Cellular senescence and its effector programs

Salama, Rafik; Sadaie, Mahito; Hoare, Matthew; Narita, Masashi

doi:10.1101/gad.235184.113

Cited by 729 publications

(734 citation statements)

References 168 publications

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“…Understanding how senescence is controlled at the molecular and cellular level is therefore crucial. The senescence‐associated cell cycle arrest is mainly induced by p53 and its downstream target p21, by the cyclin‐dependent kinase inhibitor p16 and ultimately by RB which represses pro‐proliferative E2F target genes (Salama, Sadaie, Hoare, & Narita, 2014). Interestingly, calcium signaling is also emerging as a key player in the implementation of cellular senescence (Martin, & Bernard, 2017).…”

Section: Introductionmentioning

confidence: 99%

The nuclear receptor RXRA controls cellular senescence by regulating calcium signaling

Warnier

Raynard

et al. 2018

Aging Cell

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Calcium signaling is emerging as a key pathway controlling cellular senescence, a stable cell proliferation arrest playing a fundamental role in pathophysiological conditions, such as embryonic development, wound healing, cancer, and aging. However, how calcium signaling is regulated is still only partially understood. The inositol 1, 4, 5‐trisphosphate receptor type 2 (ITPR2), an endoplasmic reticulum calcium release channel, was recently shown to critically contribute to the implementation of senescence, but how ITPR2 expression is controlled is unclear. To gain insights into the regulation of ITPR2 expression, we performed an siRNA screen targeting 160 transcription factors and epigenetic regulators. Interestingly, we discovered that the retinoid X receptor alpha (RXRA), which belongs to the nuclear receptor family, represses ITPR2 expression and regulates calcium signaling though ITPR2 and the mitochondrial calcium uniporter (MCU). Knockdown of RXRA induces the production of reactive oxygen species (ROS) and DNA damage via the ITPR2‐MCU calcium signaling axis and consequently triggers cellular senescence by activating p53, whereas RXRA overexpression decreases DNA damage accumulation and then delays replicative senescence. Altogether, our work sheds light on a novel mechanism controlling calcium signaling and cellular senescence and provides new insights into the role of nuclear receptors.

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Section: Introductionmentioning

confidence: 99%

The nuclear receptor RXRA controls cellular senescence by regulating calcium signaling

Warnier

Raynard

et al. 2018

Aging Cell

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“…This phenotype was dependent on the telomere length and on the induction of two major cell cycle inhibitory pathways: the ATM/p53/p21 Waf1 and the p16 INK4a /pRB signaling cascades. Fifty years later, we now know that cellular senescence occurs in response to a large variety of extrinsic and intrinsic signals that can be associated or not with telomere erosion and the presence of permanent DNA damage (for review, see Muñoz‐Espín & Serrano, 2014; Salama et al ., 2014). Senescent cells are detected during embryo tissue development, in highly differentiated cell types as well as during tissue repair, tumor suppression responses, and age‐associated loss of tissue functions (for review, see Muñoz‐Espín & Serrano, 2014; Salama et al ., 2014).…”

Section: Introductionmentioning

confidence: 99%

“…Fifty years later, we now know that cellular senescence occurs in response to a large variety of extrinsic and intrinsic signals that can be associated or not with telomere erosion and the presence of permanent DNA damage (for review, see Muñoz‐Espín & Serrano, 2014; Salama et al ., 2014). Senescent cells are detected during embryo tissue development, in highly differentiated cell types as well as during tissue repair, tumor suppression responses, and age‐associated loss of tissue functions (for review, see Muñoz‐Espín & Serrano, 2014; Salama et al ., 2014). The senescence‐promoting signaling cascades lead to three features found in all senescent cells: (i) permanent cell cycle arrest, associated with (ii) chromatin alterations, leading to the (iii) establishment of a specific secretome, called senescence‐associated secretory phenotype (SASP).…”

Section: Introductionmentioning

confidence: 99%

“…The SASP also triggers the detection, elimination, and rapid replacement of senescent cells by the homeostatic protective system of each tissue. Altogether, these recent findings offer new insights into the complex roles of cellular senescence during ontogenesis as well as in physiological and pathological situations conserved in many species (Campisi & Robert, 2014; Muñoz‐Espín & Serrano, 2014; Salama et al ., 2014). …”

Section: Introductionmentioning

confidence: 99%

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Cellular senescence impact on immune cell fate and function

et al. 2016

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SummaryCellular senescence occurs not only in cultured fibroblasts, but also in undifferentiated and specialized cells from various tissues of all ages, in vitro and in vivo. Here, we review recent findings on the role of cellular senescence in immune cell fate decisions in macrophage polarization, natural killer cell phenotype, and following T‐lymphocyte activation. We also introduce the involvement of the onset of cellular senescence in some immune responses including T‐helper lymphocyte‐dependent tissue homeostatic functions and T‐regulatory cell‐dependent suppressive mechanisms. Altogether, these data propose that cellular senescence plays a wide‐reaching role as a homeostatic orchestrator.

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“…The senescent cells remain metabolically active but are unable to express genes required for cell proliferation. 1,2 The known causes of cellular senescence include telomere shortening, oxidative stress, DNA damage and hyperoncogenic signaling. 3 H-RasV 12 has been used as a model to induce senescence in normal cells.…”

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confidence: 99%

JMJD3 promotes SAHF formation in senescent WI38 cells by triggering an interplay between demethylation and phosphorylation of RB protein

et al. 2015

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Primary human fibroblasts undergoing oncogene-induced or replicative senescence are known to form senescence-associated heterochromatin foci (SAHF), which can stabilize the state of senescence. The retinoblastoma (RB) protein has an important role in SAHF; cells that lack active RB pathway fail to form SAHF. It has been known that the posttranslational modifications of RB, for example, phosphorylation, regulate its function. To date, whether methylation of RB impacts on the SAHF formation is unknown. Here we report that JMJD3, a histone demethylase catalyzing the tri-methylation of H3K27 (H3K27me3), can demethylate the nonhistone protein RB at the lysine810 residue (K810), which is a target of the methyltransferase Set7/9. We detected a significant upregulation of JMJD3 during cellular senescence and SAHF formation in WI38 cells induced by H-RasV 12 , and we found that ectopic expression of JMJD3 promoted cellular senescence and SAHF formation in WI38 cells. Furthermore, during the process of SAHF assembly, JMJD3 was transported to the cytoplasm and interacted with RB through its demethylase domain JmjC. Significantly, our data demonstrated that the JMJD3-mediated demethylation of RB at K810 impeded the interaction of RB with the protein kinase CDK4 and resulted in reduced level of phosphorylation of RB at Serine807/811 (S807/811), implicating an important role of the interplay between the demethylation and phosphorylation of RB in SAHF assembly. This study highlights the role of JMJD3 as a novel inducer of SAHF formation through demethylating RB and provides new insights into the mechanisms of cellular senescence and SAHF assembly. Cellular senescence is an irreversible process of cell cycle arrest. The senescent cells remain metabolically active but are unable to express genes required for cell proliferation. 1,2 The known causes of cellular senescence include telomere shortening, oxidative stress, DNA damage and hyperoncogenic signaling. 3 H-RasV 12 has been used as a model to induce senescence in normal cells. [4][5][6] Senescent cells are typically characterized by a large flat morphology and the expression of a senescence-associated β-galactosidase activity (SA-β-gal), and nuclei of senescence cells may remodel to form the heterochromatin structures termed the senescenceassociated heterochromatin foci (SAHF). 7 SAHF are condensed regions of DNA that correlate with transcriptionally inactive sites. 8 These heterochromatin foci are hallmarked by H3K9me3 and the incorporation of heterochromatin protein HP1, macroH2A, PML (promyelocy leukemia protein) and HMGA1 (high mobility group AT-hook 1). 7,9-11 Recently, it has been shown that repressive markers, such as H3K9me3, H3K9me2 and H3K27me3, are rearranged into the nonoverlapping structural layers in SAHF. 12-14 Changes of heterochromatin organization generate a repressive chromatin environment that prevents transcription of genes that promote growth, thereby stabilize the state of senescence. 7,15 The retinoblastoma (RB) tumor suppressor is an important senesc...

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Cellular senescence and its effector programs

Cited by 729 publications

References 168 publications

The nuclear receptor RXRA controls cellular senescence by regulating calcium signaling

The nuclear receptor RXRA controls cellular senescence by regulating calcium signaling

Cellular senescence impact on immune cell fate and function

JMJD3 promotes SAHF formation in senescent WI38 cells by triggering an interplay between demethylation and phosphorylation of RB protein

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