Rb-Mediated Heterochromatin Formation and Silencing of E2F Target Genes during Cellular Senescence

Narita, Masashi; Nuñez, Sabrina; Heard, Edith; Narita, Masako; Lin, Athena W.; Hearn, Stephen; Spector, David L.; Hannon, Gregory J.; Lowe, Scott W.

doi:10.1016/s0092-8674(03)00401-x

Cited by 2,004 publications

(2,214 citation statements)

References 51 publications

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“…Inhibition of E2F transcription factors by Rb is an important pro‐senescence process (Mallette, Goumard, Gaumont‐Leclerc, Moiseeva & Ferbeyre, 2004; Narita et al., 2003; Sebastian, Malik, Thomas, Sage & Johnson, 2005). Our data support the view that plasma membrane depolarization promotes senescence through the Rb pathway, as repressed mitotic genes are known E2F targets and the inhibition of Rb prevents senescence induced by plasma membrane depolarization.…”

Section: Discussionmentioning

confidence: 99%

The SCN9A channel and plasma membrane depolarization promote cellular senescence through Rb pathway

et al. 2018

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SummaryOncogenic signals lead to premature senescence in normal human cells causing a proliferation arrest and the elimination of these defective cells by immune cells. Oncogene‐induced senescence (OIS) prevents aberrant cell division and tumor initiation. In order to identify new regulators of OIS, we performed a loss‐of‐function genetic screen and identified that the loss of SCN9A allowed cells to escape from OIS. The expression of this sodium channel increased in senescent cells during OIS. This upregulation was mediated by NF‐κB transcription factors, which are well‐known regulators of senescence. Importantly, the induction of SCN9A by an oncogenic signal or by p53 activation led to plasma membrane depolarization, which in turn, was able to induce premature senescence. Computational and experimental analyses revealed that SCN9A and plasma membrane depolarization mediated the repression of mitotic genes through a calcium/Rb/E2F pathway to promote senescence. Taken together, our work delineates a new pathway, which involves the NF‐κB transcription factor, SCN9A expression, plasma membrane depolarization, increased calcium, the Rb/E2F pathway and mitotic gene repression in the regulation of senescence. This work thus provides new insight into the involvement of ion channels and plasma membrane potential in the control of senescence.

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Section: Discussionmentioning

confidence: 99%

The SCN9A channel and plasma membrane depolarization promote cellular senescence through Rb pathway

et al. 2018

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“…This observation further confirms that nonphysiological modification of BRG1 expression triggers senescence. In fact, it has been shown that during senescence, distinct heterochromatin structures accumulate (Narita et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

“…It has been shown that distinct heterochromatin structures accumulate during senescence and could represent a hallmark of this process. In particular, Narita et al (2003) showed heterochromatin formation during cellular senescence and showed that DNA from senescent cells was more resistant to limited micrococcal nuclease digestion when compared with that from normal cells. In our experimental model, cells with silenced BRG1 showed increased resistance to nuclease digestion when compared with controls ( Figure 4a).…”

Section: Senescence Is Associated With Changes In Chromatin Statusmentioning

confidence: 99%

The BRG1 ATPase of chromatin remodeling complexes is involved in modulation of mesenchymal stem cell senescence through RB–P53 pathways

et al. 2010

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We focused our attention on brahma-related gene 1 (BRG1), the ATPase subunit of the SWItch/Sucrose NonFermentable (SWI/SNF) chromatin remodeling complex, and analyzed its role in mesenchymal stem cell (MSC) biology. We hypothesized that deviation from the correct concentration of these proteins, which act at the highest level of gene regulation, may be deleterious for cells. We wanted to know what would happen if a cell had to cope with altered regulation of gene expression, either by upregulation or downregulation of BRG1. We assumed that cells would try to restore homeostasis or, alternatively, that the event could trigger senescence/apoptosis phenomena. To this end, in MSCs, we silenced BRG1gene. Knockdown of BRG1 expression induced a significant increase in senescent cells and decrease in apoptotic cells. It is interesting that BRG1 downregulation also induced an increase in heterochromatin. At the molecular level, these phenomena were associated with activation of retinoblastoma-like protein 2 (RB2)/P130-and P53-related pathways. Senescence was accompanied by reduced expression of some stemness-related genes. This is consistent with our previous research, which showed that BRG1 upregulation by ectopic expression also induced senescence processes. Together, these data suggest that BRG1 belongs to a class of genes whose expression is tightly regulated; hence, subtle alterations in BRG1 activity seem to negatively affect mechanisms regulating chromatin status and, in turn, impair cellular physiology.

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“…This arrest serves to allow time for repair of DNA damage, which may then result in resumption of proliferation or, if the damage is too severe, permanent arrest (Linke et al, 1996) or senescence (Narita et al, 2003) to prevent further genetic instability (Almasan et al, 1995a;Bindra and Glazer, 2005;. Although this mechanism is beneficial to non-neoplastic tissues, in (Table 1) using the primers described in Table 2 (Materials and methods) at various time points following irradiation.…”

Section: Discussionmentioning

confidence: 99%

E2F4 regulates a stable G2 arrest response to genotoxic stress in prostate carcinoma

et al. 2006

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The retinoblastoma (pRB) family proteins regulate the E2F transcription factors; their complexes regulate critical transitions through the cell cycle. The function of these pRB family/E2F complexes, which includes p130/ E2F4, in response to genotoxic agents, is not well understood. We investigated the role of E2F4 in the genotoxic stress response. Following radiation treatment, E2F4 colocalized with p130 in the nucleus during a radiation-induced stable G 2 -phase arrest. Arrested cells had significantly decreased expression of Cyclins A2 and B1 and decreased phosphorylation of mitotic protein monoclonal-2 (MPM-2) mitotic proteins. Small interference RNA (siRNA)-mediated knockdown of E2F4 sensitized cells to subsequent irradiation, resulting in enhanced cellular DNA damage and cell death, as determined by caspase activation and decreased clonogenic cell survival. Downstream E2F4 targets potentially involved in the progression from G 2 into M phase were identified by oligonucleotide microarray expression profiling. Chromatin immunoprecipitation localized E2F4 at promoter regions of the Bub3 and Pttg1 mitotic genes following irradiation, which were among the downregulated genes identified by the microarray. These data suggest that in response to radiation, E2F4 becomes active in the nucleus, enforces a stable G 2 arrest by target gene repression, and thus provides increased cell survival ability by minimizing propagation of cells that have irreparable DNA damage.

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Rb-Mediated Heterochromatin Formation and Silencing of E2F Target Genes during Cellular Senescence

Cited by 2,004 publications

References 51 publications

The SCN9A channel and plasma membrane depolarization promote cellular senescence through Rb pathway

The SCN9A channel and plasma membrane depolarization promote cellular senescence through Rb pathway

The BRG1 ATPase of chromatin remodeling complexes is involved in modulation of mesenchymal stem cell senescence through RB–P53 pathways

E2F4 regulates a stable G2 arrest response to genotoxic stress in prostate carcinoma

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