimarchi and Lees, 2002)....

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  • ...…mechanisms are as yet unknown, the senescence response appears to result in a reorganization of chromatin, at least some aspects of which require pRB activity (Jacobs et al., 1999; Leung et al., 2001; Bandyopadhyay et al., 2002; Itahana et al., 2003; Narita et al., 2003; Zhang et al., 2003, 2005)....

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  • ..., 2005) which coincide with pRBdependent heterochromatic repression of genes encoding cyclins and other positive cell cycle regulators (Bandyopadhyay et al., 2002; Narita et al., 2003)....

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Journal ArticleDOI
04 Aug 2005-Nature
TL;DR: It is shown that sustained BRAFV600E expression in human melanocytes induces cell cycle arrest, which is accompanied by the induction of both p16INK4a and senescence-associated acidic β-galactosidase (SA-β-Gal) activity, a commonly usedsenescence marker.
Abstract: Cellular senescence, a growth-arrest program that limits the lifespan of mammalian cells and prevents unlimited cell proliferation, is attracting considerable interest because of its links to tumour suppression. Using a mouse model in which the oncogene Ras is activated in the haematopoietic compartment of bone marrow, Braig et al. show that cellular senescence can block lymphoma development. Genetic inactivation of the histone methyltransferase Suv39h1 that controls senescence by ‘epigenetic’ modification of DNA-associated proteins, or a pharmacological approach that mimics loss of this enzyme, allow the formation of malignant lymphomas in response to oncogenic Ras. This work has important implications for both tumour development and tumour therapy. Michaloglou et al. report that oncogene-induced senescence may be a physiologically important process in humans, keeping moles in a benign state for many years: unchecked they develop into malignant melanomas. Chen et al. also find that cellular senescence blocks tumorigenesis in vivo: they show that acting together, the p53 tumour suppressor and the cellular senescence system can prevent prostate cancer induction in mice by the PTEN mutation. Collado et al. show that cellular senescence is a defining feature of Ras-initiated premalignant tumours; this could prove valuable in the diagnosis and prognosis of cancer. See the web focus . Most normal mammalian cells have a finite lifespan1, thought to constitute a protective mechanism against unlimited proliferation2,3,4. This phenomenon, called senescence, is driven by telomere attrition, which triggers the induction of tumour suppressors including p16INK4a (ref. 5). In cultured cells, senescence can be elicited prematurely by oncogenes6; however, whether such oncogene-induced senescence represents a physiological process has long been debated. Human naevi (moles) are benign tumours of melanocytes that frequently harbour oncogenic mutations (predominantly V600E, where valine is substituted for glutamic acid) in BRAF7, a protein kinase and downstream effector of Ras. Nonetheless, naevi typically remain in a growth-arrested state for decades and only rarely progress into malignancy (melanoma)8,9,10. This raises the question of whether naevi undergo BRAFV600E-induced senescence. Here we show that sustained BRAFV600E expression in human melanocytes induces cell cycle arrest, which is accompanied by the induction of both p16INK4a and senescence-associated acidic β-galactosidase (SA-β-Gal) activity, a commonly used senescence marker. Validating these results in vivo, congenital naevi are invariably positive for SA-β-Gal, demonstrating the presence of this classical senescence-associated marker in a largely growth-arrested, neoplastic human lesion. In growth-arrested melanocytes, both in vitro and in situ, we observed a marked mosaic induction of p16INK4a, suggesting that factors other than p16INK4a contribute to protection against BRAFV600E-driven proliferation. Naevi do not appear to suffer from telomere attrition, arguing in favour of an active oncogene-driven senescence process, rather than a loss of replicative potential. Thus, both in vitro and in vivo, BRAFV600E-expressing melanocytes display classical hallmarks of senescence, suggesting that oncogene-induced senescence represents a genuine protective physiological process.

2,074 citations

Journal ArticleDOI
TL;DR: The idea that, despite seemingly opposite characteristics, the degenerative and hyperplastic pathologies of aging are at least partly linked by a common biological phenomenon: a cellular stress response known as cellular senescence is discussed.
Abstract: For most species, aging promotes a host of degenerative pathologies that are characterized by debilitating losses of tissue or cellular function. However, especially among vertebrates, aging also promotes hyperplastic pathologies, the most deadly of which is cancer. In contrast to the loss of function that characterizes degenerating cells and tissues, malignant (cancerous) cells must acquire new (albeit aberrant) functions that allow them to develop into a lethal tumor. This review discusses the idea that, despite seemingly opposite characteristics, the degenerative and hyperplastic pathologies of aging are at least partly linked by a common biological phenomenon: a cellular stress response known as cellular senescence. The senescence response is widely recognized as a potent tumor suppressive mechanism. However, recent evidence strengthens the idea that it also drives both degenerative and hyperplastic pathologies, most likely by promoting chronic inflammation. Thus, the senescence response may be the result of antagonistically pleiotropic gene action.

2,074 citations


Cites background from "Rb-mediated heterochromatin formati..."

  • ...Some senescent cells contain senescence-associated heterochromatin foci (SAHF): cytologically detectable heterochromatin domains that also contain (and presumably silence) certain proproliferative genes (60)....

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  • ...For example, global chromatin relaxation (such as that caused by broad-acting histone deacetylase inhibitors) induces senescence, often by derepressing the p16INK4a tumor suppressor (61), which promotes the formation of senescence-associated heterochromatin (60)....

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  • ...Cellular senescence entails widespread changes in chromatin organization (59), including the formation of repressive heterochromatin at several loci that encode proproliferative genes (60)....

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References
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Journal ArticleDOI
TL;DR: It is shown that several human cells express a beta-galactosidase, histochemically detectable at pH 6, upon senescence in culture, which provides in situ evidence that senescent cells may exist and accumulate with age in vivo.
Abstract: Normal somatic cells invariably enter a state of irreversibly arrested growth and altered function after a finite number of divisions. This process, termed replicative senescence, is thought to be a tumor-suppressive mechanism and an underlying cause of aging. There is ample evidence that escape from senescence, or immortality, is important for malignant transformation. By contrast, the role of replicative senescence in organismic aging is controversial. Studies on cells cultured from donors of different ages, genetic backgrounds, or species suggest that senescence occurs in vivo and that organismic lifespan and cell replicative lifespan are under common genetic control. However, senescent cells cannot be distinguished from quiescent or terminally differentiated cells in tissues. Thus, evidence that senescent cells exist and accumulate with age in vivo is lacking. We show that several human cells express a beta-galactosidase, histochemically detectable at pH 6, upon senescence in culture. This marker was expressed by senescent, but not presenescent, fibroblasts and keratinocytes but was absent from quiescent fibroblasts and terminally differentiated keratinocytes. It was also absent from immortal cells but was induced by genetic manipulations that reversed immortality. In skin samples from human donors of different age, there was an age-dependent increase in this marker in dermal fibroblasts and epidermal keratinocytes. This marker provides in situ evidence that senescent cells may exist and accumulate with age in vivo.

6,696 citations


"Rb-mediated heterochromatin formati..." refers background in this paper

  • ...(SA- -gal) activity (Campisi, 2001; Dimri et al., 1995; In many instances, p53 and Rb are activated to proShelton et al., 1999)....

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Journal ArticleDOI
TL;DR: The survival curves obtained with human diploid cell strains are comparable to “multiple-hit” or “ multiple-target” curves obtain with other biological systems where an initial threshold dose is required before an exponential form of the curve is established.

5,562 citations


Additional excerpts

  • ...Nevertheless, the Rb family con(Hayflick, 1965)....

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Journal ArticleDOI
07 Mar 1997-Cell
TL;DR: It is shown that expression of oncogenic ras in primary human or rodent cells results in a permanent G1 arrest, and that the onset of cellular senescence does not simply reflect the accumulation of cell divisions, but can be prematurely activated in response to an onCogenic stimulus.

4,770 citations


"Rb-mediated heterochromatin formati..." refers background or methods in this paper

  • ...Allis), HP1 and infections were performed as described (Serrano et al., 1997) (Chemicon), Rb (C-15, Santa Cruz), p107 (C-18, Santa Cruz), and except that amphotropic viruses were used to produce cells for the p130 (C-20, Santa Cruz) antibodies....

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  • ...…5B, Western BlottingAd-GFP was used at an MOI of 4 PFU cell 1 and Ad-E2F1 was used Western blotting analysis was carried out on 20 g whole-cell lysatein a range of 0.03 and 15 PFU cell 1. by using enhanced chemiluminescence (ECL; Amersham) detection as previously described (Serrano et al., 1997)....

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  • ...…cells (G. Nolan, Stanford University, CA) H3 (ab7312, Abcam, Upstate, or provided by C.D. Allis), HP1 and infections were performed as described (Serrano et al., 1997) (Chemicon), Rb (C-15, Santa Cruz), p107 (C-18, Santa Cruz), and except that amphotropic viruses were used to produce cells for…...

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  • ...Recent studies suggest of senescence-associated DNA foci, we focused on the effects of oncogenic ras, as it acutely and reproducibly that p107 and p130, but not Rb, are associated with E2Fresponsive genes during the cell cycle and quiescence induces senescence in IMR90 cells over several days (Serrano et al., 1997)....

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  • ...…MEK1 Q56P) (Lin et al., 1998); pWZL Cells were permeabilized with 0.01% L- -lysophosphatidylcholine Hygro (H-RasV12, p16INK4a, and human p53175H) (Serrano et al., 1997); (Sigma) in 150 mM sucrose, 80 mM KCl, 35 mM HEPES [pH 7.4], 5 pLPC-Puro (EGFP-tagged human HP1 cDNA and E1A and E1A mM K2HPO4,…...

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Journal ArticleDOI
01 Mar 2001-Nature
TL;DR: It is shown that mammalian methyltransferases that selectively methylate histone H3 on lysine 9 (Suv39h HMTases) generate a binding site for HP1 proteins—a family of heterochromatic adaptor molecules implicated in both gene silencing and supra-nucleosomal chromatin structure.
Abstract: Distinct modifications of histone amino termini, such as acetylation, phosphorylation and methylation, have been proposed to underlie a chromatin-based regulatory mechanism that modulates the accessibility of genetic information. In addition to histone modifications that facilitate gene activity, it is of similar importance to restrict inappropriate gene expression if cellular and developmental programmes are to proceed unperturbed. Here we show that mammalian methyltransferases that selectively methylate histone H3 on lysine 9 (Suv39h HMTases) generate a binding site for HP1 proteins--a family of heterochromatic adaptor molecules implicated in both gene silencing and supra-nucleosomal chromatin structure. High-affinity in vitro recognition of a methylated histone H3 peptide by HP1 requires a functional chromo domain; thus, the HP1 chromo domain is a specific interaction motif for the methyl epitope on lysine9 of histone H3. In vivo, heterochromatin association of HP1 proteins is lost in Suv39h double-null primary mouse fibroblasts but is restored after the re-introduction of a catalytically active SWUV39H1 HMTase. Our data define a molecular mechanism through which the SUV39H-HP1 methylation system can contribute to the propagation of heterochromatic subdomains in native chromatin.

2,820 citations


"Rb-mediated heterochromatin formati..." refers background in this paper

  • ...Scale bar is equal to 5 m. nister et al., 2001; Lachner et al., 2001), a family of adaptor molecules that are required for heterochromatin assembly and are involved in epigenetic gene regulation....

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Journal ArticleDOI
01 Mar 2001-Nature
TL;DR: A stepwise model for the formation of a transcriptionally silent heterochromatin is provided: SUV39H1 places a ‘methyl marker’ on histone H3, which is then recognized by HP1 through its chromo domain, which may also explain the stable inheritance of theheterochromatic state.
Abstract: Heterochromatin protein 1 (HP1) is localized at heterochromatin sites where it mediates gene silencing. The chromo domain of HP1 is necessary for both targeting and transcriptional repression. In the fission yeast Schizosaccharomyces pombe, the correct localization of Swi6 (the HP1 equivalent) depends on Clr4, a homologue of the mammalian SUV39H1 histone methylase. Both Clr4 and SUV39H1 methylate specifically lysine 9 of histone H3 (ref. 6). Here we show that HP1 can bind with high affinity to histone H3 methylated at lysine 9 but not at lysine 4. The chromo domain of HP1 is identified as its methyl-lysine-binding domain. A point mutation in the chromo domain, which destroys the gene silencing activity of HP1 in Drosophila, abolishes methyl-lysine-binding activity. Genetic and biochemical analysis in S. pombe shows that the methylase activity of Clr4 is necessary for the correct localization of Swi6 at centromeric heterochromatin and for gene silencing. These results provide a stepwise model for the formation of a transcriptionally silent heterochromatin: SUV39H1 places a 'methyl marker' on histone H3, which is then recognized by HP1 through its chromo domain. This model may also explain the stable inheritance of the heterochromatic state.

2,811 citations


"Rb-mediated heterochromatin formati..." refers background in this paper

  • ...We next examined the occupancy of E2F target proE2F-Responsive Genes Are Stably Repressed moters by K9M-H3 and HP1 : two proteins that are in Senescent Cells enriched in the SAHFs and are known to be involved in In principle, the altered chromatin state accompanying heterochromatin formation (Bannister et al., 2001; SAHF formation and the binding of K9M-H3, HP1, and Lachner et al., 2001)....

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  • ...…by K9M-H3 and HP1 : two proteins that are in Senescent Cellsenriched in the SAHFs and are known to be involved in In principle, the altered chromatin state accompanyingheterochromatin formation (Bannister et al., 2001; SAHF formation and the binding of K9M-H3, HP1, andLachner et al., 2001)....

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